Saturday, October 29, 2011
Site record
On 27th October this site broke a new record with 943 page views in a single day. Most people seemed to be looking for the article about a vaccine for shingles.
John 7: 37-39. Jesus promises the Holy Spirit
On the last and greatest day of the festival, Jesus stood and said in a loud voice, “Let anyone who is thirsty come to me and drink. Whoever believes in me, as Scripture has said, rivers of living water will flow from within them.” By this he meant the Spirit, whom those who believed in him were later to receive. Up to that time the Spirit had not been given, since Jesus had not yet been glorified.
John spells the metaphor out on plain speech. The Living Water is the Holy Sprit. On each of the days of the feast of Tabernacles, a golden flagon filled with water from the Pool of Siloam was carried by the High Priest back to the Temple where the water was offered to God at the time of the morning sacrifice.
John spells the metaphor out on plain speech. The Living Water is the Holy Sprit. On each of the days of the feast of Tabernacles, a golden flagon filled with water from the Pool of Siloam was carried by the High Priest back to the Temple where the water was offered to God at the time of the morning sacrifice.
Camped out with Occupy London
A Daily Mail undercover reporter has infiltrated the St Paul's camp in London. Here is his report:
In the 48 hours I spend at the camp, I discover that procrastination, contradiction and confusion are pretty much par for the course — and absolutely no one asks about my reason for being there. My fellow protesters are too busy posing for the world’s media, being interviewed by film crews and radio stations from around the world, and loving the attention.
Looking around, my camp comrades are more student-union common-room than dreadlocked Swampies. Earnest-looking graduates and undergraduates for the most part, their numbers are bolstered by foreign activists, some of whom have come straight from Central Casting: the Spaniard with beard and beret, and the three young German students in army surplus boots and parkas.
A key activity is sitting around smoking joints and knocking back lager. Complaints circulate about drunk people urinating on the steps of the cathedral and on each other’s tents. It becomes clear that undisciplined behaviour is affecting the camp’s image and driving some of its residents away. Among the professional protesters, those from the anarchist group Anonymous form a tight knot of tents and are distinguishable by the plastic Guy Fawkes masks they carry and sometimes wear to obscure their faces.
The only uniformity in the camp is that just about everyone, when not inhaling marijuana, smokes cigarettes (roll-ups, of course). The mornings are a cacophony of hacking coughs.
Everyone looks exhausted. For starters, the cathedral bells peel every 15 minutes, and buses roar past throughout the night. The City starts work early and finishes late. At 6.30am on Tuesday I am roused by a passer-by yelling: 'Get up, you lazy bastards.’ Not that they do.
The 12th meeting of the General Assembly of the London wing of the international revolution against capitalism is not going smoothly. The first item on the agenda relates to changing the banner that fronts the sprawling camp in the piazza surrounding London’s St Paul’s Cathedral. It currently reads 'Capitalism is crisis’, but some demonstrators want it changed to: 'We are the 99 per cent.’ Unfortunately, there is a snag. Someone has nicked the banner.
If anyone asks why I am here, my cover story is that I am demonstrating against the banks, having had to close a business as a result of their unwillingness to lend. But in the 48 hours I spend at the camp, I discover that procrastination, contradiction and confusion are pretty much par for the course — and absolutely no one asks about my reason for being there. My fellow protesters are too busy posing for the world’s media, being interviewed by film crews and radio stations from around the world, and loving the attention.
Even after living cheek-by-jowl with the demonstrators for two days and nights, what they stand for and what they hope to achieve by occupying this half-acre of paving slabs remains an utter mystery to me. They purport to be running their campaign to fight against capitalism. But what I encountered was a disparate group of freelance travelling protesters with little or no discernible philosophy and a penchant for petty squabbles. 'Our response to systemic failure is not to propose a new system, but to start making one,’ wrote members of the camp in one of a number of articles published in The Guardian, the protesters’ newspaper of choice. 'We are providing an example of how the 99 per cent might move forward.’
Therein lies the problem because, as examples go, theirs is a deeply flawed one. This point is driven home to me on Wednesday at 6.45am, as I stand in the drizzle outside my tent. At the previous evening’s meeting, we had been encouraged to join a march in support of electricians who are on strike at nearby Blackfriars Bridge.
Six people including myself turn up. Even after one of our number, a wispy-bearded white Muslim convert, tours the site with a megaphone shouting 'Wake up. This is not a picnic’, the contingent barely reaches double figures. It’s pretty pathetic given that the previous evening, the 100-strong crowd at the meeting had applauded speakers stressing the importance of spreading the anti-capitalist message to the working classes.
That said, they had also given the thumbs up to holding a mass meditation session on the grounds that 'a load of guys sitting round in silence would look really cool from a photo-opportunity perspective’. Such apathy is all the more depressing given that while I am there, accusations about the dedication and motives of the protesters is a hot topic in the world outside.
On Tuesday, the press revealed that only one in ten of the 200-odd tents is occupied overnight. Evidence of this came from a thermal imaging camera deployed from a police helicopter. The daytime-only brigade make a mockery of the slogan posted on camp tents and buildings, which declares: 'All day, all week, we’ll sleep on London’s freezing streets. Solidarity!’ But predictably, my comrades are outraged by this 'slander’, claiming modern tents are so well-insulated they would conceal any occupants. I nod, while wondering why, if that’s so, I nearly froze the previous night.
From what I see on the ground, I’d concur with the thermal imaging —this is a part-time camp with many part-time protesters. My tent is touching five others, three of which I never see anyone enter or leave. Many tell me they attend London universities, dividing their time between their studies and the protest. Hardly surprising, then, that much of the business of the camp has the whiff of student politics. Twenty-something and predominantly female, the middle-class accents of the 'facilitators’ — yes, that’s what they call themselves — fill the piazza as they do 'shout-outs’ for people to join caucuses for women and ethnic minorities, and for Lesbian Gay Bisexual Transgender (LBGT) support groups. Alongside them in equal number are foreign activists living in London. Smaller in number but perhaps most vocal of all are the professional activists. Several tell me they have just returned from the Dale Farm traveller evictions. Others are veterans of protest camps dating back decades.
At the meeting on Monday, one activist complains that his partner was almost assaulted yesterday by a drunk. 'And I saw the camp’s kitchen staff being harassed by someone who was drunk,’ he says. 'I was also harassed by someone who was drunk. I have reason to be a little bit afraid for our safety.’ His words are warmly applauded, as are those of a facilitator who reveals there have been complaints about boozed-up people urinating on the cathedral steps and on tents. 'No one should pee on the church or the tents,’ she instructs. 'That is just not OK. We have big issues with peeing. A bag of s*** was also put in the bin. That is also not OK.’
Another protester implores those who want to block a proposed ban on drink and drugs to remember why they are there. 'Recreational drinking isn’t something we should passionately support — this is a movement trying to overthrow capitalism,’ she says, adding that anyone wanting to have a drink or 'do a few lines’ (presumably of cocaine) could go off-site.
A member of the so-called Tranquillity Team, a roster of protesters who spend the nights trying to quell trouble, says they have been rushed off their feet dealing with problems, and that people carousing on the cathedral steps have been keeping everyone awake until dawn. Meanwhile, a member of the finance team implores people to stop asking for money that has been donated to the camp. 'We won’t give out money for cigarettes or booze,’ he says, clearly exasperated. 'Please don’t even bother asking.’ Another man takes to the microphone and says it’s not just the drink and drugs that have given the protesters a bad name. 'People have been going out to buy Starbucks coffee,’ he says. 'I would like to see people not displaying Tesco stuff and Coca-Cola because that s*** is as bad as alcohol.’
After an hour-long debate, a hard core of protesters, many of whom have been watching the meeting while drinking and rolling joints, attempt to block the motion. While the General Assembly aims to reach decisions unanimously, the facilitator invokes a rule that says important decisions can be implemented with 75 per cent support. In the end, the drink and drugs ban is carried — 100 vote for and 15 against. Of course, in the world that the protesters inhabit, that doesn’t mean anything. Once again, no decision is reached.
Later that evening, a man I saw drinking earlier in the day is taken to hospital by ambulance. The following morning, another protester is still so drunk he descends the steps of St Paul’s on his bottom as tourists watch in bemused horror.
In PR terms, the location is clearly a disaster, and it is one that, in private, the protesters are deeply concerned about. 'Support is ebbing away,’ says one. 'And with Remembrance Sunday coming up, it is only going to get worse.’ Another tells me his group of a dozen protesters would be happy to leave if some way of packing up without losing face could be found. Others are preparing for a lengthy legal battle, busily convincing themselves that the cathedral’s volte-face is because the Church is in thrall to the City’s money men. And, anyway, the chances of reaching any agreement are unlikely, not without a lengthy meeting or ten. So the protesters continue to labour under the illusion that this is the start of a global revolution, ending each General Assembly with news of how the movement is progressing around the world. But with each chime of St Paul’s august bells, confidence in this haphazard and strangely disingenuous protest grows more hollow.
In the 48 hours I spend at the camp, I discover that procrastination, contradiction and confusion are pretty much par for the course — and absolutely no one asks about my reason for being there. My fellow protesters are too busy posing for the world’s media, being interviewed by film crews and radio stations from around the world, and loving the attention.
Looking around, my camp comrades are more student-union common-room than dreadlocked Swampies. Earnest-looking graduates and undergraduates for the most part, their numbers are bolstered by foreign activists, some of whom have come straight from Central Casting: the Spaniard with beard and beret, and the three young German students in army surplus boots and parkas.
A key activity is sitting around smoking joints and knocking back lager. Complaints circulate about drunk people urinating on the steps of the cathedral and on each other’s tents. It becomes clear that undisciplined behaviour is affecting the camp’s image and driving some of its residents away. Among the professional protesters, those from the anarchist group Anonymous form a tight knot of tents and are distinguishable by the plastic Guy Fawkes masks they carry and sometimes wear to obscure their faces.
The only uniformity in the camp is that just about everyone, when not inhaling marijuana, smokes cigarettes (roll-ups, of course). The mornings are a cacophony of hacking coughs.
Everyone looks exhausted. For starters, the cathedral bells peel every 15 minutes, and buses roar past throughout the night. The City starts work early and finishes late. At 6.30am on Tuesday I am roused by a passer-by yelling: 'Get up, you lazy bastards.’ Not that they do.
The 12th meeting of the General Assembly of the London wing of the international revolution against capitalism is not going smoothly. The first item on the agenda relates to changing the banner that fronts the sprawling camp in the piazza surrounding London’s St Paul’s Cathedral. It currently reads 'Capitalism is crisis’, but some demonstrators want it changed to: 'We are the 99 per cent.’ Unfortunately, there is a snag. Someone has nicked the banner.
If anyone asks why I am here, my cover story is that I am demonstrating against the banks, having had to close a business as a result of their unwillingness to lend. But in the 48 hours I spend at the camp, I discover that procrastination, contradiction and confusion are pretty much par for the course — and absolutely no one asks about my reason for being there. My fellow protesters are too busy posing for the world’s media, being interviewed by film crews and radio stations from around the world, and loving the attention.
Even after living cheek-by-jowl with the demonstrators for two days and nights, what they stand for and what they hope to achieve by occupying this half-acre of paving slabs remains an utter mystery to me. They purport to be running their campaign to fight against capitalism. But what I encountered was a disparate group of freelance travelling protesters with little or no discernible philosophy and a penchant for petty squabbles. 'Our response to systemic failure is not to propose a new system, but to start making one,’ wrote members of the camp in one of a number of articles published in The Guardian, the protesters’ newspaper of choice. 'We are providing an example of how the 99 per cent might move forward.’
Therein lies the problem because, as examples go, theirs is a deeply flawed one. This point is driven home to me on Wednesday at 6.45am, as I stand in the drizzle outside my tent. At the previous evening’s meeting, we had been encouraged to join a march in support of electricians who are on strike at nearby Blackfriars Bridge.
Six people including myself turn up. Even after one of our number, a wispy-bearded white Muslim convert, tours the site with a megaphone shouting 'Wake up. This is not a picnic’, the contingent barely reaches double figures. It’s pretty pathetic given that the previous evening, the 100-strong crowd at the meeting had applauded speakers stressing the importance of spreading the anti-capitalist message to the working classes.
That said, they had also given the thumbs up to holding a mass meditation session on the grounds that 'a load of guys sitting round in silence would look really cool from a photo-opportunity perspective’. Such apathy is all the more depressing given that while I am there, accusations about the dedication and motives of the protesters is a hot topic in the world outside.
On Tuesday, the press revealed that only one in ten of the 200-odd tents is occupied overnight. Evidence of this came from a thermal imaging camera deployed from a police helicopter. The daytime-only brigade make a mockery of the slogan posted on camp tents and buildings, which declares: 'All day, all week, we’ll sleep on London’s freezing streets. Solidarity!’ But predictably, my comrades are outraged by this 'slander’, claiming modern tents are so well-insulated they would conceal any occupants. I nod, while wondering why, if that’s so, I nearly froze the previous night.
From what I see on the ground, I’d concur with the thermal imaging —this is a part-time camp with many part-time protesters. My tent is touching five others, three of which I never see anyone enter or leave. Many tell me they attend London universities, dividing their time between their studies and the protest. Hardly surprising, then, that much of the business of the camp has the whiff of student politics. Twenty-something and predominantly female, the middle-class accents of the 'facilitators’ — yes, that’s what they call themselves — fill the piazza as they do 'shout-outs’ for people to join caucuses for women and ethnic minorities, and for Lesbian Gay Bisexual Transgender (LBGT) support groups. Alongside them in equal number are foreign activists living in London. Smaller in number but perhaps most vocal of all are the professional activists. Several tell me they have just returned from the Dale Farm traveller evictions. Others are veterans of protest camps dating back decades.
At the meeting on Monday, one activist complains that his partner was almost assaulted yesterday by a drunk. 'And I saw the camp’s kitchen staff being harassed by someone who was drunk,’ he says. 'I was also harassed by someone who was drunk. I have reason to be a little bit afraid for our safety.’ His words are warmly applauded, as are those of a facilitator who reveals there have been complaints about boozed-up people urinating on the cathedral steps and on tents. 'No one should pee on the church or the tents,’ she instructs. 'That is just not OK. We have big issues with peeing. A bag of s*** was also put in the bin. That is also not OK.’
Another protester implores those who want to block a proposed ban on drink and drugs to remember why they are there. 'Recreational drinking isn’t something we should passionately support — this is a movement trying to overthrow capitalism,’ she says, adding that anyone wanting to have a drink or 'do a few lines’ (presumably of cocaine) could go off-site.
A member of the so-called Tranquillity Team, a roster of protesters who spend the nights trying to quell trouble, says they have been rushed off their feet dealing with problems, and that people carousing on the cathedral steps have been keeping everyone awake until dawn. Meanwhile, a member of the finance team implores people to stop asking for money that has been donated to the camp. 'We won’t give out money for cigarettes or booze,’ he says, clearly exasperated. 'Please don’t even bother asking.’ Another man takes to the microphone and says it’s not just the drink and drugs that have given the protesters a bad name. 'People have been going out to buy Starbucks coffee,’ he says. 'I would like to see people not displaying Tesco stuff and Coca-Cola because that s*** is as bad as alcohol.’
After an hour-long debate, a hard core of protesters, many of whom have been watching the meeting while drinking and rolling joints, attempt to block the motion. While the General Assembly aims to reach decisions unanimously, the facilitator invokes a rule that says important decisions can be implemented with 75 per cent support. In the end, the drink and drugs ban is carried — 100 vote for and 15 against. Of course, in the world that the protesters inhabit, that doesn’t mean anything. Once again, no decision is reached.
Later that evening, a man I saw drinking earlier in the day is taken to hospital by ambulance. The following morning, another protester is still so drunk he descends the steps of St Paul’s on his bottom as tourists watch in bemused horror.
In PR terms, the location is clearly a disaster, and it is one that, in private, the protesters are deeply concerned about. 'Support is ebbing away,’ says one. 'And with Remembrance Sunday coming up, it is only going to get worse.’ Another tells me his group of a dozen protesters would be happy to leave if some way of packing up without losing face could be found. Others are preparing for a lengthy legal battle, busily convincing themselves that the cathedral’s volte-face is because the Church is in thrall to the City’s money men. And, anyway, the chances of reaching any agreement are unlikely, not without a lengthy meeting or ten. So the protesters continue to labour under the illusion that this is the start of a global revolution, ending each General Assembly with news of how the movement is progressing around the world. But with each chime of St Paul’s august bells, confidence in this haphazard and strangely disingenuous protest grows more hollow.
Friday, October 28, 2011
Jojn 7:35-36. They see but they do not see.
The Jews said to one another, “Where does this man intend to go that we cannot find him? Will he go where our people live scattered among the Greeks, and teach the Greeks? What did he mean when he said, ‘You will look for me, but you will not find me,’ and ‘Where I am, you cannot come’?”
The Jerusalem Jews are thoroughly confused. I have seen various comments recently about what Jesus would do if he were here now. "Jesus was a socialist," says one. "Jesus was too intelligent to believe in God," says Dawkins.
It is clear that these people have never read the Bible, which is our only source of what Jesus actually said on earth. From Scripture it is clear that Jesus spoke in metaphor and that his subject was the Kingdom of Heaven.
The Jerusalem Jews are thoroughly confused. I have seen various comments recently about what Jesus would do if he were here now. "Jesus was a socialist," says one. "Jesus was too intelligent to believe in God," says Dawkins.
It is clear that these people have never read the Bible, which is our only source of what Jesus actually said on earth. From Scripture it is clear that Jesus spoke in metaphor and that his subject was the Kingdom of Heaven.
Point of contact testing
In today's Lancet there is an article on point of Care (POC) testing in the context of HIV in Africa.
New durable, simple, and affordable cytometric CD4 testing devices aim to decrease the time to beginning antiretroviral therapy and loss to follow-up. Rapid testing with microfluidics meets the criteria for true POC testing, providing immediate results without needing laboratory personnel or infrastructure. These tests will conserve diagnostic resources and provide convenience and savings for patients. Whether the availability of such technology will help to overcome the many obstacles to successful delivery and scale-up of antiretroviral therapy in resource-limited settings is still to be shown.
CD4 staging establishes eligibility for antiretroviral therapy after HIV diagnosis. To obtain a CD4 cell count in resource-limited settings presents many challenges, and the scale of these challenges is often underestimated. The required two minimum clinic visits often span a month or longer, and associated transport costs can deter access to care. Pre-analysis infrastructure includes blood collection apparatus, a trained phlebotomist, and quick, reliable, and accountable transport and tracking of samples. Laboratories need functioning and calibrated instruments, trained and disciplined personnel, and quality assurance programmes. Finally, the return of CD4 results to a distant clinic is fraught with the difficulties of handwritten medical records and unique identifiers. POC testing offers a solution to many of these difficulties by dispensing with these multiple steps without compromising the accuracy of the result. But many of these difficulties are specific to rural Africa and cannot be extrapolated to downtown New York of even Cape Town.
The clinical settings in which POC CD4 testing might be most effective in treatment and retention have not been identified. Based on an observational study carried out in primary health clinics in Mozambique, Jani and colleagues report varied effects of POC CD4 testing on loss to follow-up at different points between enrolment and initiation of antiretroviral treatment. Decreased loss to follow-up was reported between enrolment and CD4 staging but not between CD4 staging and initiation of antiretroviral therapy in treatment-eligible patients. Time from enrolment to CD4 testing also decreased with POC testing, but this finding did not result in a difference in time to initiation of antiretroviral therapy after treatment eligibility was established. The largest loss, noted in many studies from Africa, occurs between rapid POC diagnosis of HIV infection and referral to a programme including CD4 testing. Efficiency could be improved through linkage of POC CD4 counts with HIV testing so that people who are HIV positive immediately receive CD4 testing, and targeted post-test counselling about risk of disease progression, transmission, and treatment eligibility. This approach might be particularly germane to programmes for the prevention of mother-to-child transmission of HIV, in which the time to initiation of antiretroviral therapy needs to be short for maximum benefit. In resource-limited settings, where late attendance to antenatal clinics is common, the need for urgent initiation of antiretroviral therapy in treatment-eligible pregnant women is even greater.
POC CD4 testing may not be ideal for every situation. In cities in Africa with well developed transportation and laboratory infrastructure, centralised, high-throughput flow-cytometry might be most efficient. At 20 min per sample, POC CD4 testing could rapidly overwhelm a busy clinic's capacity for patient throughput and service delivery. Conversely, POC capacity in rural clinics and mobile diagnostic services depends on sufficient demand to justify the expense of services in dispersed communities. The cost-effectiveness of placement of these units in voluntary counselling and testing for adults and antenatal clinics for prevention of mother-to-child transmission has not yet been tested, although the urgency of rapid initiation of antiretroviral treatment in eligible pregnant women is clearly of high importance for maternal health and transmission prevention. Feasibility and sustainability depend on the long-term durability of instruments; ease of maintenance, repairs, and replacements; availability of an adequate supply chain; and reasonable costs.
POC testing is a promising advance in efficient service delivery and monitoring in resource-limited settings. However, persistent, albeit lower, loss to follow-up occurs despite the introduction of this technology, which emphasises the complexity of health-seeking behaviour especially for HIV and acceptance of lifelong antiretroviral therapy. Successful HIV programmes should efficiently identify people with HIV by rapid testing, engage HIV-positive patients in care with rapid provision of CD4 staging, provide appropriate counselling, and assess readiness, then initiate antiretroviral therapy and retain individuals in care and treatment with appropriate monitoring. Although technology such as POC CD4 testing might improve service efficiency, such advances must be accompanied by increased knowledge about the barriers to retention, and implementation of solutions to prevent loss to follow-up, and to realise the full potential of HIV treatment, care, and prevention.
The AIDS epidemic has been the beneficiary of vast amounts of cash, no doubt driven by the homosexual lobby. Undoubtedly, the sciences of virology, immunology, gene therapy and molecular medicine have benefited from the attention paid to HIV. Point of Care testing has been an important issue in hematology. Anticoagulant control, diabetic control, pre-chemotherapy blood tests and even chemotherapy trough levels have been areas where POC testing might be thought to be beneficial. The drawback have always been expense and reliability. Reliable POC machines are very expensive and each individual measurement is slow. No doubt patients like them for their convenience, but money spent on them is money not spent elsewhere.
New durable, simple, and affordable cytometric CD4 testing devices aim to decrease the time to beginning antiretroviral therapy and loss to follow-up. Rapid testing with microfluidics meets the criteria for true POC testing, providing immediate results without needing laboratory personnel or infrastructure. These tests will conserve diagnostic resources and provide convenience and savings for patients. Whether the availability of such technology will help to overcome the many obstacles to successful delivery and scale-up of antiretroviral therapy in resource-limited settings is still to be shown.
CD4 staging establishes eligibility for antiretroviral therapy after HIV diagnosis. To obtain a CD4 cell count in resource-limited settings presents many challenges, and the scale of these challenges is often underestimated. The required two minimum clinic visits often span a month or longer, and associated transport costs can deter access to care. Pre-analysis infrastructure includes blood collection apparatus, a trained phlebotomist, and quick, reliable, and accountable transport and tracking of samples. Laboratories need functioning and calibrated instruments, trained and disciplined personnel, and quality assurance programmes. Finally, the return of CD4 results to a distant clinic is fraught with the difficulties of handwritten medical records and unique identifiers. POC testing offers a solution to many of these difficulties by dispensing with these multiple steps without compromising the accuracy of the result. But many of these difficulties are specific to rural Africa and cannot be extrapolated to downtown New York of even Cape Town.
The clinical settings in which POC CD4 testing might be most effective in treatment and retention have not been identified. Based on an observational study carried out in primary health clinics in Mozambique, Jani and colleagues report varied effects of POC CD4 testing on loss to follow-up at different points between enrolment and initiation of antiretroviral treatment. Decreased loss to follow-up was reported between enrolment and CD4 staging but not between CD4 staging and initiation of antiretroviral therapy in treatment-eligible patients. Time from enrolment to CD4 testing also decreased with POC testing, but this finding did not result in a difference in time to initiation of antiretroviral therapy after treatment eligibility was established. The largest loss, noted in many studies from Africa, occurs between rapid POC diagnosis of HIV infection and referral to a programme including CD4 testing. Efficiency could be improved through linkage of POC CD4 counts with HIV testing so that people who are HIV positive immediately receive CD4 testing, and targeted post-test counselling about risk of disease progression, transmission, and treatment eligibility. This approach might be particularly germane to programmes for the prevention of mother-to-child transmission of HIV, in which the time to initiation of antiretroviral therapy needs to be short for maximum benefit. In resource-limited settings, where late attendance to antenatal clinics is common, the need for urgent initiation of antiretroviral therapy in treatment-eligible pregnant women is even greater.
POC CD4 testing may not be ideal for every situation. In cities in Africa with well developed transportation and laboratory infrastructure, centralised, high-throughput flow-cytometry might be most efficient. At 20 min per sample, POC CD4 testing could rapidly overwhelm a busy clinic's capacity for patient throughput and service delivery. Conversely, POC capacity in rural clinics and mobile diagnostic services depends on sufficient demand to justify the expense of services in dispersed communities. The cost-effectiveness of placement of these units in voluntary counselling and testing for adults and antenatal clinics for prevention of mother-to-child transmission has not yet been tested, although the urgency of rapid initiation of antiretroviral treatment in eligible pregnant women is clearly of high importance for maternal health and transmission prevention. Feasibility and sustainability depend on the long-term durability of instruments; ease of maintenance, repairs, and replacements; availability of an adequate supply chain; and reasonable costs.
POC testing is a promising advance in efficient service delivery and monitoring in resource-limited settings. However, persistent, albeit lower, loss to follow-up occurs despite the introduction of this technology, which emphasises the complexity of health-seeking behaviour especially for HIV and acceptance of lifelong antiretroviral therapy. Successful HIV programmes should efficiently identify people with HIV by rapid testing, engage HIV-positive patients in care with rapid provision of CD4 staging, provide appropriate counselling, and assess readiness, then initiate antiretroviral therapy and retain individuals in care and treatment with appropriate monitoring. Although technology such as POC CD4 testing might improve service efficiency, such advances must be accompanied by increased knowledge about the barriers to retention, and implementation of solutions to prevent loss to follow-up, and to realise the full potential of HIV treatment, care, and prevention.
The AIDS epidemic has been the beneficiary of vast amounts of cash, no doubt driven by the homosexual lobby. Undoubtedly, the sciences of virology, immunology, gene therapy and molecular medicine have benefited from the attention paid to HIV. Point of Care testing has been an important issue in hematology. Anticoagulant control, diabetic control, pre-chemotherapy blood tests and even chemotherapy trough levels have been areas where POC testing might be thought to be beneficial. The drawback have always been expense and reliability. Reliable POC machines are very expensive and each individual measurement is slow. No doubt patients like them for their convenience, but money spent on them is money not spent elsewhere.
Occupy latest news
An interesting article by George Carey, the ex-Archbishop of Canterbury on the St Paul's debacle in today's Telegraph.
The inevitable resignation of the Canon Chancellor of St Paul’s, Giles Fraser, via the predictable medium of Twitter, is a sad day for one of our great national churches. But the departure of this able man, and now the planned reopening of the cathedral, should at least bring to an end the hand-wringing and posturing of the past two weeks. My paramount concern throughout has been that the reputation of Christianity is being damaged by the episode, and, more widely, that the possibility of fruitful and peaceful protest has been brought into disrepute.
The Blitz only closed St Paul’s for four days. By contrast, the Occupy London Stock Exchange protesters, camped outside Wren’s masterpiece, managed to put it out of business for a week. It has been a debacle that should prompt urgent public debate both within the Church of England, and throughout society at large.
For countless others, though, not least in the churches, this was a hopeful sign that peaceful protests could indeed take place at a time when so many civil liberties have been eroded. Furthermore, it demonstrated that the Church is willing to play a sympathetic role in the lives of young people who are drawn to a movement calling for economic justice.
Like many others in the Church, I have a great deal of sympathy for the raw idealism of the protesters. Their contention that the banks have not paid an equitable price for the damage caused, in part, by their reckless lending and profiteering strikes a powerful chord.
However, after their initial welcome to Occupy, the cathedral authorities then seemed to lose their nerve. In daily-changing news reports, the story see-sawed between a public debate about the merits or otherwise of the protest, the drama of internal disputes at St Paul’s over lost income from tourists, and the ill-defined health, safety and fire concerns that caused it to close its doors to worshippers.
One moment the church was reclaiming a valuable role in hosting public protest and scrutiny, the next it was looking in turns like the temple which Jesus cleansed, or the officious risk-averse ’elf ’n safety bureaucracy of urban legend. How could the dean and chapter at St Paul’s have let themselves get into such a position?
And what of the protesters themselves in this sorry story? Their intransigence, once the cathedral stopped welcoming them with open arms and began to plead with them to leave, did them no favours. Ironically, they started off fulsomely thanking the Church for allowing them to stay, but then repaid that generosity by refusing to leave when asked.
At a time when secularists are striving to drive Christian voices from public life with strident campaigns to abolish church schools and council prayers, and when workers can be suspended for offering to say a prayer for colleagues or for wearing a cross, it seems that on the doorstep of St Paul’s, of all places, yet another blow has been struck against Christian worshippers. In this case, “anarchist” protesters threatened the freedom to worship – one of our most basic and hard-fought-for rights – by forcing the cathedral authorities to halt public access.
But surely the protesters and the Church were, by one measure, on the same side? How could Occupy be unaware of the immense contribution of all the churches to justice and peace through international development and social services? The St Paul’s Institute alone has been addressing precisely the issues Occupy is raising.
Yet the very fact that they are prepared to continue their own protest at the expense of Christian worship in one of our greatest cathedrals surely gives the lie to the protesters’ claim that they represent 99 per cent of society. Furthermore, their determination to engage in an open-ended campaign in the churchyard is opportunistic and cynical. If their protest is truly against the tax evaders of the City and reckless banking practices, why are they not protesting at Canary Wharf, or on the thresholds of the banks themselves?
As the story developed, thermal images of empty tents seemed to illustrate the hollow nature of the protest movement. The emerging picture of spoilt middle-class children returning home at night for a shower and a warm bed begged questions about their commitment to their cause. It also seemed to suggest that the cathedral authorities in their initial welcome had been duped.
And what was the cause anyway? “This is what democracy looks like,” claimed Occupy’s opening statement. It explained that it was engaged in a process of public assemblies in a democratic process. But it is making up its demands as it goes along – truly rebels without a cause.
In some senses this is what our society now looks like. We are all protesters, even if we don’t take to the streets. We all have an inchoate sense that something is wrong and we have any number of culprits to blame – from Europe, to immigrants, to the banks, to politicians and media barons. Public distrust of the institutions of a civil society has reached an all-time high as the performance of some bankers, public servants and even recently some sections of our media has sunk to the lowest depths after waves of recent scandal.
And where are the ideas for restoring public trust and rebuilding our now fragile democracy? We are divided as never before, not into one per cent of the very rich, versus 99 per cent of the not-so-rich, as the protesters would have us believe, but into many factions and separate communities. Gone is any sense of an overarching narrative to form our identity as a nation. We have effectively forgotten who we are because we have rejected the very faith and heritage that set us on our way as a great country.
The story of the St Paul’s encampment, with its empty tents and hollowed-out protest, together with the uncertain note sounded by the dean and chapter, is simply a parable for our times.
It would be a tragedy now if, by the mismanagement of the St Paul’s authorities and the self-indulgence of the protesters, the right of peaceful protest and the urgency of widespread public debate became the subject of even greater cynicism and apathy. This opportunity to rebuild our ailing public life around gospel values of public service, self-restraint, equality, hard work and charitable concern for the poor, must not be squandered.
Protest has always been with us, particularly in times of crisis, and the churches have often been at the centre of popular movements and campaigns. In the past, the churchyard of St Paul’s was a well-known scene of public preaching which was often political in nature.
It should not be forgotten that this week is not the first time that St Paul’s has played an ambivalent and even wrongful role in the politics of protest. In the 16th century, a Bishop of London, Cuthbert Tunstall, publicly burned copies of Tyndale’s New Testament at St Paul’s Cross. Tyndale’s was one of the first translations of the Bible into the vernacular, and became the basis of the influential King James Bible, whose 400th anniversary we are celebrating this year.
I’m not convinced that the Occupy protesters were aware of the history of St Paul’s when they chose the churchyard for their encampment. Denied room at nearby Paternoster Square, they were pushed back to St Paul’s, where Giles Fraser offered them a warm welcome and preached a sermon that they saw as favourable to their anti-capitalist agenda. For many people, Fraser’s intervention struck a dissonant note. Rather than entreating the protesters to move on, he asked the police to leave the steps of St Paul’s and declared to the cameras that the protest was peaceful.
The inevitable resignation of the Canon Chancellor of St Paul’s, Giles Fraser, via the predictable medium of Twitter, is a sad day for one of our great national churches. But the departure of this able man, and now the planned reopening of the cathedral, should at least bring to an end the hand-wringing and posturing of the past two weeks. My paramount concern throughout has been that the reputation of Christianity is being damaged by the episode, and, more widely, that the possibility of fruitful and peaceful protest has been brought into disrepute.
The Blitz only closed St Paul’s for four days. By contrast, the Occupy London Stock Exchange protesters, camped outside Wren’s masterpiece, managed to put it out of business for a week. It has been a debacle that should prompt urgent public debate both within the Church of England, and throughout society at large.
For countless others, though, not least in the churches, this was a hopeful sign that peaceful protests could indeed take place at a time when so many civil liberties have been eroded. Furthermore, it demonstrated that the Church is willing to play a sympathetic role in the lives of young people who are drawn to a movement calling for economic justice.
Like many others in the Church, I have a great deal of sympathy for the raw idealism of the protesters. Their contention that the banks have not paid an equitable price for the damage caused, in part, by their reckless lending and profiteering strikes a powerful chord.
However, after their initial welcome to Occupy, the cathedral authorities then seemed to lose their nerve. In daily-changing news reports, the story see-sawed between a public debate about the merits or otherwise of the protest, the drama of internal disputes at St Paul’s over lost income from tourists, and the ill-defined health, safety and fire concerns that caused it to close its doors to worshippers.
One moment the church was reclaiming a valuable role in hosting public protest and scrutiny, the next it was looking in turns like the temple which Jesus cleansed, or the officious risk-averse ’elf ’n safety bureaucracy of urban legend. How could the dean and chapter at St Paul’s have let themselves get into such a position?
And what of the protesters themselves in this sorry story? Their intransigence, once the cathedral stopped welcoming them with open arms and began to plead with them to leave, did them no favours. Ironically, they started off fulsomely thanking the Church for allowing them to stay, but then repaid that generosity by refusing to leave when asked.
At a time when secularists are striving to drive Christian voices from public life with strident campaigns to abolish church schools and council prayers, and when workers can be suspended for offering to say a prayer for colleagues or for wearing a cross, it seems that on the doorstep of St Paul’s, of all places, yet another blow has been struck against Christian worshippers. In this case, “anarchist” protesters threatened the freedom to worship – one of our most basic and hard-fought-for rights – by forcing the cathedral authorities to halt public access.
But surely the protesters and the Church were, by one measure, on the same side? How could Occupy be unaware of the immense contribution of all the churches to justice and peace through international development and social services? The St Paul’s Institute alone has been addressing precisely the issues Occupy is raising.
Yet the very fact that they are prepared to continue their own protest at the expense of Christian worship in one of our greatest cathedrals surely gives the lie to the protesters’ claim that they represent 99 per cent of society. Furthermore, their determination to engage in an open-ended campaign in the churchyard is opportunistic and cynical. If their protest is truly against the tax evaders of the City and reckless banking practices, why are they not protesting at Canary Wharf, or on the thresholds of the banks themselves?
As the story developed, thermal images of empty tents seemed to illustrate the hollow nature of the protest movement. The emerging picture of spoilt middle-class children returning home at night for a shower and a warm bed begged questions about their commitment to their cause. It also seemed to suggest that the cathedral authorities in their initial welcome had been duped.
And what was the cause anyway? “This is what democracy looks like,” claimed Occupy’s opening statement. It explained that it was engaged in a process of public assemblies in a democratic process. But it is making up its demands as it goes along – truly rebels without a cause.
In some senses this is what our society now looks like. We are all protesters, even if we don’t take to the streets. We all have an inchoate sense that something is wrong and we have any number of culprits to blame – from Europe, to immigrants, to the banks, to politicians and media barons. Public distrust of the institutions of a civil society has reached an all-time high as the performance of some bankers, public servants and even recently some sections of our media has sunk to the lowest depths after waves of recent scandal.
And where are the ideas for restoring public trust and rebuilding our now fragile democracy? We are divided as never before, not into one per cent of the very rich, versus 99 per cent of the not-so-rich, as the protesters would have us believe, but into many factions and separate communities. Gone is any sense of an overarching narrative to form our identity as a nation. We have effectively forgotten who we are because we have rejected the very faith and heritage that set us on our way as a great country.
The story of the St Paul’s encampment, with its empty tents and hollowed-out protest, together with the uncertain note sounded by the dean and chapter, is simply a parable for our times.
It would be a tragedy now if, by the mismanagement of the St Paul’s authorities and the self-indulgence of the protesters, the right of peaceful protest and the urgency of widespread public debate became the subject of even greater cynicism and apathy. This opportunity to rebuild our ailing public life around gospel values of public service, self-restraint, equality, hard work and charitable concern for the poor, must not be squandered.
Protest has always been with us, particularly in times of crisis, and the churches have often been at the centre of popular movements and campaigns. In the past, the churchyard of St Paul’s was a well-known scene of public preaching which was often political in nature.
It should not be forgotten that this week is not the first time that St Paul’s has played an ambivalent and even wrongful role in the politics of protest. In the 16th century, a Bishop of London, Cuthbert Tunstall, publicly burned copies of Tyndale’s New Testament at St Paul’s Cross. Tyndale’s was one of the first translations of the Bible into the vernacular, and became the basis of the influential King James Bible, whose 400th anniversary we are celebrating this year.
I’m not convinced that the Occupy protesters were aware of the history of St Paul’s when they chose the churchyard for their encampment. Denied room at nearby Paternoster Square, they were pushed back to St Paul’s, where Giles Fraser offered them a warm welcome and preached a sermon that they saw as favourable to their anti-capitalist agenda. For many people, Fraser’s intervention struck a dissonant note. Rather than entreating the protesters to move on, he asked the police to leave the steps of St Paul’s and declared to the cameras that the protest was peaceful.
Wednesday, October 26, 2011
Lenalidomide as frontline treatment in the elderly
An important paper was published in Blood in September of the use of lenalidomide as front line therapy for elderly patients with CLL.
Despite the fact that two-thirds of the patients diagnosed with CLL are older than 65 there is no frontline therapy for elderly patients that is superior to any other.
The GCLLSG conducted a trial randomizing 193 patients over-65 to fludarabine or chlorambucil. Although there were higher response rates with fludarabine PFS and OS wee identical. Hillmen et al compared alemtuzumab and chlorambucil. Again, despite a higher overall response rate observed with alemtuzumab in a subgroup analysis of 105 patients older than 65 years, median PFS was only 12.5 months in both treatment arms. In both those trials suboptimal doses of chlorambucil were used.
Chemoimmunotherapy combinations like FCR have led to improvements in survival in younger patients with CLL and have become the standard of care but when offered to older patients, there are higher rates of treatment-related toxicities. Patients older than 70 years have an increased rate of myelotoxicity and are less likely to complete 6 cycles of therapy. Dose-reduced purine analog trials, such as the “FCR-Lite” and PCR, have been developed to reduce myelotoxicity and improve tolerability in the elderly; but there are few comparative data.
In this age group, cure is usually not the option, but longer remissions are. In addition, the impact of treatment on daily life activities and the intensity of monitoring requirements are particularly important to this population. Because of convenient oral administration and favorable toxicity profile, chlorambucil is often chosen as initial therapy for elderly patients.
Based on the efficacy observed with lenalidomide in patients with relapsed or refractory disease, MD Anderson designed a phase 2 trial to study lenalidomide in elderly patients requiring initial treatment. In vitro evidence for an immunostimulatory effect of lenalidomide on T-lymphocytes made this particularly appealing for elderly patients who are especially vulnerable to myelosuppressive and immunosuppressive treatments. The convenient oral route of administration of lenalidomide is also particularly attractive.
Sixty untreated patients with symptomatic CLL were enrolled in this phase 2 prospective study. All patients were age 65 years or older, and indication for treatment initiation by National Cancer Institute (NCI 2008) Working Group criteria.1Entry criteria also required a performance status of 0 to 3, and serum creatinine, bilirubin, and alanine transaminase were required to be less than or equal to twice the upper limit of normal. Patients were able to participate on this study regardless of absolute neutrophil or platelet count.
Pretreatment evaluation included medical history, physical examination, complete blood count with differential and serum creatinine, electrolytes, albumin, calcium, uric acid, LDH, ALT, serum Ig levels, β2-M levels, and peripheral T-cell lymphocyte subset analysis by flow cytometry were also measured. Bone marrow aspiration and biopsy were performed before therapy, including infiltration assessment, immunophenotype by flow cytometry, IGHV gene mutaions, and Zap-70 expression by flow cytometry. Standard metaphase karyotype analysis and FISH. CCL3 and CCL4 protein levels were measured in peripheral blood plasma samples of 31 patients before therapy and at study assessment time points.
Patients received lenalidomide orally at the initial dose of 5 mg daily administered continuously for 56 days (cycles 1 and 2). After day 56, the dose could be titrated up by 5 mg every 28 days to a maximum dose of 25 mg/day as tolerated. One cycle of therapy consisted of 28 days of lenalidomide. Dosing of lenalidomide could be increased to optimize response as per the treating physician's discretion and in accordance with protocol guidelines. If patients did not tolerate higher doses of lenalidomide, dosing was adjusted to the highest tolerated dose. Patients deemed at high risk for thrombotic events could receive aspirin as prophylaxis. Hematopoietic growth factor support was allowed according to ASCO guidelines. Allopurinol (300 mg daily) was administered as tumor lysis prophylaxis on days 1 to 14 of cycle 1. There was no mandated antibacterial or antiviral prophylaxis. Lenalidomide dose was withheld in patients experiencing CTC grade 3 or 4 toxicities, and treatment was restarted at a reduced dose of lenalidomide on resolution of toxicity to grade 2 or lower.
Response assessment was performed using 2008 NCI criteria after the first 3 cycles of therapy and every 6 cycles thereafter. Assessment included physical examination, peripheral blood examination, bone marrow aspirate and biopsy, and lymphocyte immunophenotyping on bone marrow aspirate. CT scans were not routinely performed for response assessment. Flow cytometric assessment of bone marrow aspirate using 3-color (this is less sensitive than other centers use) flow cytometry was performed to estimate MRD by evaluating for CD5+/CD19+ lymphocytes with light-chain restriction.
Treatment was discontinued at disease progression or if patients experienced excessive toxicity. Patients who had stable disease or better after 3 cycles continued on therapy. Trial design recommended discontinuation of therapy if there was no objective evidence of response by 9 cycles of therapy, although this decision was left to treating physician's discretion. Tumor flare was defined as painful acute lymph node enlargement or lymph node enlargement with evidence of local inflammation occurring with initiation or reinitiation of therapy.
The primary endpoint of this study was PFS, which was defined as time from the start of therapy to death or progression of disease. Additional endpoints were OS, CR, and overall response rate (ORR), and nonhematologic toxicity.
The median time from diagnosis of CLL to initiation of therapy was 29 months (range, 1-202 months). The predominant indication for initiation of therapy was rapid lymphocyte doubling time for 26 patients (43%), bulky or progressive adenopathy or splenomegaly for 16 patients (27%), Rai stage III or IV CLL for 13 patients (22%), CLL related B-symptoms for 3 patients (5%), and autoimmune cytopenia for 2 patients (3%).
The median follow-up for all patients was 29 months (range, 1.5-38 months). A median of 27 cycles (range, 1-41 cycles) were administered. The median daily dose was 5 mg with a maximum tolerated dose of 20 mg and minimum dose of 2.5 mg. Lenalidomide daily dose was titrated up to 10 mg in 36 patients (60%) and to 15 mg or more in 8 patients (13%), although only 26 patients (43%) were able to continue on a dose of at least 10 mg for 2 or more cycles of therapy.
By intention to treat, the ORR was 65%, including 6 patients (10%) with CR, 3 patients (5%) with CR with residual cytopenia, 4 patients (7%) with nodular PRs, and 26 patients (43%) with partial response (PR). Four patients achieved a CR with no identifiable CLL clones by bone marrow flow cytometry (negative minimal residual disease). The median time to achievement of a PR or better was 3 months (range, 3-15 months), and the median time to achievement of CR or CR with residual cytopenia was 18 months (range, 9-27 months). Of the patients who received at least 3 cycles of therapy, most improved their response if they could tolerate further treatment.
There was no statistically significant difference in CR or ORR between patients with Rai stage or by prognostic markers, though the numbers were too small to be sure. However there were no responses among the the del 17p group.
ORR and CR rates for patients who tolerated an average dose of at least 5 mg (34 patients, ORR 82% and CR 26%) were significantly higher compared with those who received an average dose of < 5 mg (26 patients, ORR 52% and CR 3%). As a continuous variable, higher average daily dose of lenalidomide during the first 6 cycles was associated with a higher likelihood to achieve an objective response (P < .001) or CR (P = .018). Patients who could tolerate > 5 mg of lenalidomide had higher pretreatment hemoglobin level and were less likely to have 17p deletion.
At a median follow-up of 31 months, 32 patients (53%) remain on therapy with an estimated 2-year PFS of 60% (95% CI, 46%-72%). Responses to lenalidomide appeared durable with continuing therapy. Of 39 patients who achieved at least a PR, 33 patients (85%) have retained or improved their response, 5 patients (13%) have discontinued therapy in continued response because of toxicity or unrelated reasons, and 1 patient (3%) has progressed while on therapy.
PFS was significantly shorter for the 6 patients with deletion of 17p compared with patients with other FISH results (median PFS 6 months vs not reached, P = .002). Patients who experienced a tumor flare reaction of any grade had a longer PFS than patients who did not have a tumor flare reaction (median PFS not reached vs 15 months, P = .03). The average dose of lenalidomide in the first 6 cycles of therapy was also associated with PFS. At last follow-up, only 7 of 34 patients (21%) who tolerated an average dose of 5 mg or more had progressed or died compared with 16 of 26 patients (62%) who received an average dose < 5 mg (P = .003).
88% of patients were alive at a median follow-up of 31 months. Of the patients who achieved a response, 97% were alive and 85% progression-free. 3 patients died > 18 months after starting subsequent therapy after discontinuing treatment because of intolerance after < 1, 1, and 6 cycles. One patient declined further therapy after 2 cycles because of devastating social circumstances and concurrent medical issues and died 1 month later and 1 patient died after development of Richter transformation after 10 months of therapy. Two patients died of unrelated malignancies.
Twenty-eight patients discontinued treatment. Causes for discontinuation of therapy included lack or response or progressive disease (11 patients), lenalidomide intolerance without response (8 patients), lenalidomide intolerance or late adverse events (after 9 cycles of therapy) in patients with a response (4 patients), nonhematologic malignancy (3 patients), and patient preference (2 patients). Among patients intolerant of medication, reasons for discontinuation included rash (3 patients), shortness of breath (1 patient), fatigue (1 patient), infections (1 patient), fevers (1 patient), allergy (1 patient), or diarrhea (1 patient). Late adverse events (after 9 cycles of therapy) included a cerebrovascular accident, a veno-thromboembolic event, and pneumonia.
The most common toxicity was grade 3 or 4 neutropenia, which occurred in 34% of evaluable cycles. The majority of patients (83%) experienced at least one episode of grade 3 or 4 neutropenia. Grade 3 or 4 neutropenia was managed with transient interruption of therapy followed by dose reduction. Other hematologic toxicities were less common, with grade 3 or 4 thrombocytopenia and anemia occurring in only 12% and < 1% of cycles, respectively. Eight patients (13%) experienced at least one severe (grade 3 or 4) infection or neutropenic fever, including one fatal infection. In terms of grade 3 or 4 infections, there were 3 patients with pneumonia (4 episodes), 2 patients (3 episodes) with uncomplicated respiratory tract infections who received intravenous antibiotics because of neutropenia, and 3 patients admitted with febrile neutropenia (including 1 bacteremia episode). Four of the documented infections were associated with grade 3 or 4 neutropenia. Seven of the 9 severe infectious events occurred within the first 9 cycles of . Minor infections were common, with 53% of patients experiencing at least one minor infection during therapy. Minor infections included mostly upper respiratory tract infections, sinus infections, or bronchitis. Grade 1 and 2 nonhematologic or noninfectious toxicities were more common and included fatigue (92% of patients), diarrhea (55%), constipation (55%), rash (48%), and/or pruritus (43%). Grade 1 or 2 tumor flare reactions occurred in 31 (52%) patients, but these were generally mild and tolerated without further therapy (18 patients) or treated with short administration of nonsteroidal anti-inflammatory drugs (5 patients), steroids (9 patients), or dose adjustment of lenalidomide (10 patients). Almost all tumor flare reactions occurred within the first 3 cycles of therapy, with the majority occurring in the cycle. There were no grade 3 or 4 episodes of tumor flare or any tumor lysis in this study.
Serum Ig levels were measured at baseline and during treatment in the 34 patients who completed at least 15 cycles of therapy; 33 of these patients achieved an objective response. An increase in Ig levels across all Ig classes was noted. The rise in IgG and IgA was most pronounced between 3 and 9 cycles of therapy, whereas the rise in IgM occurred by the third cycle of therapy. Sixteen patients had decreased IgG levels (< 700 mg/dL) before therapy. In 8 patients (50%), IgG levels normalized after 15 cycles of therapy, and another 3 patients (19%) demonstrated an increase in IgG of greater than 50% from baseline. The rise in serum Ig levels was durable through therapy.
In the majority of patients, the number of total circulating lymphocytes decreased significantly during the first 3 cycles, which was sustained for the duration of therapy. The absolute number of CD3+ T cells was elevated in the majority of patients before start of therapy and decreased during therapy, 27 of 34 patients (79%) attained normal absolute CD3+ T-cell counts after 15 cycles of therapy. For these patients, T-cell numbers and the proportion of CD4 to CD8 lymphocytes remained within normal limits during treatment. There was no statistically significant association between severe infections and absolute T- or B-cell numbers or subsets in the periphery or in bone marrow before therapy.
CCL4 are chemokines secreted by CLL cells in the lymph node microenvironment in response to B-cell receptor (BCR) activation and can be detected in patient's plasma, where their concentrations predict for disease progression and time to first treatment. There was no correlation between pretreatment CCL3 or CCL4 levels and likelihood of response. Although no significant difference was observed in CCL3 and CCL4 levels after 3 cycles of therapy between responders (PR or CR) and nonresponders, after 9 cycles of therapy responders had significantly lower levels of CCL3 or CCL4 relative to pretreatment.
In this study, median PFS has not been reached after 30 months of follow-up. This duration of response compares favorably with the results of studies of chlorambucil, fludarabine, or alemtuzumab monotherapy that have generally been associated with median PFS of < 2 years. The ORR rate of 65% is similar to published results for monotherapy in elderly untreated patients with CLL, and the 2-year OS rate of 88% is promising in this older patient group. This is not a comparative study; therefore, these results require confirmation with larger phase 3 trials.
Overall, lenalidomide was well tolerated with neutropenia as the most common associated toxicity occurring in 34% of the cycles. Patients with neutropenia had doses withheld and/or reduced; therefore, the rate of neutropenia may have impacted on the exposure to lenalidomide and consequent efficacy. Although the rate of neutropenia was high, neutrophil recovery generally occurred spontaneously after withdrawal of therapy for 7-10 days and the overall rate of febrile neutropenic events was low. The rate of grade 3 or 4 infection was low and decreased in patients who continued therapy.
Prior studies of lenalidomide have reported frequent tumor flare reactions and severe tumor lysis syndrome in patients with CLL. Patients in this study did not experience any severe tumor flare or tumor lysis on this dose regimen. Grade 1 or 2 tumor flare was common and either resolved spontaneously or responded well to simple measures, such as nonsteroidal anti-inflammatory drugs, dose reduction of lenalidomide, or corticosteroids in a minority of patients. The low incidence of severe tumor flare that observed is probably related to the low starting dose of lenalidomide and gradual dose escalation. The development of tumor flare was associated with a higher likelihood of response as suggested by previously published findings in patients with CLL. This finding supports the recommendation to continue therapy with lenalidomide if tumor flare is not severe.
Lenalidomide exposure is associated with reversal of defective ability to form immune synapses between CLL cells and T cells and promotes costimulatory activation of B cells. In this study, an increase in Ig levels during treatment with lenalidomide occurred. This increased production of Igs is an interesting finding, which may be explained by enhanced B-cell costimulatory activity via activation of lymphocytes through phosphoinositide-3-kinase dependent up-regulation of CD154. In addition, a stimulatory effect of lenalidomide on T cells and NK cells has been demonstrated in vitro and in other hematologic malignancies. One study demonstrated up-regulation of costimulatory molecules, such as CD80 on CLL cells associated with T-cell activation after administration of lenalidomide in patients with CLL. The increase in CD80 expression correlated with tumor flare reaction, but the investigators were unable to correlate this with tumor response. NK-cell activation has also been demonstrated in lymphoproliferative disorders and myeloma. This, together with the dynamic changes noted in the repertoire of functional T cells in a subset of patients enrolled in this study, supports the immunomodulatory properties of this class of agents in CLL, similarly observed in other lymphoproliferative disorders after lenalidomide therapy.
Another interesting finding from this study is that responders exhibited a significant decrease in CCL3 and CCL4 levels during lenalidomide therapy compared with nonresponders. These chemokines are secreted by CLL cells after BCR signaling. It has been previously demonstrated that decreasing CCL3 and CLL4 levels are associated with response to therapy after inhibition of the BCR signaling pathway using the phosphoinositide 3′-kinase delta inhibitor CAL-101 or the Bruton tyrosine kinase inhibitor PCI-32765. The increase in CCL3 and CCL4 levels in nonresponders may represent continued activation of CLL cells via BCR signaling pathways, other microenvironmental stimulating pathways, or because of an increased burden of CLL cells. These data should be confirmed by larger studies and suggest that further studies examining combinations of lenalidomide with agents targeting the BCR signaling pathways may be of interest.
This is the best evidence yet that Revlimid is going to be an important player in CLL treatment.
Despite the fact that two-thirds of the patients diagnosed with CLL are older than 65 there is no frontline therapy for elderly patients that is superior to any other.
The GCLLSG conducted a trial randomizing 193 patients over-65 to fludarabine or chlorambucil. Although there were higher response rates with fludarabine PFS and OS wee identical. Hillmen et al compared alemtuzumab and chlorambucil. Again, despite a higher overall response rate observed with alemtuzumab in a subgroup analysis of 105 patients older than 65 years, median PFS was only 12.5 months in both treatment arms. In both those trials suboptimal doses of chlorambucil were used.
Chemoimmunotherapy combinations like FCR have led to improvements in survival in younger patients with CLL and have become the standard of care but when offered to older patients, there are higher rates of treatment-related toxicities. Patients older than 70 years have an increased rate of myelotoxicity and are less likely to complete 6 cycles of therapy. Dose-reduced purine analog trials, such as the “FCR-Lite” and PCR, have been developed to reduce myelotoxicity and improve tolerability in the elderly; but there are few comparative data.
In this age group, cure is usually not the option, but longer remissions are. In addition, the impact of treatment on daily life activities and the intensity of monitoring requirements are particularly important to this population. Because of convenient oral administration and favorable toxicity profile, chlorambucil is often chosen as initial therapy for elderly patients.
Based on the efficacy observed with lenalidomide in patients with relapsed or refractory disease, MD Anderson designed a phase 2 trial to study lenalidomide in elderly patients requiring initial treatment. In vitro evidence for an immunostimulatory effect of lenalidomide on T-lymphocytes made this particularly appealing for elderly patients who are especially vulnerable to myelosuppressive and immunosuppressive treatments. The convenient oral route of administration of lenalidomide is also particularly attractive.
Sixty untreated patients with symptomatic CLL were enrolled in this phase 2 prospective study. All patients were age 65 years or older, and indication for treatment initiation by National Cancer Institute (NCI 2008) Working Group criteria.1Entry criteria also required a performance status of 0 to 3, and serum creatinine, bilirubin, and alanine transaminase were required to be less than or equal to twice the upper limit of normal. Patients were able to participate on this study regardless of absolute neutrophil or platelet count.
Pretreatment evaluation included medical history, physical examination, complete blood count with differential and serum creatinine, electrolytes, albumin, calcium, uric acid, LDH, ALT, serum Ig levels, β2-M levels, and peripheral T-cell lymphocyte subset analysis by flow cytometry were also measured. Bone marrow aspiration and biopsy were performed before therapy, including infiltration assessment, immunophenotype by flow cytometry, IGHV gene mutaions, and Zap-70 expression by flow cytometry. Standard metaphase karyotype analysis and FISH. CCL3 and CCL4 protein levels were measured in peripheral blood plasma samples of 31 patients before therapy and at study assessment time points.
Patients received lenalidomide orally at the initial dose of 5 mg daily administered continuously for 56 days (cycles 1 and 2). After day 56, the dose could be titrated up by 5 mg every 28 days to a maximum dose of 25 mg/day as tolerated. One cycle of therapy consisted of 28 days of lenalidomide. Dosing of lenalidomide could be increased to optimize response as per the treating physician's discretion and in accordance with protocol guidelines. If patients did not tolerate higher doses of lenalidomide, dosing was adjusted to the highest tolerated dose. Patients deemed at high risk for thrombotic events could receive aspirin as prophylaxis. Hematopoietic growth factor support was allowed according to ASCO guidelines. Allopurinol (300 mg daily) was administered as tumor lysis prophylaxis on days 1 to 14 of cycle 1. There was no mandated antibacterial or antiviral prophylaxis. Lenalidomide dose was withheld in patients experiencing CTC grade 3 or 4 toxicities, and treatment was restarted at a reduced dose of lenalidomide on resolution of toxicity to grade 2 or lower.
Response assessment was performed using 2008 NCI criteria after the first 3 cycles of therapy and every 6 cycles thereafter. Assessment included physical examination, peripheral blood examination, bone marrow aspirate and biopsy, and lymphocyte immunophenotyping on bone marrow aspirate. CT scans were not routinely performed for response assessment. Flow cytometric assessment of bone marrow aspirate using 3-color (this is less sensitive than other centers use) flow cytometry was performed to estimate MRD by evaluating for CD5+/CD19+ lymphocytes with light-chain restriction.
Treatment was discontinued at disease progression or if patients experienced excessive toxicity. Patients who had stable disease or better after 3 cycles continued on therapy. Trial design recommended discontinuation of therapy if there was no objective evidence of response by 9 cycles of therapy, although this decision was left to treating physician's discretion. Tumor flare was defined as painful acute lymph node enlargement or lymph node enlargement with evidence of local inflammation occurring with initiation or reinitiation of therapy.
The primary endpoint of this study was PFS, which was defined as time from the start of therapy to death or progression of disease. Additional endpoints were OS, CR, and overall response rate (ORR), and nonhematologic toxicity.
The median time from diagnosis of CLL to initiation of therapy was 29 months (range, 1-202 months). The predominant indication for initiation of therapy was rapid lymphocyte doubling time for 26 patients (43%), bulky or progressive adenopathy or splenomegaly for 16 patients (27%), Rai stage III or IV CLL for 13 patients (22%), CLL related B-symptoms for 3 patients (5%), and autoimmune cytopenia for 2 patients (3%).
The median follow-up for all patients was 29 months (range, 1.5-38 months). A median of 27 cycles (range, 1-41 cycles) were administered. The median daily dose was 5 mg with a maximum tolerated dose of 20 mg and minimum dose of 2.5 mg. Lenalidomide daily dose was titrated up to 10 mg in 36 patients (60%) and to 15 mg or more in 8 patients (13%), although only 26 patients (43%) were able to continue on a dose of at least 10 mg for 2 or more cycles of therapy.
By intention to treat, the ORR was 65%, including 6 patients (10%) with CR, 3 patients (5%) with CR with residual cytopenia, 4 patients (7%) with nodular PRs, and 26 patients (43%) with partial response (PR). Four patients achieved a CR with no identifiable CLL clones by bone marrow flow cytometry (negative minimal residual disease). The median time to achievement of a PR or better was 3 months (range, 3-15 months), and the median time to achievement of CR or CR with residual cytopenia was 18 months (range, 9-27 months). Of the patients who received at least 3 cycles of therapy, most improved their response if they could tolerate further treatment.
There was no statistically significant difference in CR or ORR between patients with Rai stage or by prognostic markers, though the numbers were too small to be sure. However there were no responses among the the del 17p group.
ORR and CR rates for patients who tolerated an average dose of at least 5 mg (34 patients, ORR 82% and CR 26%) were significantly higher compared with those who received an average dose of < 5 mg (26 patients, ORR 52% and CR 3%). As a continuous variable, higher average daily dose of lenalidomide during the first 6 cycles was associated with a higher likelihood to achieve an objective response (P < .001) or CR (P = .018). Patients who could tolerate > 5 mg of lenalidomide had higher pretreatment hemoglobin level and were less likely to have 17p deletion.
At a median follow-up of 31 months, 32 patients (53%) remain on therapy with an estimated 2-year PFS of 60% (95% CI, 46%-72%). Responses to lenalidomide appeared durable with continuing therapy. Of 39 patients who achieved at least a PR, 33 patients (85%) have retained or improved their response, 5 patients (13%) have discontinued therapy in continued response because of toxicity or unrelated reasons, and 1 patient (3%) has progressed while on therapy.
PFS was significantly shorter for the 6 patients with deletion of 17p compared with patients with other FISH results (median PFS 6 months vs not reached, P = .002). Patients who experienced a tumor flare reaction of any grade had a longer PFS than patients who did not have a tumor flare reaction (median PFS not reached vs 15 months, P = .03). The average dose of lenalidomide in the first 6 cycles of therapy was also associated with PFS. At last follow-up, only 7 of 34 patients (21%) who tolerated an average dose of 5 mg or more had progressed or died compared with 16 of 26 patients (62%) who received an average dose < 5 mg (P = .003).
88% of patients were alive at a median follow-up of 31 months. Of the patients who achieved a response, 97% were alive and 85% progression-free. 3 patients died > 18 months after starting subsequent therapy after discontinuing treatment because of intolerance after < 1, 1, and 6 cycles. One patient declined further therapy after 2 cycles because of devastating social circumstances and concurrent medical issues and died 1 month later and 1 patient died after development of Richter transformation after 10 months of therapy. Two patients died of unrelated malignancies.
Twenty-eight patients discontinued treatment. Causes for discontinuation of therapy included lack or response or progressive disease (11 patients), lenalidomide intolerance without response (8 patients), lenalidomide intolerance or late adverse events (after 9 cycles of therapy) in patients with a response (4 patients), nonhematologic malignancy (3 patients), and patient preference (2 patients). Among patients intolerant of medication, reasons for discontinuation included rash (3 patients), shortness of breath (1 patient), fatigue (1 patient), infections (1 patient), fevers (1 patient), allergy (1 patient), or diarrhea (1 patient). Late adverse events (after 9 cycles of therapy) included a cerebrovascular accident, a veno-thromboembolic event, and pneumonia.
The most common toxicity was grade 3 or 4 neutropenia, which occurred in 34% of evaluable cycles. The majority of patients (83%) experienced at least one episode of grade 3 or 4 neutropenia. Grade 3 or 4 neutropenia was managed with transient interruption of therapy followed by dose reduction. Other hematologic toxicities were less common, with grade 3 or 4 thrombocytopenia and anemia occurring in only 12% and < 1% of cycles, respectively. Eight patients (13%) experienced at least one severe (grade 3 or 4) infection or neutropenic fever, including one fatal infection. In terms of grade 3 or 4 infections, there were 3 patients with pneumonia (4 episodes), 2 patients (3 episodes) with uncomplicated respiratory tract infections who received intravenous antibiotics because of neutropenia, and 3 patients admitted with febrile neutropenia (including 1 bacteremia episode). Four of the documented infections were associated with grade 3 or 4 neutropenia. Seven of the 9 severe infectious events occurred within the first 9 cycles of . Minor infections were common, with 53% of patients experiencing at least one minor infection during therapy. Minor infections included mostly upper respiratory tract infections, sinus infections, or bronchitis. Grade 1 and 2 nonhematologic or noninfectious toxicities were more common and included fatigue (92% of patients), diarrhea (55%), constipation (55%), rash (48%), and/or pruritus (43%). Grade 1 or 2 tumor flare reactions occurred in 31 (52%) patients, but these were generally mild and tolerated without further therapy (18 patients) or treated with short administration of nonsteroidal anti-inflammatory drugs (5 patients), steroids (9 patients), or dose adjustment of lenalidomide (10 patients). Almost all tumor flare reactions occurred within the first 3 cycles of therapy, with the majority occurring in the cycle. There were no grade 3 or 4 episodes of tumor flare or any tumor lysis in this study.
Serum Ig levels were measured at baseline and during treatment in the 34 patients who completed at least 15 cycles of therapy; 33 of these patients achieved an objective response. An increase in Ig levels across all Ig classes was noted. The rise in IgG and IgA was most pronounced between 3 and 9 cycles of therapy, whereas the rise in IgM occurred by the third cycle of therapy. Sixteen patients had decreased IgG levels (< 700 mg/dL) before therapy. In 8 patients (50%), IgG levels normalized after 15 cycles of therapy, and another 3 patients (19%) demonstrated an increase in IgG of greater than 50% from baseline. The rise in serum Ig levels was durable through therapy.
In the majority of patients, the number of total circulating lymphocytes decreased significantly during the first 3 cycles, which was sustained for the duration of therapy. The absolute number of CD3+ T cells was elevated in the majority of patients before start of therapy and decreased during therapy, 27 of 34 patients (79%) attained normal absolute CD3+ T-cell counts after 15 cycles of therapy. For these patients, T-cell numbers and the proportion of CD4 to CD8 lymphocytes remained within normal limits during treatment. There was no statistically significant association between severe infections and absolute T- or B-cell numbers or subsets in the periphery or in bone marrow before therapy.
CCL4 are chemokines secreted by CLL cells in the lymph node microenvironment in response to B-cell receptor (BCR) activation and can be detected in patient's plasma, where their concentrations predict for disease progression and time to first treatment. There was no correlation between pretreatment CCL3 or CCL4 levels and likelihood of response. Although no significant difference was observed in CCL3 and CCL4 levels after 3 cycles of therapy between responders (PR or CR) and nonresponders, after 9 cycles of therapy responders had significantly lower levels of CCL3 or CCL4 relative to pretreatment.
In this study, median PFS has not been reached after 30 months of follow-up. This duration of response compares favorably with the results of studies of chlorambucil, fludarabine, or alemtuzumab monotherapy that have generally been associated with median PFS of < 2 years. The ORR rate of 65% is similar to published results for monotherapy in elderly untreated patients with CLL, and the 2-year OS rate of 88% is promising in this older patient group. This is not a comparative study; therefore, these results require confirmation with larger phase 3 trials.
Overall, lenalidomide was well tolerated with neutropenia as the most common associated toxicity occurring in 34% of the cycles. Patients with neutropenia had doses withheld and/or reduced; therefore, the rate of neutropenia may have impacted on the exposure to lenalidomide and consequent efficacy. Although the rate of neutropenia was high, neutrophil recovery generally occurred spontaneously after withdrawal of therapy for 7-10 days and the overall rate of febrile neutropenic events was low. The rate of grade 3 or 4 infection was low and decreased in patients who continued therapy.
Prior studies of lenalidomide have reported frequent tumor flare reactions and severe tumor lysis syndrome in patients with CLL. Patients in this study did not experience any severe tumor flare or tumor lysis on this dose regimen. Grade 1 or 2 tumor flare was common and either resolved spontaneously or responded well to simple measures, such as nonsteroidal anti-inflammatory drugs, dose reduction of lenalidomide, or corticosteroids in a minority of patients. The low incidence of severe tumor flare that observed is probably related to the low starting dose of lenalidomide and gradual dose escalation. The development of tumor flare was associated with a higher likelihood of response as suggested by previously published findings in patients with CLL. This finding supports the recommendation to continue therapy with lenalidomide if tumor flare is not severe.
Lenalidomide exposure is associated with reversal of defective ability to form immune synapses between CLL cells and T cells and promotes costimulatory activation of B cells. In this study, an increase in Ig levels during treatment with lenalidomide occurred. This increased production of Igs is an interesting finding, which may be explained by enhanced B-cell costimulatory activity via activation of lymphocytes through phosphoinositide-3-kinase dependent up-regulation of CD154. In addition, a stimulatory effect of lenalidomide on T cells and NK cells has been demonstrated in vitro and in other hematologic malignancies. One study demonstrated up-regulation of costimulatory molecules, such as CD80 on CLL cells associated with T-cell activation after administration of lenalidomide in patients with CLL. The increase in CD80 expression correlated with tumor flare reaction, but the investigators were unable to correlate this with tumor response. NK-cell activation has also been demonstrated in lymphoproliferative disorders and myeloma. This, together with the dynamic changes noted in the repertoire of functional T cells in a subset of patients enrolled in this study, supports the immunomodulatory properties of this class of agents in CLL, similarly observed in other lymphoproliferative disorders after lenalidomide therapy.
Another interesting finding from this study is that responders exhibited a significant decrease in CCL3 and CCL4 levels during lenalidomide therapy compared with nonresponders. These chemokines are secreted by CLL cells after BCR signaling. It has been previously demonstrated that decreasing CCL3 and CLL4 levels are associated with response to therapy after inhibition of the BCR signaling pathway using the phosphoinositide 3′-kinase delta inhibitor CAL-101 or the Bruton tyrosine kinase inhibitor PCI-32765. The increase in CCL3 and CCL4 levels in nonresponders may represent continued activation of CLL cells via BCR signaling pathways, other microenvironmental stimulating pathways, or because of an increased burden of CLL cells. These data should be confirmed by larger studies and suggest that further studies examining combinations of lenalidomide with agents targeting the BCR signaling pathways may be of interest.
This is the best evidence yet that Revlimid is going to be an important player in CLL treatment.
The phoenix burns out
Aldershot's dream has ended. Last night they played Manchester United in the 4th round of the Carling Cup and lost 3-0 with Manchester's goals coming from international players from England, Bulgaria and Ecuador. I remember watching Aldershot draw with Stoke City 1-1 in an FA Cup match about 50 years ago and they lost 3-1 to Manchester United in the Cup in the days of Law, Charlton and Best, but teams then can't compare with those of today.
Aldrrshot went out of business in 1991 and took 16 years to re-establish themselves in the Football League by the device of refounding themselves and entering leagues 5 divisions below teh Football League and gaining successive promotions.
Aldrrshot went out of business in 1991 and took 16 years to re-establish themselves in the Football League by the device of refounding themselves and entering leagues 5 divisions below teh Football League and gaining successive promotions.
Dawkins: cowardice or ignorance
In today's Daily Telegraph Tim Stanley castigates Richard Dawkins for refusing to debate with William Lane Craig over the existance of God. Dawkins has a post at Oxford which obliges him to defend Science against "religion", but he has chickened out of facing William Lane Craig.
Dawkins has been doing a little internet trolling. He has dug up an online debate in which William Lane Craig apparently defends the massacre of a city of heathen Canaanites ordered by God in Deuteronomy 20:13-15. “Listen to Craig,” Dawkins writes, as if imagining Craig were a demon sitting on his shoulder. “He begins by arguing that the Canaanites were debauched and sinful and therefore deserved to be slaughtered. He then notices the plight of the Canaanite children [and concludes] … ‘We are so wedded to an earthly, naturalistic perspective that we forget that those who die are happy to quit this earth for heaven's incomparable joy. Therefore, God does these children no wrong in taking their lives.’” Dawkins writes that he is so disgusted with Craig's thesis that he cannot possibly agree to meet him in person. “Do not plead that I have taken these revolting words out of context," he adds. "What context could possibly justify them?”
Actually, the context is called “Christian apologetics”, and it’s been around for centuries. It's the attempt by scholars to present a rational basis for belief in God. Part of that process is running difficult bits of the Bible past the tests of reason and ethics. To return to the entire post that Dawkins quotes from (because, contrary to what he wrote, context does matter to a serious thinker), Craig begins thus: “These stories offend our moral sensibilities. Ironically, however, our moral sensibilities in the West have been largely, and for many people unconsciously, shaped by our Judaeo-Christian heritage, which has taught us the intrinsic value of human beings, the importance of dealing justly rather than capriciously, and the necessity of the punishment’s fitting the crime. The Bible itself inculcates the values which these stories seem to violate.”
Ergo, Craig’s purpose in writing this piece is to unravel the paradox of a moral Bible that also includes lashings of apparently random violence. Craig stresses that these passages of the Bible are difficult for us to read because we are not of the age in which they are written – they are just as alien to us as Beowulf or the Iliad. That’s because Christian society has been shaped by the rules of life outlined in the New Testament, not in the section of The Bible in which this massacre occurs. Far from using this passage to celebrate the slaughter of heathen, Craig is making the point that the revelation of God’s justice has changed over time. The horrors of the Old Testament have been rendered unnecessary by Christ’s ultimate sacrifice. That’s why the idiots who protest the funerals of gay soldiers or blow up abortion clinics aren’t just cruel, they’re bad theologians.
We are left with two possible conclusions from Richard Dawkin’s flimsy sick note. The first is that he doesn’t understand Christian apologetics, which is why he unintentionally misrepresents Craig’s piece. The most frustrating thing about the New Atheism is that it rarely debates theology on theology's own terms. It approaches metaphor and mysticism as if they were statements of fact to be tested in the laboratory. Worse still, it takes the crudest equations of faith (total submission to an angry sky god) and assumes that they apply to all its believers at all times equally. That most Christians living in the 21st century don’t know who the Canaanites were and only go to church because it brings them an intangible inner peace, totally escapes these atheist pedants.
The second explanation is that Dawkins is a coward. He likes to pick fights either with dunces (like the deliciously silly and obviously gay Ted Haggard) or with incredibly nice old Christians with no fire in their belly (like Rowan Williams). Dawkins has gotten away with his illiterate, angry schtick for so many years because his opponents have been so woolly. This is a damning indictment not only of him, but of the clerical establishment of Great Britain. But this time, he understood that he was up against a pro. In America, evangelicals have to compete in a vibrant, competitive marketplace of different denominations. That breeds the very guile and theatricality that are so sorely lacking among the Anglican clergy. In Craig, Dawkins met his match. Like Jonah, he was confronted by the truth and he ran away.
Dawkins has been doing a little internet trolling. He has dug up an online debate in which William Lane Craig apparently defends the massacre of a city of heathen Canaanites ordered by God in Deuteronomy 20:13-15. “Listen to Craig,” Dawkins writes, as if imagining Craig were a demon sitting on his shoulder. “He begins by arguing that the Canaanites were debauched and sinful and therefore deserved to be slaughtered. He then notices the plight of the Canaanite children [and concludes] … ‘We are so wedded to an earthly, naturalistic perspective that we forget that those who die are happy to quit this earth for heaven's incomparable joy. Therefore, God does these children no wrong in taking their lives.’” Dawkins writes that he is so disgusted with Craig's thesis that he cannot possibly agree to meet him in person. “Do not plead that I have taken these revolting words out of context," he adds. "What context could possibly justify them?”
Actually, the context is called “Christian apologetics”, and it’s been around for centuries. It's the attempt by scholars to present a rational basis for belief in God. Part of that process is running difficult bits of the Bible past the tests of reason and ethics. To return to the entire post that Dawkins quotes from (because, contrary to what he wrote, context does matter to a serious thinker), Craig begins thus: “These stories offend our moral sensibilities. Ironically, however, our moral sensibilities in the West have been largely, and for many people unconsciously, shaped by our Judaeo-Christian heritage, which has taught us the intrinsic value of human beings, the importance of dealing justly rather than capriciously, and the necessity of the punishment’s fitting the crime. The Bible itself inculcates the values which these stories seem to violate.”
Ergo, Craig’s purpose in writing this piece is to unravel the paradox of a moral Bible that also includes lashings of apparently random violence. Craig stresses that these passages of the Bible are difficult for us to read because we are not of the age in which they are written – they are just as alien to us as Beowulf or the Iliad. That’s because Christian society has been shaped by the rules of life outlined in the New Testament, not in the section of The Bible in which this massacre occurs. Far from using this passage to celebrate the slaughter of heathen, Craig is making the point that the revelation of God’s justice has changed over time. The horrors of the Old Testament have been rendered unnecessary by Christ’s ultimate sacrifice. That’s why the idiots who protest the funerals of gay soldiers or blow up abortion clinics aren’t just cruel, they’re bad theologians.
We are left with two possible conclusions from Richard Dawkin’s flimsy sick note. The first is that he doesn’t understand Christian apologetics, which is why he unintentionally misrepresents Craig’s piece. The most frustrating thing about the New Atheism is that it rarely debates theology on theology's own terms. It approaches metaphor and mysticism as if they were statements of fact to be tested in the laboratory. Worse still, it takes the crudest equations of faith (total submission to an angry sky god) and assumes that they apply to all its believers at all times equally. That most Christians living in the 21st century don’t know who the Canaanites were and only go to church because it brings them an intangible inner peace, totally escapes these atheist pedants.
The second explanation is that Dawkins is a coward. He likes to pick fights either with dunces (like the deliciously silly and obviously gay Ted Haggard) or with incredibly nice old Christians with no fire in their belly (like Rowan Williams). Dawkins has gotten away with his illiterate, angry schtick for so many years because his opponents have been so woolly. This is a damning indictment not only of him, but of the clerical establishment of Great Britain. But this time, he understood that he was up against a pro. In America, evangelicals have to compete in a vibrant, competitive marketplace of different denominations. That breeds the very guile and theatricality that are so sorely lacking among the Anglican clergy. In Craig, Dawkins met his match. Like Jonah, he was confronted by the truth and he ran away.
John 7:33-34. Jesus is such a tease
Jesus said, “I am with you for only a short time, and then I am going to the one who sent me. You will look for me, but you will not find me; and where I am, you cannot come.”
Jesus seems given to teasing the Jews. He is clearly refering to where he will be going to after his crucifixion, which we see after the event, but which is opaque to them.
Jesus seems given to teasing the Jews. He is clearly refering to where he will be going to after his crucifixion, which we see after the event, but which is opaque to them.
More on Occupy
Protesters at Occupy London are now complaining about the media attention they are getting. They want a little privacy. Easy to get. Go home.
Tuesday, October 25, 2011
More on Occupy
Apparently the Occupy London lot outside St Paul's Cathedral go home to mummy for a nice cup of hot chocolate now the cold evenings are setting in. Infra-red cameras have shown that 90% of the tents are unoccupied during the early hours. One 'protester' even claimed that he had to go home at night to run his internet business. Some anti-capitalist!
Free speech
Dorset gardener fired 'over anti fox hunting views'
A Dorset man was dismissed from his job at a garden centre because of his anti fox hunting beliefs, an employment tribunal has heard. Joe Hashman, 43, from Shaftesbury was fired from Orchard Park, Gillingham, after he was a witness in two hunting prosecutions, the hearing was told. The centre had told Mr Hashman the vegetable patch he was working was being cut. But he claims he was sacked after clashing with a manager over protests.
Mr Hashman told the Southampton tribunal the owners employed "hunt supporter" Andrew Prater, who he had seen during hunt protests. In July 2009, Mr Hashman was a witness for a prosecution of two landowners charged under the Hunting Act 2004. He wrote about this on his internet blog as well as criticisms of the Gillingham and Shaftesbury Agricultural Show for its "hunting influences".
Mr Prater died in an accident at this show. Mr Hashman was asked not to return to work on the day of the funeral on 3 September 2009, the tribunal heard. Two days previously, he had been a witness for another court case in Scarborough involving the celebrity chef Clarissa Dickson-Wright. Mr Hashman said: "I believe now that my involvement in relation to hunting issues and ultimately my philosophical belief was the reason for my dismissal."
It is just as outrageous for someone to be dismissed for their private views on fox-hunting as it was for someone to be demoted for their private views on gay marriage. What has happened to free speech in this country?
A Dorset man was dismissed from his job at a garden centre because of his anti fox hunting beliefs, an employment tribunal has heard. Joe Hashman, 43, from Shaftesbury was fired from Orchard Park, Gillingham, after he was a witness in two hunting prosecutions, the hearing was told. The centre had told Mr Hashman the vegetable patch he was working was being cut. But he claims he was sacked after clashing with a manager over protests.
Mr Hashman told the Southampton tribunal the owners employed "hunt supporter" Andrew Prater, who he had seen during hunt protests. In July 2009, Mr Hashman was a witness for a prosecution of two landowners charged under the Hunting Act 2004. He wrote about this on his internet blog as well as criticisms of the Gillingham and Shaftesbury Agricultural Show for its "hunting influences".
Mr Prater died in an accident at this show. Mr Hashman was asked not to return to work on the day of the funeral on 3 September 2009, the tribunal heard. Two days previously, he had been a witness for another court case in Scarborough involving the celebrity chef Clarissa Dickson-Wright. Mr Hashman said: "I believe now that my involvement in relation to hunting issues and ultimately my philosophical belief was the reason for my dismissal."
It is just as outrageous for someone to be dismissed for their private views on fox-hunting as it was for someone to be demoted for their private views on gay marriage. What has happened to free speech in this country?
John 7:32. Opposition
The Pharisees heard the crowd whispering such things about him. Then the chief priests and the Pharisees sent temple guards to arrest him.
The pharisees could not act alone. They needed the Saducees and the Elders to unite against their common enemy. There is no doubt that the Jewish opposition to Jesus was united against him as later Pilate and Herod would be. We should not be surprised that Christians are being persecuted by Muslims, Hindus, atheists and secularists. The demands that Jesus makes prick the consciences of those who do not know the grace of God and invoke even violence in their fervent denial of him.
The pharisees could not act alone. They needed the Saducees and the Elders to unite against their common enemy. There is no doubt that the Jewish opposition to Jesus was united against him as later Pilate and Herod would be. We should not be surprised that Christians are being persecuted by Muslims, Hindus, atheists and secularists. The demands that Jesus makes prick the consciences of those who do not know the grace of God and invoke even violence in their fervent denial of him.
Monday, October 24, 2011
Bernard Nathanson
Bernard Nathanson, who died this year, is the only gynaecologist to get it in the neck from both sides of the abortion debate. In the 1960s and 70s he was a passionate advocate of easy abortion. He was first under the spell of his father at New York Women's Hospital and then dominated by passionate pro-abortionist Larry Lader who recruited Nathanson to perform the first large series of suction terminations necessary to cope with the industrial workload.
Nathanson soon became a leading campaigner for the liberalization of abortion laws until the mid 1970s when he found the 'moral whipsaw' of both aborting and delivering babies intolerable. In 1984 after he and a fellow abortionist examined ultrasound tales they had recorded during abortions, neither of them did a single abortion again. Nathanson was seized by a black despair and contemplated suicide. For the first time in his life he began to seriously entertain the notion of God who had led him through the proverbial circles of Hell, only to show him the way to redemption and mercy through his grace.
Nathanson soon became a leading campaigner for the liberalization of abortion laws until the mid 1970s when he found the 'moral whipsaw' of both aborting and delivering babies intolerable. In 1984 after he and a fellow abortionist examined ultrasound tales they had recorded during abortions, neither of them did a single abortion again. Nathanson was seized by a black despair and contemplated suicide. For the first time in his life he began to seriously entertain the notion of God who had led him through the proverbial circles of Hell, only to show him the way to redemption and mercy through his grace.
Vitamin E and cancer
We all think of vitamin supplements as beneficial or at the very least harmless, but a study published in JAMA questions that. Men taking a vitamin E supplement for 7 years were 17% more likely than those taking a placebo to develop cancer. The difference was statistically significant. The trials was looking at whether vitamin E and selenium either together or separately could help prevent prostate cancer, and involved 35,000 healthy middle aged men. There was no impact on the incidence of other cancers, diabetes or cardiovascular events. The supplements did not save lives. Vitamin E may be natural but it is not harmless. The same, of course might be said of snakebite and the GREAT WHITE SHARK.
XMRV and chronic fatigue syndrome
Judy Mikovits, the scientist who discovered the XMRV virus might be linked to the chronic fatigue syndrome (CFS) has be sacked by the Whittemore Peterson Institute in Reno, Nevada. They were investigating allegations of data manipulations. She was dismissed for failing to pass on a cell line to a fellow researcher.
Although her 2009 paper in Science brought new hope to sufferers of CFS that there might be a physical cause for their syndrome, other laboratories have failed to confirm her results and a study last year suggested that samples were contaminated with mouse DNA. On September 22 the authors of the science paper retracted part of the paper. and on the same day Science published a paper from nine separate laboratories including the Reno laboratory which failed to find XMRV in blinded samples.
Now Science is investigating images published with the paper after Abbie Smith, a graduate student blogged that it was suspiciously like an image used by Dr Mikovits in another context in a lecture given in Ottawa last year.
Although her 2009 paper in Science brought new hope to sufferers of CFS that there might be a physical cause for their syndrome, other laboratories have failed to confirm her results and a study last year suggested that samples were contaminated with mouse DNA. On September 22 the authors of the science paper retracted part of the paper. and on the same day Science published a paper from nine separate laboratories including the Reno laboratory which failed to find XMRV in blinded samples.
Now Science is investigating images published with the paper after Abbie Smith, a graduate student blogged that it was suspiciously like an image used by Dr Mikovits in another context in a lecture given in Ottawa last year.
Screening for cancer
To most people it seems sensible that if we can screen for occult disease then we ought to. Strangely, the figures don't add up that way. If it were the case that every occult case of disease would eventually turn up and need to be treated, and if it were the case that there were no false positives picked up by the screening test and if it were the case that none of those false positives came to any harm for being detected, then, no matter the cost, it would be worthwhile to screen for occult disease.
The two areas where the value of screening tests is disputed are breast cancer and prostate cancer.
The problem with mammography for breast cancer is first that the premeonpausal breast is too dense to see cancer in and second that nobody advocates screening for the over-70s when breast cancer is at its most prevalent. Third, many of the precancerous lesions found will never require any treatment during the lady's lifespan. Fourth, there are many false positives. Fifth, managing those false positives cause harm to the patient who at very least has a period of unjustified anxiety but may need a biopsy and in extreme cases a mastectomy.
Time and again the figures have shown that mammography for this population is not wise. It is true that life expectancy for breast cancer has increased since mammography was introduced, but this is also true for the under-50s and over-70s who were not screened. It is most likely due to the introduction of Nolvadex for treatment.
Now the US Preventative Services Task Force has ruled that the PSA blood test should not be used to screen for prostate cancer on the grounds that it does not save lives and can lead to harm. The review concludes, "The widespread US practice of annual PSA-based screening for prostate cancer in men aged 50 years and older is not supported by results from randomized controled trials. PSA-based screening may modestly reduce prostate cancer mortality; but this absolute benefit is small relative to other causes of death in this age group and is associated with substantial harm. The vast majority of men treated for PSA-detected prostate cancer will not have death from prostate cancer prevented but there is convincing evidence that treatment of prostate cancer detected through PSA screening causes at least moderate harm such as erectile dysfunction, urinary incontinence, bowel dysfunction and death.
The two areas where the value of screening tests is disputed are breast cancer and prostate cancer.
The problem with mammography for breast cancer is first that the premeonpausal breast is too dense to see cancer in and second that nobody advocates screening for the over-70s when breast cancer is at its most prevalent. Third, many of the precancerous lesions found will never require any treatment during the lady's lifespan. Fourth, there are many false positives. Fifth, managing those false positives cause harm to the patient who at very least has a period of unjustified anxiety but may need a biopsy and in extreme cases a mastectomy.
Time and again the figures have shown that mammography for this population is not wise. It is true that life expectancy for breast cancer has increased since mammography was introduced, but this is also true for the under-50s and over-70s who were not screened. It is most likely due to the introduction of Nolvadex for treatment.
Now the US Preventative Services Task Force has ruled that the PSA blood test should not be used to screen for prostate cancer on the grounds that it does not save lives and can lead to harm. The review concludes, "The widespread US practice of annual PSA-based screening for prostate cancer in men aged 50 years and older is not supported by results from randomized controled trials. PSA-based screening may modestly reduce prostate cancer mortality; but this absolute benefit is small relative to other causes of death in this age group and is associated with substantial harm. The vast majority of men treated for PSA-detected prostate cancer will not have death from prostate cancer prevented but there is convincing evidence that treatment of prostate cancer detected through PSA screening causes at least moderate harm such as erectile dysfunction, urinary incontinence, bowel dysfunction and death.
Latest on the riots
More figures are coming out about the London riots in August. It appears that gang culture was not the overriding factor with only 1 in 5 convicted being a gang member. One in 7 of all those convicted was born outside the UK.
The biggest factor seems to have been membership of an underclass of criminals with 40% haveing been convicted at least twice before. A third of young people convicted had been excluded (expelled) from school during the previous year. Two thirds of young people had 'special educational needs' though what this means is dubious since one third of all pupils fall into this category.
The biggest factor seems to have been membership of an underclass of criminals with 40% haveing been convicted at least twice before. A third of young people convicted had been excluded (expelled) from school during the previous year. Two thirds of young people had 'special educational needs' though what this means is dubious since one third of all pupils fall into this category.
Joung 7:31. More miraculous.
Still, many in the crowd believed in him. They said, “When the Messiah comes, will he perform more signs than this man?”
There was one more miraculous sign yet to perform. Jesus would die for the sins of the world and be raise again on the third day.
There was one more miraculous sign yet to perform. Jesus would die for the sins of the world and be raise again on the third day.
Saturday, October 22, 2011
miR181a
Also in the Sepember 15th Blood is an article from Ohio on the micro RNA 181a. To remind you, microRNAs are part of the epigentic mechanism for controling which genes are switched on or off. The most prominent micro RNAs have been miR 15 and 16, which are deleted in patients with del 13q14. miR181a has been looked at by Visone et al in a large number of cases of CLL and they have found that levels fall with progression. This is a dynamic marker that is believed to target MCL1 and BCL2. They find evidence in this paper that TCL1 and AID are also targeted. Future treatment might be directed to restoring miR181a levels.
The Lucky generation.
The postwar generation has enjoyed a seemingly unbroken run of good luck, from free university education to the house price boom. Even in retirement their good fortune continues, with many enjoying generous final salary pensions. The facts speak for themselves. More than 80% of the nation's £6.7 trillion in wealth is owned by baby boomers (those born between 1946 and 1964). Collectively, the country owns £2.6 trillion in shares and savings – and those aged 50 to 64 own £1 trillion of this. A third of the £1.8 trillion held in pension funds is owned by this age group (and a further quarter is owned by those aged between 45 and 50). And they own 40% of the £2.5trn tied up in property. In fact, property has been such a staggeringly good investment for this generation that one in five baby boomers owns a second home.
As Will Hutton of the Work Foundation – and a baby boomer himself – pointed out: "Having enjoyed a life of free love, free school meals, free universities, defined benefit pensions, mainly full employment and a 40-year-long housing boom, the baby boomers are bequeathing their children sky-high house prices, debts and shrivelled pensions. A 60 year-old today is a very privileged and lucky human being."
The question is how much we owe to future generations. Having benefited so much from our circumstances, I believe we have a duty to care for our children and our children's children. Which is why I approve of the austerity packages being introduced in Europe and America. To spend even more on our ease and comfort and load the bill (as debt) on future generations seems to me to be wickedly selfish. In particular, our 10-year extra longevity should be paid for by us, not our children and pensions must be adjusted accordingly. Neither should we be 'ski-ing' (spending the kids' inheritance). All that wealth accumulated in property should be passed on.
As Will Hutton of the Work Foundation – and a baby boomer himself – pointed out: "Having enjoyed a life of free love, free school meals, free universities, defined benefit pensions, mainly full employment and a 40-year-long housing boom, the baby boomers are bequeathing their children sky-high house prices, debts and shrivelled pensions. A 60 year-old today is a very privileged and lucky human being."
The question is how much we owe to future generations. Having benefited so much from our circumstances, I believe we have a duty to care for our children and our children's children. Which is why I approve of the austerity packages being introduced in Europe and America. To spend even more on our ease and comfort and load the bill (as debt) on future generations seems to me to be wickedly selfish. In particular, our 10-year extra longevity should be paid for by us, not our children and pensions must be adjusted accordingly. Neither should we be 'ski-ing' (spending the kids' inheritance). All that wealth accumulated in property should be passed on.
Acquired genomic copy number aberrations
We all know by now that TP53 malfunction carries a dreadful prognosis in CLL, but there are relapsed and refractory cases that do not have anything ostensibly wrong with TP53. Is it possible to detect these and being pre-warned direct such patients into more effective treatments?
An attempt has been made in an article in Blood from September 15th. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia.
The limitations of FISH are that it only gives infromation in the areas that are probed for - usually on chromosomes 11, 12, 13 and 17. The group at Ann Arbor have analyzed high-purity DNA isolated from FACS-sorted CD19(+) cells and paired CD3(+) or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays.
Overall, ≥ 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas ≥ 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array-based genomic lesion loads at various thresholds, they identified elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival. The only other marker to show up as of independent significance in the multivariate analysis was IGHV mutational status.
An attempt has been made in an article in Blood from September 15th. Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia.
The limitations of FISH are that it only gives infromation in the areas that are probed for - usually on chromosomes 11, 12, 13 and 17. The group at Ann Arbor have analyzed high-purity DNA isolated from FACS-sorted CD19(+) cells and paired CD3(+) or buccal cells from 255 patients with CLL for acquired genomic copy number aberrations (aCNAs) with the use of ultra-high-density Affymetrix SNP 6.0 arrays.
Overall, ≥ 2 subchromosomal aCNAs were found in 39% (100 of 255) of all cases analyzed, whereas ≥ 3 subchromosomal aCNAs were detected in 20% (50 of 255) of cases. With the use of multivariate analyses incorporating the most important prognostic factors in CLL together with SNP 6.0 array-based genomic lesion loads at various thresholds, they identified elevated CLL genomic complexity as an independent and powerful marker for the identification of patients with aggressive CLL and short survival. The only other marker to show up as of independent significance in the multivariate analysis was IGHV mutational status.
John 7:30. A miraculous escape?
At this they tried to seize him but no-one laid a hand on him because his time had not yet come.
Yet another indication that Jesus was divinely protected during his ministry. The intervention of the supernatural in everyday life is a mystery. We know that it is very unusual but it is impossible to prove a negative. A GP in Southampton, Dr Peter May, has spent a lifetime debunking 'miraculous' cures, but his fellow evangelicals in London have been prosecuted for persuading AIDS sufferers to stop their anti-HIV medicines in favor of prayer. The AIDS patients subsequently died. The church in question was Nigerian with 12000 members with the pastor on £175,000 a year, lots of 'business' interests and four personal jets. Evangelical Christianity covers a multitude of meanings from hypercalvinism to the prosperity gospel.
My attitude to miracles is that they are exceedingly rare or they would not be miracles. We should never rely on them but be grateful if they occur. There is no harm in praying for them, but like St Paul we should rather pray for grace to bear life's hardships.
Yet another indication that Jesus was divinely protected during his ministry. The intervention of the supernatural in everyday life is a mystery. We know that it is very unusual but it is impossible to prove a negative. A GP in Southampton, Dr Peter May, has spent a lifetime debunking 'miraculous' cures, but his fellow evangelicals in London have been prosecuted for persuading AIDS sufferers to stop their anti-HIV medicines in favor of prayer. The AIDS patients subsequently died. The church in question was Nigerian with 12000 members with the pastor on £175,000 a year, lots of 'business' interests and four personal jets. Evangelical Christianity covers a multitude of meanings from hypercalvinism to the prosperity gospel.
My attitude to miracles is that they are exceedingly rare or they would not be miracles. We should never rely on them but be grateful if they occur. There is no harm in praying for them, but like St Paul we should rather pray for grace to bear life's hardships.
Friday, October 21, 2011
Muammar Gaddafi
Muammar Gaddafi is dead and very few people in the world will regret it. Like Saddam Hussain he was found hiding in a hole. Very appropriate.
Some may regret that he wasn't arrested and tried at the Hague, but it makes no practical difference. I suppose the same could be said for Richard III after the Battle of Bosworth Field.
Rebuilding some of these Arab states is going to be difficult, but there is at least plenty of oil money in Libya. Hasn't helped much in Iraq, though.
Some may regret that he wasn't arrested and tried at the Hague, but it makes no practical difference. I suppose the same could be said for Richard III after the Battle of Bosworth Field.
Rebuilding some of these Arab states is going to be difficult, but there is at least plenty of oil money in Libya. Hasn't helped much in Iraq, though.
Occupy
The worldwide "Occupy" movement has its representation in London on the steps of St Paul's Cathedral. The Guardian sent a reporter out to interview them to see what they want. The truth is that they don't know what they want except something different. They are a self-important, self-indulgent, over-privileged groups of spoiled children. A jogger passing by shouted, "Get a job." at them and that is probably an impossibility; who would employ them? But there are probably a large number of refugee camps in Africa who would be glad to have their free labor.
John 7: 28-29. Whose agenda are you following?
Then Jesus, still teaching in the temple courts, cried out, “Yes, you know me, and you know where I am from. I am not here on my own authority, but he who sent me is true. You do not know him, but I know him because I am from him and he sent me.”
Jesus is not content to leave them confused, but spells it out for them. Yes he is the Messaiah; he has come from God the Father and the Jewish authorities do not know God; they are estranged from him.
How many Christians have assumed that they are following God yet in reality have departed from him, follwoing the world's agenda rather than a divine one?
Jesus is not content to leave them confused, but spells it out for them. Yes he is the Messaiah; he has come from God the Father and the Jewish authorities do not know God; they are estranged from him.
How many Christians have assumed that they are following God yet in reality have departed from him, follwoing the world's agenda rather than a divine one?
Thursday, October 20, 2011
Abuse of the law in the UK
I thought I would give my opinions on several instances of the tolerance of lawlessness that have been apparent in Britain lately. We live in a free society where every opportunity is given for citizens to express their dissent. First we live in a parliamentary democracy with universal suffrage for all over the age of 18. Even convicted felons are allowed a vote unless they are actually in prison. In addition citizens of the Irish Republic are allowed to vote in British elections and postal votes are available for those who are away from where they are registered to vote. There is no doubt that the voting system is widely abused, but it is believed that the balance between liberty and oppression is best maintained at this level.
In addition to the vote for both local and national government, the right to make peaceful demonstrations against particular decisions by government is strictly preserved.
The Dale Farm incident
Currently police and bailiffs are removing Irish Travelers from an illegally occupied site in Essex. Polls show that this move is supported by 87% of the general public. This is a dispute that has been going on for ten years. It is complicated. Irish Travelers have been living in the UK for more than 200 years and probably had their origin from the time when they arrived as laborers to build the canals. They have refused to integrate with the general population. They have jumped on the 'race' bandwagon so that racist legislation applies to them and laws introduced by the last Labour government require each local authority to provide sites where they may park their caravans on a temporary bases.
Their lifestyle is not compatible with the modern day. Children do not receive a proper education and healthcare is poor. However, the lifestyle is supplemented by a good deal of criminality and fraud. Generally, Irish travelers make bad neighbors and a lot of illegal squatting occurs leaving local authorities with huge clean-up bills.
The Dale Farm dispute has been going on for 10 years. There is a legitimate site on Dale farm, but in order to extend this the travelers bought some adjacent agricultural land and have set up a further 51 dwellings on it. They paid agricultural prices for land without planning permission and were unable to obtain planning permission for residential properties. Planning permission would have increased the value of the land by at least tenfold.
The travelers do in fact have luxury properties in Ireland but choose to live in Britain largely off state benefits and cash-in-hand laboring jobs for which they pay no income tax. They do this in England because Irish laws have made it impossible for them to do so over there. After 10 years of going through the courts the local authority have finally got permission to break up the travelers' camp and have done this despite the violent opposition of 'rentamob'.
Second example. The streets of central London are overrun with child beggars. These children are of Romanian Gypsy origin and are taking advantage of lax EU legislation which has allowed them into the UK. Begging is illegal in Britain but each of these children who target the Muslim community, are making £300 a day from begging. Romanians are not Muslims but they dress up as if they were. They are virtual slaves and are being run by organized crime families in Romania. These families live in huge villas in Romania and drive luxury cars. They are also being used for child benefit scams. One family was found to have defrauded the British taxpayer of £800,000 in a single year. Under British law these children should be taken into social care and their parents imprisoned, but hardly anything has happened for fear of transgressing laws about racism.
Third example. The streets of Southall in west London have seen a great increase in the construction of garden sheds. These sheds at the bottom people's gardens house up to 6 illegal immigrants who pay exorbitant rents to unscrupulous and criminal landlords. The local councils have a duty to prosecute but are unlikely to do so because the local councillors comprise the very same criminals who own the garden sheds. They think they are fireproof.
These are three examples of where a crazy softness has beset British society. We voted for a conservative government in the hope that these abuses would end. Next time more people will vote for a more Nationalistic government.
In addition to the vote for both local and national government, the right to make peaceful demonstrations against particular decisions by government is strictly preserved.
The Dale Farm incident
Currently police and bailiffs are removing Irish Travelers from an illegally occupied site in Essex. Polls show that this move is supported by 87% of the general public. This is a dispute that has been going on for ten years. It is complicated. Irish Travelers have been living in the UK for more than 200 years and probably had their origin from the time when they arrived as laborers to build the canals. They have refused to integrate with the general population. They have jumped on the 'race' bandwagon so that racist legislation applies to them and laws introduced by the last Labour government require each local authority to provide sites where they may park their caravans on a temporary bases.
Their lifestyle is not compatible with the modern day. Children do not receive a proper education and healthcare is poor. However, the lifestyle is supplemented by a good deal of criminality and fraud. Generally, Irish travelers make bad neighbors and a lot of illegal squatting occurs leaving local authorities with huge clean-up bills.
The Dale Farm dispute has been going on for 10 years. There is a legitimate site on Dale farm, but in order to extend this the travelers bought some adjacent agricultural land and have set up a further 51 dwellings on it. They paid agricultural prices for land without planning permission and were unable to obtain planning permission for residential properties. Planning permission would have increased the value of the land by at least tenfold.
The travelers do in fact have luxury properties in Ireland but choose to live in Britain largely off state benefits and cash-in-hand laboring jobs for which they pay no income tax. They do this in England because Irish laws have made it impossible for them to do so over there. After 10 years of going through the courts the local authority have finally got permission to break up the travelers' camp and have done this despite the violent opposition of 'rentamob'.
Second example. The streets of central London are overrun with child beggars. These children are of Romanian Gypsy origin and are taking advantage of lax EU legislation which has allowed them into the UK. Begging is illegal in Britain but each of these children who target the Muslim community, are making £300 a day from begging. Romanians are not Muslims but they dress up as if they were. They are virtual slaves and are being run by organized crime families in Romania. These families live in huge villas in Romania and drive luxury cars. They are also being used for child benefit scams. One family was found to have defrauded the British taxpayer of £800,000 in a single year. Under British law these children should be taken into social care and their parents imprisoned, but hardly anything has happened for fear of transgressing laws about racism.
Third example. The streets of Southall in west London have seen a great increase in the construction of garden sheds. These sheds at the bottom people's gardens house up to 6 illegal immigrants who pay exorbitant rents to unscrupulous and criminal landlords. The local councils have a duty to prosecute but are unlikely to do so because the local councillors comprise the very same criminals who own the garden sheds. They think they are fireproof.
These are three examples of where a crazy softness has beset British society. We voted for a conservative government in the hope that these abuses would end. Next time more people will vote for a more Nationalistic government.
Does boozing lower immunity?
From today's New Scientist
Alcohol suppresses immune cells, making heavy drinkers more vulnerable to infection
Too much alcohol dulls more than your wits. It also weakens your immune system and could make you more vulnerable to viruses.
Gyongyi Szabo at the University of Massachusetts Medical School in Worcester and colleagues exposed monocytes – white blood cells involved in the defence against infection – to chemicals that mimic viruses and bacteria. Half of the cells were also soused in the levels of alcohol that a person might have in their blood after quaffing four or five alcoholic drinks daily for a week.
When the over-the-limit cells were exposed to a virus mimic, they made only a quarter as much of the virus-fighting signalling molecule type-1 interferon as teetotal monocytes made. Monocytes exposed to alcohol and a bacterial chemical not only made half as much type-1 interferon as their abstemious equivalents, they also overproduced an inflammatory chemical called tumour necrosis factor-alpha that in high volumes can damage tissue.
Alcohol suppresses immune cells, making heavy drinkers more vulnerable to infection
Too much alcohol dulls more than your wits. It also weakens your immune system and could make you more vulnerable to viruses.
Gyongyi Szabo at the University of Massachusetts Medical School in Worcester and colleagues exposed monocytes – white blood cells involved in the defence against infection – to chemicals that mimic viruses and bacteria. Half of the cells were also soused in the levels of alcohol that a person might have in their blood after quaffing four or five alcoholic drinks daily for a week.
When the over-the-limit cells were exposed to a virus mimic, they made only a quarter as much of the virus-fighting signalling molecule type-1 interferon as teetotal monocytes made. Monocytes exposed to alcohol and a bacterial chemical not only made half as much type-1 interferon as their abstemious equivalents, they also overproduced an inflammatory chemical called tumour necrosis factor-alpha that in high volumes can damage tissue.
John 7:25-27. Interpreting prophesy
At that point some of the people of Jerusalem began to ask, “Isn’t this the man they are trying to kill? Here he is, speaking publicly, and they are not saying a word to him. Have the authorities really concluded that he is the Messiah? But we know where this man is from; when the Messiah comes, no one will know where he is from.”
There seems to have been genuine confusion among the people of Jerusalem about Jesus. Were the authorities trying to kill Jesus or not? Had they accepted him as the Messiah? His apparent origin in Nazareth seemed to be against that and he didn't fit with their preconceptions about how the Messiah would appear.
There is a preacher somewhere out west who tells us the world will end on Friday. He's not got a very good track record - he has already been wrong twice. Down through the ages there have been many amateur experts who have tried to interpret Biblical prophesy. I don't try. Prophesy is easy to interpret after the event but I am content that Jesus will return like a thief in the night, so like the wise virgins we must always be ready for the bridegroom.
There seems to have been genuine confusion among the people of Jerusalem about Jesus. Were the authorities trying to kill Jesus or not? Had they accepted him as the Messiah? His apparent origin in Nazareth seemed to be against that and he didn't fit with their preconceptions about how the Messiah would appear.
There is a preacher somewhere out west who tells us the world will end on Friday. He's not got a very good track record - he has already been wrong twice. Down through the ages there have been many amateur experts who have tried to interpret Biblical prophesy. I don't try. Prophesy is easy to interpret after the event but I am content that Jesus will return like a thief in the night, so like the wise virgins we must always be ready for the bridegroom.
Behind the eight ball
On several occasions now I have heard British journalists use the phrase "behind the eight ball" in the sense that someone is so far behind that they are unlikely to succeed in their task. This is the danger of using sports-derived phrases from a different culture.
The phrase almost certainly derives from the game of pool, which although played in the UK is very much a minor game compared with snooker. To be behind the eight ball in pool means that your cue ball is in a very difficult position from which it is next to impossible to escape. The equivalent in snooker would to be snookered.
Journalists, who are my bete noir at the moment, are lazy, poorly educated copycats.
The phrase almost certainly derives from the game of pool, which although played in the UK is very much a minor game compared with snooker. To be behind the eight ball in pool means that your cue ball is in a very difficult position from which it is next to impossible to escape. The equivalent in snooker would to be snookered.
Journalists, who are my bete noir at the moment, are lazy, poorly educated copycats.
Wednesday, October 19, 2011
How are you making out?
The worldwide financial crisis continues. What started as a scam to bundle sub-prime mortgages into packages that were worth less than the sum of their parts has undermined tho investment banks which over the whole world have been bailed out by the taxpayer. It became an illustration of the old saw - If I owe the bank $100 that's my problem: if I owe the bank $100 million that's the bank's problem. The banks were simply too big to be allowed to fail. It turned out that the banks were undercapitalized and in recapitalizing themselves, they could not afford to lend to small businesses. The credit crunch has slowed down the global economy.
In addition it turned out that governments, thinking that the boom could never end, ignored the prudent course of repaying debts when the economy boomed, instead took on yet bigger debts.
In Europe there was an extra dimension. Politicians, keen to deliver a United States of Europe tried to introduce a single currency. Without a uniform fiscal policy there was no way that countries like Greece and Germany could make a once and for all unification of their currencies. Rules were set and rules were broken. Countries, quite frankly, lied about whether they were meeting the conditions. Honest countries like the UK and Scandinavia stayed out of the Euro, dishonest ones like Greece, Portugal, Ireland, Spain and Italy joined. Now when their desperate need is to devalue their currencies they are unable to. The Euro cannot possibly be sustained and the fall of the Euro, which is inevitable is suppressing the markets by about 10%.
My finances have taken that 10% hit, like anybody else's, but paradoxically have benefited by profligate spending of the last Labour government. Healthcare spending has delivered me first rate care for my cancer at no direct cost to me. Education spending has meant that all four children have received an excellent education at no direct cost to me and all are in well paid employment. We have excellent local authority services including weekly refuse collection and waste recycling, a safe environment with excellent policing, good social services and wonderful amenities.
I guess I have been one of the lucky ones.
In addition it turned out that governments, thinking that the boom could never end, ignored the prudent course of repaying debts when the economy boomed, instead took on yet bigger debts.
In Europe there was an extra dimension. Politicians, keen to deliver a United States of Europe tried to introduce a single currency. Without a uniform fiscal policy there was no way that countries like Greece and Germany could make a once and for all unification of their currencies. Rules were set and rules were broken. Countries, quite frankly, lied about whether they were meeting the conditions. Honest countries like the UK and Scandinavia stayed out of the Euro, dishonest ones like Greece, Portugal, Ireland, Spain and Italy joined. Now when their desperate need is to devalue their currencies they are unable to. The Euro cannot possibly be sustained and the fall of the Euro, which is inevitable is suppressing the markets by about 10%.
My finances have taken that 10% hit, like anybody else's, but paradoxically have benefited by profligate spending of the last Labour government. Healthcare spending has delivered me first rate care for my cancer at no direct cost to me. Education spending has meant that all four children have received an excellent education at no direct cost to me and all are in well paid employment. We have excellent local authority services including weekly refuse collection and waste recycling, a safe environment with excellent policing, good social services and wonderful amenities.
I guess I have been one of the lucky ones.
Questions and answers on CD38
To complete this series on CD38, here are some outstanding questions and answers.
Why do the numbers of CD38-expressing cells in a CLL clone predict clinical course?
A definite answer to this question is not available at this point; the following is the view of the authors on this issue. CD38 expression is dynamic and indicates the proliferative activity of members of the leukemic clone at the time of analysis. Therefore, it is a “real-time” indicator of the level of leukemic proliferation and thereby actual or potential clonal evolution, which ultimately determines the clinical course and outcome for an individual patient. This evolutionary change can be affected by many parameters; in particular, it can be influenced by stimulation through cell surface receptors for antigens, cytokines, chemokines, etc, within the microenvironment. Simplistically viewed, the more CD38+ cells in a clone, the greater the number of dividing cells and hence the greater the chance for occurrence of new DNA lesions, enhanced clonal aggressiveness, and worse clinical outcome.
Why and how do the numbers of CD38-expressing cells and IGHV mutation status of a CLL clone interrelate and herald clinical course?
IGHV mutation status is a more static marker, indicative of the cell of origin and the maturational events that occurred in the life of the B cell before its leukemic transformation. In particular, the absence or presence of IGHV mutations could report the ability and type of antigen binding that the BCR can accomplish (eg, polyreactive vs oligoreactive vs monoreactive). Antigen binding specificity correlates with outcome because it indicates the breadth of antigenic epitopes that the BCR can engage, the affinity of these engagements, and therefore the likelihood that survival/proliferation signals will be delivered to the CLL cell. It is for these reasons that CD38 expression, which is a reflection of the existing level of cellular activation within a leukemic clone, often correlates with a lack of IGHV somatic mutations, which is more likely to lead to polyspecific binding, cell signaling, and eventual cellular proliferation. Thus, both prognostic indicators can be linked by the common thread of leukemic cell proliferation: IGHV mutations indicating the likelihood of binding multiple antigens and of cellular stimulation and CD38 expression representing the consequence of such binding and stimulation.
What are the advantages of using CD38 clonal percentages as a prognostic marker?
As mentioned, the number of CD38-expressing cells can be considered a real-time indicator of the proliferative activity of a patient's CLL clone. As such, it is a reflection or harbinger of new genomic lesions, which require DNA replication and subsequently of clonal evolution to a more dangerous leukemic variant.
What are the disadvantages of using CD38 clonal percentages as a prognostic marker?
It has been documented that CD38 levels can change over time. Although this change is usually not large (∼ 10%) and more often than not does not overstep the boundaries that mark “better” or “worse” clinical outcome, it can occur. However, when it does, the suggested downside can be actually viewed as a positive feature of this prognostic indicator as an upward trend in CD38-expressing cells may signal clonal evolution to a more aggressive state. Therefore, serial analyses of the percentage of CD38+ cells, real-time indicators of leukemic cell proliferation, can have an additional advantage of indicating a change in clonal behavior.
Is there a role for CD38 SNP analysis?
The C > G SNP identified in the regulatory region is localized within an E-box and conditions the affinity of E2A binding. The consequence is that G carriers up-regulate CD38 in response to environmental signals with a higher efficiency than CC homozygotes. It would be of interest to test, in a retrospective cohort, whether the C > G SNP affects the stability of CD38 expression over time. The prediction based on in vitro observations would be that G carriers up-regulate CD38 more readily in response to specific external signals and then become CD38+. CC homozygotes, on the other hand, would be less prone to do so. If confirmed, this observation would support the clinical usefulness of identifying the CD38 SNP at diagnosis, with closer monitoring of CD38 expression over time selectively in G carriers. In addition, clinical testing for the G allele, one of the few risk factors for RS transformation, may highlight patients more susceptible to this dangerous event.
How can CD38 expression be best used as a prognostic indicator?
The current National Cancer Institute guidelines recommend that treatment be initiated at disease progression (ie, in patients at Binet stage C or Rai stage III or IV). This strategy is suggested because patients are heterogeneous in clinical course and certain patients never progress, often dying of a different disease, whereas others do progress, at times quite rapidly. Thus, to prevent unnecessary treatment of a large segment of affected persons, a watch-and-wait attitude is chosen and treatment is generally delayed until patients become symptomatic. The disadvantage of this understandably prudent approach is that treatment may come too late for those persons requiring it, when a number of unfavorable cytogenetic lesions have already accumulated in CLL subclones. Therefore, the option of early treatment should be carefully considered if markers were available to precisely predict clinical course and progression to select patients based on real treatment requirement. So far, none of the available predictors alone is sufficiently precise to mandate a change in the present therapeutic strategy. In addition, most of the available studies with marker combinations have been carried out retrospectively and in studies where the precise assessment of the value of CD38 can be hampered by the time of marker determination during the clinical course, perhaps because of change that can occur longitudinally.
Despite these limitations, scoring systems involving a multiplicity of markers (eg, IGHV mutations), CD38 and/or ZAP-70 levels, chromosomal abnormalities, p53 mutations, and serum molecules such as β2-microglobulin, can be effective risk assessors and group stratifiers. The issue of markers is covered by a wide literature. These approaches may require further prospective testing to refine and simplify the methods. At this point, the watch-and-wait strategy should be compared with that of early, potentially aggressive treatments in patients randomized into a formal clinical trial and selected for expression of unfavorable prognostic markers.
Is there a role for CD38 as a therapeutic target?
Targeted immunotherapy with mAbs has become critical for the successful treatment of many forms of cancer. This is exemplified by rituximab, a chimeric anti-CD20 mAb, which has revolutionized the treatment of several B-cell malignancies. The main concern about in vivo use of anti-CD38 mAbs is its widespread expression in multiple cell types and differentiation stages, such as early committed BM precursors, activated T cells, and cells of the innate immune response. Another serious drawback is the presence of CD38 in the brain, pancreas, and retina, although the earliest hematopoietic stem cells do not appear to express CD38. Another potentially useful approach could rely on the use of inhibitors of the enzymatic activities of CD38, even if experience is so far limited.
These intrinsic limits, however, have not prevented the design of models for in vivo applications. In the past, several Abs to human CD38 have been generated that induce killing of neoplastic B-cell lines. Two CD38 mAbs are currently in clinical development: a humanized mAb (SAR650984, http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01084252) and a human mAb (daratumumab). Ongoing clinical trials will determine whether these reagents are effective (alone or in combination) and at the same time safe.
Why do the numbers of CD38-expressing cells in a CLL clone predict clinical course?
A definite answer to this question is not available at this point; the following is the view of the authors on this issue. CD38 expression is dynamic and indicates the proliferative activity of members of the leukemic clone at the time of analysis. Therefore, it is a “real-time” indicator of the level of leukemic proliferation and thereby actual or potential clonal evolution, which ultimately determines the clinical course and outcome for an individual patient. This evolutionary change can be affected by many parameters; in particular, it can be influenced by stimulation through cell surface receptors for antigens, cytokines, chemokines, etc, within the microenvironment. Simplistically viewed, the more CD38+ cells in a clone, the greater the number of dividing cells and hence the greater the chance for occurrence of new DNA lesions, enhanced clonal aggressiveness, and worse clinical outcome.
Why and how do the numbers of CD38-expressing cells and IGHV mutation status of a CLL clone interrelate and herald clinical course?
IGHV mutation status is a more static marker, indicative of the cell of origin and the maturational events that occurred in the life of the B cell before its leukemic transformation. In particular, the absence or presence of IGHV mutations could report the ability and type of antigen binding that the BCR can accomplish (eg, polyreactive vs oligoreactive vs monoreactive). Antigen binding specificity correlates with outcome because it indicates the breadth of antigenic epitopes that the BCR can engage, the affinity of these engagements, and therefore the likelihood that survival/proliferation signals will be delivered to the CLL cell. It is for these reasons that CD38 expression, which is a reflection of the existing level of cellular activation within a leukemic clone, often correlates with a lack of IGHV somatic mutations, which is more likely to lead to polyspecific binding, cell signaling, and eventual cellular proliferation. Thus, both prognostic indicators can be linked by the common thread of leukemic cell proliferation: IGHV mutations indicating the likelihood of binding multiple antigens and of cellular stimulation and CD38 expression representing the consequence of such binding and stimulation.
What are the advantages of using CD38 clonal percentages as a prognostic marker?
As mentioned, the number of CD38-expressing cells can be considered a real-time indicator of the proliferative activity of a patient's CLL clone. As such, it is a reflection or harbinger of new genomic lesions, which require DNA replication and subsequently of clonal evolution to a more dangerous leukemic variant.
What are the disadvantages of using CD38 clonal percentages as a prognostic marker?
It has been documented that CD38 levels can change over time. Although this change is usually not large (∼ 10%) and more often than not does not overstep the boundaries that mark “better” or “worse” clinical outcome, it can occur. However, when it does, the suggested downside can be actually viewed as a positive feature of this prognostic indicator as an upward trend in CD38-expressing cells may signal clonal evolution to a more aggressive state. Therefore, serial analyses of the percentage of CD38+ cells, real-time indicators of leukemic cell proliferation, can have an additional advantage of indicating a change in clonal behavior.
Is there a role for CD38 SNP analysis?
The C > G SNP identified in the regulatory region is localized within an E-box and conditions the affinity of E2A binding. The consequence is that G carriers up-regulate CD38 in response to environmental signals with a higher efficiency than CC homozygotes. It would be of interest to test, in a retrospective cohort, whether the C > G SNP affects the stability of CD38 expression over time. The prediction based on in vitro observations would be that G carriers up-regulate CD38 more readily in response to specific external signals and then become CD38+. CC homozygotes, on the other hand, would be less prone to do so. If confirmed, this observation would support the clinical usefulness of identifying the CD38 SNP at diagnosis, with closer monitoring of CD38 expression over time selectively in G carriers. In addition, clinical testing for the G allele, one of the few risk factors for RS transformation, may highlight patients more susceptible to this dangerous event.
How can CD38 expression be best used as a prognostic indicator?
The current National Cancer Institute guidelines recommend that treatment be initiated at disease progression (ie, in patients at Binet stage C or Rai stage III or IV). This strategy is suggested because patients are heterogeneous in clinical course and certain patients never progress, often dying of a different disease, whereas others do progress, at times quite rapidly. Thus, to prevent unnecessary treatment of a large segment of affected persons, a watch-and-wait attitude is chosen and treatment is generally delayed until patients become symptomatic. The disadvantage of this understandably prudent approach is that treatment may come too late for those persons requiring it, when a number of unfavorable cytogenetic lesions have already accumulated in CLL subclones. Therefore, the option of early treatment should be carefully considered if markers were available to precisely predict clinical course and progression to select patients based on real treatment requirement. So far, none of the available predictors alone is sufficiently precise to mandate a change in the present therapeutic strategy. In addition, most of the available studies with marker combinations have been carried out retrospectively and in studies where the precise assessment of the value of CD38 can be hampered by the time of marker determination during the clinical course, perhaps because of change that can occur longitudinally.
Despite these limitations, scoring systems involving a multiplicity of markers (eg, IGHV mutations), CD38 and/or ZAP-70 levels, chromosomal abnormalities, p53 mutations, and serum molecules such as β2-microglobulin, can be effective risk assessors and group stratifiers. The issue of markers is covered by a wide literature. These approaches may require further prospective testing to refine and simplify the methods. At this point, the watch-and-wait strategy should be compared with that of early, potentially aggressive treatments in patients randomized into a formal clinical trial and selected for expression of unfavorable prognostic markers.
Is there a role for CD38 as a therapeutic target?
Targeted immunotherapy with mAbs has become critical for the successful treatment of many forms of cancer. This is exemplified by rituximab, a chimeric anti-CD20 mAb, which has revolutionized the treatment of several B-cell malignancies. The main concern about in vivo use of anti-CD38 mAbs is its widespread expression in multiple cell types and differentiation stages, such as early committed BM precursors, activated T cells, and cells of the innate immune response. Another serious drawback is the presence of CD38 in the brain, pancreas, and retina, although the earliest hematopoietic stem cells do not appear to express CD38. Another potentially useful approach could rely on the use of inhibitors of the enzymatic activities of CD38, even if experience is so far limited.
These intrinsic limits, however, have not prevented the design of models for in vivo applications. In the past, several Abs to human CD38 have been generated that induce killing of neoplastic B-cell lines. Two CD38 mAbs are currently in clinical development: a humanized mAb (SAR650984, http://clinicaltrialsfeeds.org/clinical-trials/show/NCT01084252) and a human mAb (daratumumab). Ongoing clinical trials will determine whether these reagents are effective (alone or in combination) and at the same time safe.
Italian Guidelines
In its mandate to promote the best hematological care, the Italian Society of Hematology (SIE) and the affiliate societies SIES (Società Italiana di Ematologia Sperimentale) and GITMO (Gruppo Italiano Trapianto di Midollo Osseo) issued guidelines for the management of patients with CLL in 2006. They have now updated these guidelines in Leukemia Research.
Recommendations
In order to plan an optimal clinical management, they recommended that the following information should be obtained at the time of CLL diagnosis: serum lactate dehydrogenase and β2-microglobulin level; imaging of adenomegalies as assessed either by total body computed tomography or by the combination of chest X-ray and abdomen ultrasound; direct Coombs’ test in patients with anemia.
Del [11q], del [17p] and the IgVH mutational profile should be investigated, especially in patients who are eligible for more intensive treatments. In patients with no del [17p], testing of p53 deletions or mutations is recommended.
The indication for treatment initiation includes the presence of at least one of the following features: B symptoms (i.e. fever, sweats, fatigue or weight loss), rapid lymphocyte doubling time, progressive enlargement of lymph nodes or hepatosplenomegaly, obstructive adenopathy, development or worsening of thrombocytopenia or anemia, immune hemolysis or thrombocytopenia not responsive to steroids.
In the clinical practice, the presence of an unfavourable biologic profile is not a reason to start treatment when the disease is in an early stage and clinically stable.
In patients with no treatment indication, a disease monitoring should be made at least every 6 months and should include: physical examination, hematologic evaluation and biochemistry, including serum lactate dehydrogenasis and β2-microglobulin. Patients with a poor prognostic biologic profile or clinical signs of a more aggressive disease should be evaluated more frequently, at least every 3 months. An abdominal ultrasound should be monitored every 6–12 months. Chest X-ray should be evaluated when informative at diagnosis.
Before starting treatment, the following information should be obtained in order to evaluate the more appropriate treatment approach: physical examination, performance status, co-morbidity assessment, peripheral blood count with morphologic examination, when required, bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound.
Treatment Recommendations
In summary, even though superior CR and OR rates were observed across all trials comparing fludarabine with chlorambucil, no advantage in terms of PFS and OS were demonstrated in 2 out of 3 analyzed trials. The panel, concluded that first-line therapy with fludarabine given as a single agent had better benefit/risk profile compared with chlorambucil in younger patients but not in elderly patients where fludarabine was associated with a higher myelotoxicity and no advantage in terms of PFS and OS.
Should fludarabine monotherapy or fludarabine plus cyclophosphamide combination therapy be preferred to chlorambucil monotherapy in first- line therapy for previously untreated CLL patients? Recommendation - Use it, weak positive evidence.
Bendamustine and chlorambucil given as single agents were compared in a RCT including 319 patients with B or C Binet stage. Bendamustine arm yielded a higher OR rate (68% vs. 31%) and CR rate (31% vs. 3%) than chlorambucil arm. Furthermore, the median PFS was superior for bendamustine than chlorambucil arm (21.6 vs. 8.3 months). However, severe infections were more frequently observed in bendamustine than in chlorambucil-treated patients (8% vs. 3%). The strength of evidence was judged weak due to the fact that a single trial could not make consistency of the results possible (weak positive). The EP judged that the benefit of using bendamustine instead of chlorambucil as first line treatment of patients with CLL results in a better clinical benefit/risk ratio.
Should bendamustine be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Use it, weak positive evidence.
Alemtuzumab was compared with chlorambucil in a RCT (CAM307. Patients treated with alemtuzumab obtained a significantly higher CR rate (24.2% vs. 2%) and median PFS (14.6 vs. 11.7 months) than patients treated with chlorambucil. However, serious drug-related AEs were more common in patients treated with alemtuzumab (26.5% vs. 6.8%). The EP deemed a higher activity of alemtuzumab as compared to chlorambucil. However, the EP judged that the benefit of alemtuzumab was offset by an increase in the toxicity.
Should alemtuzumab monotherapy be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Probably don’t use it, weak negative evidence.
Since the publication of the last SIE guidelines in 2006, the results of two RCTs comparing FC combination to fludarabine as single agent have been published. Both studies demonstrated the superiority of FC in terms of CR rate and PFS. Moreover, a meta-analysis performed by Catovsky et al. focused on the published RCTs comparing FC combination versus fludarabine monotherapy confirmed the superiority of FC schedule in terms of PFS. On this basis, the panel judged that the benefit/risk ratio of using FC combination was higher than that proved by fludarabine given as single agent.
Non RCTs evaluated alternative FC schedules and were also discussed by the EP, even though they were not considered for the strength of evidence. Two trials proved the efficacy and safety of the oral FC schedule. In a Spanish study the addition of mitoxantrone to the FC combination resulted in a high response rate (90%).
Should fludarabine-cyclophosphamide combination be preferred to fludarabine monotherapy in first- line therapy for previously untreated CLL patients? Recommendation Probably use it, weak positive evidence.
The efficacy of cladribine as single agent or in combination with other drugs has been investigated by the Polish Adult Leukemia Group. Front-line cladribine-cyclophosphamide-mitoxantrone (CCM) combination was associated with a higher CR rate as compared to cladribine-cyclophosphamide (CC) or cladribine (C) monotherapy. However CCM regimen showed no advantage in terms of PFS and OS and was associated with a higher myelotoxicity. In a more recent RCT including previously untreated patients, no significant differences in the CR rates, PFS, OS and severe AEs were observed between patients treated with CC or FC. Both combinations proved unsatisfactory activity in patients with deletion 17p-. Due to the patient sample size and the short follow-up, the evidence provided by these studies was judged too weak by the EP to formulate a recommendation.
In a open-label randomized trial by the GCLLSG, the activity and safety of FC regimen (409 patients) was compared to that of FC plus rituximab (FCR; 408 patients). The primary end-point of the study was PFS. FCR was more effective than FC in terms of CR rate (44% vs. 22%), PFS (at 3 years: 65% vs. 45%) and OS (at 3 years: 87% vs. 83%). Despite the higher rate of grade 3–4 granulocytopenia, FCR was not associated with a significant increase in the infection rate. In addition, no differences in the health related quality of life were noted between the 2 arms. The presence of deletion 17p- was the strongest unfavourable prognostic variable for both PFS and OS. The evidence derived from this trial was judged of good quality and on this basis, the EP produced a strong positive recommendation in favour of front-line FCR for CLL patients with good physical fitness.
Should Rituximab be added to FC in first- line therapy for previously untreated CLL patients? Recommendation Use it, strong positive evidence.
Treatment options for patients with deletion 17p- and/or p53 mutations were separately discussed. In the study by Hillmen et al., previously untreated patients with deletion 17p- showed a better OR rate with alemtuzumab than with chlorambucil (64 vs. 20%). In a study by Stilgenbauer et al. presented in an abstract form at the 2010 ASH meeting, 25 previously untreated patients with del [17p] showed a very high OR rate (96%) with 24% CR rate after a front-line treatment including alemtuzumab and dexamethasone. In a study by the GIMEMA group presented in an abstract form at the same meeting, fludarabine and alemtuzumab combination (FluCam) was investigated in 43 younger patients with an adverse biologic profile. The CR rate for the 9 patients with del [17p] included in this study was 46%.
Recommendation
Younger CLL patients and selected older patients with a good performance status, no clinically significant co-morbidities and with no deletion 17p-and/or p53 mutations, should receive FCR regimen.
Patients not eligible for FCR regimen should be treated with a less toxic regimen in order to pursue a control of the diseases and a good quality of life, while preserving overall survival. Chlorambucil, bendamustine, fludarabine, cladribine, as single agents, fludarabine or cladribine associated with cyclophosphamide have been tested in RCTs and there is evidence of the efficacy and safety of use. The lack of RCTs, the small sample size or the poor directness of the existing evidence, do not allow to grade alternative treatment options that have demonstrated efficacy and safety such as fludarabine and rituximab schedule, modified FCR regimens (FCR lite, FCR according to Sloan Kettering), pentostatin including regimen (PCR), chlorambucil or bendamustine combined with rituximab.
In patients with del [17p] and/or p53 mutations and active disease the EP agreed that the use of alemtuzumab-based treatments should be preferred. In younger patients with del [17p] and/or p53 mutations, adequate fitness status and no significant co-morbidities, the strategy approach should include an allogeneic SCT.
Monitoring
Patients in clinical CR or PR after therapy should have the following parameters assessed during follow-up: physical examination (every 3–6 months), peripheral blood count (every 3–6 months), imaging of abdomen every 6–12 months.
Minimal residual disease (MRD) assessment performed by any method on bone marrow is not recommended since the eradication of MRD cannot be considered a therapeutic goal for all patients outside clinical trials.
Consolidation
Only one randomized controlled trial tackled the key question of appropriateness of a consolidation therapy in CLL. Patients in CR or PR after fludarabine or FC first-line treatment were randomized to receive alemtuzumab or only clinical observation. The primary endpoint was the PFS. The trial was prematurely stopped after the enrolment of the first 21 patients because of a severe infection rate in the alemtuzumab group. However, the PFS at month 36 after randomization was 81.8% for patients in the alemtuzumab arm vs. 20.6% in the observation arm. On the basis of these results and data derived from a non RCT the EP deemed that at present there was no evidence that patients in CR or PR may benefit from a consolidation treatment and provided the following recommendations: The panel agreed that at present a consolidation/maintenance treatment approach in CLL patients should be undertaken only in the setting of controlled clinical trials.
Relapsed and refractory patients
Robak et al. randomized 552 patients (≤70 years: 83% of patients) who had received one prior line of therapy. Eligible patients were required to be sensitive (55% of patients) or refractory (27% of patients) to prior alkylating agents but had to be sensitive to fludarabine (prior responses ≥6 months; 17% of patients). A prior treatment with interferon, rituximab, other monoclonal antibodies, alkylators/nucleoside analogues combinations or transplantation was not allowed. Patients treated with FCR showed a significantly higher PFS than patients treated with FC (median PFS, FCR vs. FC: 30.6 vs. 20.6 months). The CR rate was also in favour of the FCR group. Of note, both Binet stage B and C patients benefited from FCR, as did patients with high lymphocyte count, poor renal function, poor prognostic factors such as del [11q], unmutated IgVH, positive ZAP-70 while no benefit emerged for patients with del [17p]. Univariate and multivariate Cox regression analyses for PFS confirmed the advantage of FCR over FC. The AEs rate leading to dose modification or treatment interruption were 39% for the FCR group and 51% for the FC group. The evidence was graded as strong and the EP decided that the benefit of using FCR rather than FC in patients relapsed or refractory after single agent therapy overcome the risks.
In order to analyze the effect of the prior therapy on the response to FCR, Badoux et al. explored the efficacy of FCR given to 284 patients beyond first relapse. The overall RR in patients who were previously exposed to a single agent such as rituximab, fludarabine, alkylating agents were 92%, 90%, 78%, respectively, while the response rate of patients previously exposed to fludarabine combined with an alkylating agent was 73%. Patients refractory to fludarabine and those who had received more than three prior therapies, experienced short PFS. Del [17p] was also an adverse factor for PFS. Moreover, elderly patients were less likely to complete more than three courses of FCR, had a lower CR rate and experienced more infectious complications. Taken together these data suggest that FCR is an effective treatment option in relapsed and fit patients without del [17p].
Engert et al. presented at the 2010 ASH meeting the results of a multicentre randomized study including 335 relapsed or refractory patients after one prior regimen that included fludarabine in only 15% of the cases. Patients were randomized to receive fludarabine as single agent or fludarabine and alemtuzumab (FluCam) combination. Patients treated with FluCam showed a better outcome in terms of CR rate (12.5% vs. 4%) and PFS (24 vs. 18 months) with a similar infection rate.
Should R-FC be preferred to FC in previously treated CLL patients? Recommendation Use it, weak positive evidence
Oblimerson
In a RCT including 241 patients with relapsed or refractory CLL after one prior first line fludarabine, patients were randomized to receive FC or FC plus oblimersen. Patients treated with FC-oblimersen showed a better response rate (17% vs. 7%). However, the OS between the 2 groups was not significantly different. The evidence was graded as weak.
Should oblimersen plus fludarabine and cyclophosphamide be preferred to fludarabine and cyclophosphamide in previously treated CLL patients? Recommendation Probably don’t use it, weak negative evidence
Allogeneic stem cell transplantation (SCT)
No prospective RCTs comparing allogeneic SCT to conventional chemotherapy or immunochemotherapy have been carried out in the setting of CLL patients. Phase II studies with a follow-up longer than 2 years were considered by the EP. Among these, the study by Dreger et al. including 90 poor risk CLL patients, ≤65 years, who underwent allogeneic SCT. The CR and overall response rates were 73% and 94%, respectively. The OS, relapse rate and EFS at 4 years were 65%, 40% and 42%, respectively.
Sorror et al. treated 82 patients (median age, 56 years) with fludarabine-refractory CLL with a conditioning regimen including 2 Gy TBI alone or combined with fludarabine followed by an allogeneic SCT from a related (52 patients) or unrelated (30 patients) donor. A CR and a PR were observed in 55% and 15% of patients respectively. After a median follow-up of 5 years, the non transplant related mortality (NTRM), the OS and the PFS were 23%, 50% and 39%, respectively.
A retrospective analysis of the European Blood and Marrow Transplantation Group (EBMTR) included 44 patients (median age, 54 years) with deletion 17 p-. Patients received an allogeneic SCT after a median number of 3 prior treatments. The OS, PFS, and NTRM at 3 years were 44%, 37% and 32%, respectively.
Treatment options for patients refractory to a prior fludarabine-based treatment, patients with early relapse and patients with del [17p] and/or p53 mutations.
In an analysis from the GCLLSG CLL8 trial comparing FC and FCR regimens an inverse relationship between response duration and survival probability has been observed. The median OS of patients with a PFS lower than 12 months (47 patients), between 12 and 24 months (45 patients) or higher than 24 months from the time point of a second-line treatment, were 13.1, 20.3 and 44.6 months, respectively (p< 0.01). These findings indicate that the small subgroup of patients who relapse within 24 months after a fludarabine based treatment is characterized by a very poor prognosis.
Second-line treatment options for this subgroup of patients have been separately discussed. The evidence derived from subgroup analysis of comparative trials carried on relapsed or refractory patients was integrated by the EP with the results of phase II non RCTs. Stilgenbauer et al. reported an OR rate of 34% with a median PFS of 8 months in 103 fludarabine-refractory patients treated with alemtuzumab given as single agent. The OR rate of the 31 patients with del [17p] included in this study was 39% with a median PFS of 6 months. In a study presented in an abstract form at the 2010 ASH meeting by the same Author, alemtuzumab and dexamethasone combination was given to 23 fludarabine-refractory patients and to 12 patients with del [17p] treated in first relapse. The OR rate was 56% for the fludarabine-refractory patients and 75% for the relapsed patients with del [17p].
Recently, a new anti-CD20 monoclonal antibody, ofatumumab has been investigated by Wierda et al. in a non RCT including patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy. The OR rates in the two groups were 58% and 47%, respectively. The median PFS and OS were 5.7 months and 13.7 months, respectively, for the first group, 5.9 and 15.4 months, respectively, for the second group. Survival parameters seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients.
Recommendations
In patients requiring a second-line treatment, del [17p] and/or p53 mutations should be checked. In patients with no del [17p] and/or p53 mutations and relapsed after 24 months, the same front-line therapy including rituximab can be considered.
In patients with del [17p] and/or p53 mutations, in patients refractory or relapsed within 24 months from a fludarabine-based treatment, alemtuzumab containing regimens, or experimental treatment approaches within controlled trials should be given.
Furthermore, in poor prognosis younger patients with adequate fitness status and no significant co-morbidities, a treatment approach including an allogeneic SCT, from either a sibling or well-matched unrelated donor, should be offered after an appropriate cytoreductive treatment.
Recommendations
In order to plan an optimal clinical management, they recommended that the following information should be obtained at the time of CLL diagnosis: serum lactate dehydrogenase and β2-microglobulin level; imaging of adenomegalies as assessed either by total body computed tomography or by the combination of chest X-ray and abdomen ultrasound; direct Coombs’ test in patients with anemia.
Del [11q], del [17p] and the IgVH mutational profile should be investigated, especially in patients who are eligible for more intensive treatments. In patients with no del [17p], testing of p53 deletions or mutations is recommended.
The indication for treatment initiation includes the presence of at least one of the following features: B symptoms (i.e. fever, sweats, fatigue or weight loss), rapid lymphocyte doubling time, progressive enlargement of lymph nodes or hepatosplenomegaly, obstructive adenopathy, development or worsening of thrombocytopenia or anemia, immune hemolysis or thrombocytopenia not responsive to steroids.
In the clinical practice, the presence of an unfavourable biologic profile is not a reason to start treatment when the disease is in an early stage and clinically stable.
In patients with no treatment indication, a disease monitoring should be made at least every 6 months and should include: physical examination, hematologic evaluation and biochemistry, including serum lactate dehydrogenasis and β2-microglobulin. Patients with a poor prognostic biologic profile or clinical signs of a more aggressive disease should be evaluated more frequently, at least every 3 months. An abdominal ultrasound should be monitored every 6–12 months. Chest X-ray should be evaluated when informative at diagnosis.
Before starting treatment, the following information should be obtained in order to evaluate the more appropriate treatment approach: physical examination, performance status, co-morbidity assessment, peripheral blood count with morphologic examination, when required, bone marrow evaluation, serum biochemistry including serum lactate dehydrogenasis and β2-microglobulin, Coombs’ test, imaging of adenomegalies, assessed either by CT scan or by the combination of chest X-ray and abdomen ultrasound.
Treatment Recommendations
In summary, even though superior CR and OR rates were observed across all trials comparing fludarabine with chlorambucil, no advantage in terms of PFS and OS were demonstrated in 2 out of 3 analyzed trials. The panel, concluded that first-line therapy with fludarabine given as a single agent had better benefit/risk profile compared with chlorambucil in younger patients but not in elderly patients where fludarabine was associated with a higher myelotoxicity and no advantage in terms of PFS and OS.
Should fludarabine monotherapy or fludarabine plus cyclophosphamide combination therapy be preferred to chlorambucil monotherapy in first- line therapy for previously untreated CLL patients? Recommendation - Use it, weak positive evidence.
Bendamustine and chlorambucil given as single agents were compared in a RCT including 319 patients with B or C Binet stage. Bendamustine arm yielded a higher OR rate (68% vs. 31%) and CR rate (31% vs. 3%) than chlorambucil arm. Furthermore, the median PFS was superior for bendamustine than chlorambucil arm (21.6 vs. 8.3 months). However, severe infections were more frequently observed in bendamustine than in chlorambucil-treated patients (8% vs. 3%). The strength of evidence was judged weak due to the fact that a single trial could not make consistency of the results possible (weak positive). The EP judged that the benefit of using bendamustine instead of chlorambucil as first line treatment of patients with CLL results in a better clinical benefit/risk ratio.
Should bendamustine be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Use it, weak positive evidence.
Alemtuzumab was compared with chlorambucil in a RCT (CAM307. Patients treated with alemtuzumab obtained a significantly higher CR rate (24.2% vs. 2%) and median PFS (14.6 vs. 11.7 months) than patients treated with chlorambucil. However, serious drug-related AEs were more common in patients treated with alemtuzumab (26.5% vs. 6.8%). The EP deemed a higher activity of alemtuzumab as compared to chlorambucil. However, the EP judged that the benefit of alemtuzumab was offset by an increase in the toxicity.
Should alemtuzumab monotherapy be preferred to chlorambucil in first-line therapy for previously untreated CLL patients? Recommendation Probably don’t use it, weak negative evidence.
Since the publication of the last SIE guidelines in 2006, the results of two RCTs comparing FC combination to fludarabine as single agent have been published. Both studies demonstrated the superiority of FC in terms of CR rate and PFS. Moreover, a meta-analysis performed by Catovsky et al. focused on the published RCTs comparing FC combination versus fludarabine monotherapy confirmed the superiority of FC schedule in terms of PFS. On this basis, the panel judged that the benefit/risk ratio of using FC combination was higher than that proved by fludarabine given as single agent.
Non RCTs evaluated alternative FC schedules and were also discussed by the EP, even though they were not considered for the strength of evidence. Two trials proved the efficacy and safety of the oral FC schedule. In a Spanish study the addition of mitoxantrone to the FC combination resulted in a high response rate (90%).
Should fludarabine-cyclophosphamide combination be preferred to fludarabine monotherapy in first- line therapy for previously untreated CLL patients? Recommendation Probably use it, weak positive evidence.
The efficacy of cladribine as single agent or in combination with other drugs has been investigated by the Polish Adult Leukemia Group. Front-line cladribine-cyclophosphamide-mitoxantrone (CCM) combination was associated with a higher CR rate as compared to cladribine-cyclophosphamide (CC) or cladribine (C) monotherapy. However CCM regimen showed no advantage in terms of PFS and OS and was associated with a higher myelotoxicity. In a more recent RCT including previously untreated patients, no significant differences in the CR rates, PFS, OS and severe AEs were observed between patients treated with CC or FC. Both combinations proved unsatisfactory activity in patients with deletion 17p-. Due to the patient sample size and the short follow-up, the evidence provided by these studies was judged too weak by the EP to formulate a recommendation.
In a open-label randomized trial by the GCLLSG, the activity and safety of FC regimen (409 patients) was compared to that of FC plus rituximab (FCR; 408 patients). The primary end-point of the study was PFS. FCR was more effective than FC in terms of CR rate (44% vs. 22%), PFS (at 3 years: 65% vs. 45%) and OS (at 3 years: 87% vs. 83%). Despite the higher rate of grade 3–4 granulocytopenia, FCR was not associated with a significant increase in the infection rate. In addition, no differences in the health related quality of life were noted between the 2 arms. The presence of deletion 17p- was the strongest unfavourable prognostic variable for both PFS and OS. The evidence derived from this trial was judged of good quality and on this basis, the EP produced a strong positive recommendation in favour of front-line FCR for CLL patients with good physical fitness.
Should Rituximab be added to FC in first- line therapy for previously untreated CLL patients? Recommendation Use it, strong positive evidence.
Treatment options for patients with deletion 17p- and/or p53 mutations were separately discussed. In the study by Hillmen et al., previously untreated patients with deletion 17p- showed a better OR rate with alemtuzumab than with chlorambucil (64 vs. 20%). In a study by Stilgenbauer et al. presented in an abstract form at the 2010 ASH meeting, 25 previously untreated patients with del [17p] showed a very high OR rate (96%) with 24% CR rate after a front-line treatment including alemtuzumab and dexamethasone. In a study by the GIMEMA group presented in an abstract form at the same meeting, fludarabine and alemtuzumab combination (FluCam) was investigated in 43 younger patients with an adverse biologic profile. The CR rate for the 9 patients with del [17p] included in this study was 46%.
Recommendation
Younger CLL patients and selected older patients with a good performance status, no clinically significant co-morbidities and with no deletion 17p-and/or p53 mutations, should receive FCR regimen.
Patients not eligible for FCR regimen should be treated with a less toxic regimen in order to pursue a control of the diseases and a good quality of life, while preserving overall survival. Chlorambucil, bendamustine, fludarabine, cladribine, as single agents, fludarabine or cladribine associated with cyclophosphamide have been tested in RCTs and there is evidence of the efficacy and safety of use. The lack of RCTs, the small sample size or the poor directness of the existing evidence, do not allow to grade alternative treatment options that have demonstrated efficacy and safety such as fludarabine and rituximab schedule, modified FCR regimens (FCR lite, FCR according to Sloan Kettering), pentostatin including regimen (PCR), chlorambucil or bendamustine combined with rituximab.
In patients with del [17p] and/or p53 mutations and active disease the EP agreed that the use of alemtuzumab-based treatments should be preferred. In younger patients with del [17p] and/or p53 mutations, adequate fitness status and no significant co-morbidities, the strategy approach should include an allogeneic SCT.
Monitoring
Patients in clinical CR or PR after therapy should have the following parameters assessed during follow-up: physical examination (every 3–6 months), peripheral blood count (every 3–6 months), imaging of abdomen every 6–12 months.
Minimal residual disease (MRD) assessment performed by any method on bone marrow is not recommended since the eradication of MRD cannot be considered a therapeutic goal for all patients outside clinical trials.
Consolidation
Only one randomized controlled trial tackled the key question of appropriateness of a consolidation therapy in CLL. Patients in CR or PR after fludarabine or FC first-line treatment were randomized to receive alemtuzumab or only clinical observation. The primary endpoint was the PFS. The trial was prematurely stopped after the enrolment of the first 21 patients because of a severe infection rate in the alemtuzumab group. However, the PFS at month 36 after randomization was 81.8% for patients in the alemtuzumab arm vs. 20.6% in the observation arm. On the basis of these results and data derived from a non RCT the EP deemed that at present there was no evidence that patients in CR or PR may benefit from a consolidation treatment and provided the following recommendations: The panel agreed that at present a consolidation/maintenance treatment approach in CLL patients should be undertaken only in the setting of controlled clinical trials.
Relapsed and refractory patients
Robak et al. randomized 552 patients (≤70 years: 83% of patients) who had received one prior line of therapy. Eligible patients were required to be sensitive (55% of patients) or refractory (27% of patients) to prior alkylating agents but had to be sensitive to fludarabine (prior responses ≥6 months; 17% of patients). A prior treatment with interferon, rituximab, other monoclonal antibodies, alkylators/nucleoside analogues combinations or transplantation was not allowed. Patients treated with FCR showed a significantly higher PFS than patients treated with FC (median PFS, FCR vs. FC: 30.6 vs. 20.6 months). The CR rate was also in favour of the FCR group. Of note, both Binet stage B and C patients benefited from FCR, as did patients with high lymphocyte count, poor renal function, poor prognostic factors such as del [11q], unmutated IgVH, positive ZAP-70 while no benefit emerged for patients with del [17p]. Univariate and multivariate Cox regression analyses for PFS confirmed the advantage of FCR over FC. The AEs rate leading to dose modification or treatment interruption were 39% for the FCR group and 51% for the FC group. The evidence was graded as strong and the EP decided that the benefit of using FCR rather than FC in patients relapsed or refractory after single agent therapy overcome the risks.
In order to analyze the effect of the prior therapy on the response to FCR, Badoux et al. explored the efficacy of FCR given to 284 patients beyond first relapse. The overall RR in patients who were previously exposed to a single agent such as rituximab, fludarabine, alkylating agents were 92%, 90%, 78%, respectively, while the response rate of patients previously exposed to fludarabine combined with an alkylating agent was 73%. Patients refractory to fludarabine and those who had received more than three prior therapies, experienced short PFS. Del [17p] was also an adverse factor for PFS. Moreover, elderly patients were less likely to complete more than three courses of FCR, had a lower CR rate and experienced more infectious complications. Taken together these data suggest that FCR is an effective treatment option in relapsed and fit patients without del [17p].
Engert et al. presented at the 2010 ASH meeting the results of a multicentre randomized study including 335 relapsed or refractory patients after one prior regimen that included fludarabine in only 15% of the cases. Patients were randomized to receive fludarabine as single agent or fludarabine and alemtuzumab (FluCam) combination. Patients treated with FluCam showed a better outcome in terms of CR rate (12.5% vs. 4%) and PFS (24 vs. 18 months) with a similar infection rate.
Should R-FC be preferred to FC in previously treated CLL patients? Recommendation Use it, weak positive evidence
Oblimerson
In a RCT including 241 patients with relapsed or refractory CLL after one prior first line fludarabine, patients were randomized to receive FC or FC plus oblimersen. Patients treated with FC-oblimersen showed a better response rate (17% vs. 7%). However, the OS between the 2 groups was not significantly different. The evidence was graded as weak.
Should oblimersen plus fludarabine and cyclophosphamide be preferred to fludarabine and cyclophosphamide in previously treated CLL patients? Recommendation Probably don’t use it, weak negative evidence
Allogeneic stem cell transplantation (SCT)
No prospective RCTs comparing allogeneic SCT to conventional chemotherapy or immunochemotherapy have been carried out in the setting of CLL patients. Phase II studies with a follow-up longer than 2 years were considered by the EP. Among these, the study by Dreger et al. including 90 poor risk CLL patients, ≤65 years, who underwent allogeneic SCT. The CR and overall response rates were 73% and 94%, respectively. The OS, relapse rate and EFS at 4 years were 65%, 40% and 42%, respectively.
Sorror et al. treated 82 patients (median age, 56 years) with fludarabine-refractory CLL with a conditioning regimen including 2 Gy TBI alone or combined with fludarabine followed by an allogeneic SCT from a related (52 patients) or unrelated (30 patients) donor. A CR and a PR were observed in 55% and 15% of patients respectively. After a median follow-up of 5 years, the non transplant related mortality (NTRM), the OS and the PFS were 23%, 50% and 39%, respectively.
A retrospective analysis of the European Blood and Marrow Transplantation Group (EBMTR) included 44 patients (median age, 54 years) with deletion 17 p-. Patients received an allogeneic SCT after a median number of 3 prior treatments. The OS, PFS, and NTRM at 3 years were 44%, 37% and 32%, respectively.
Treatment options for patients refractory to a prior fludarabine-based treatment, patients with early relapse and patients with del [17p] and/or p53 mutations.
In an analysis from the GCLLSG CLL8 trial comparing FC and FCR regimens an inverse relationship between response duration and survival probability has been observed. The median OS of patients with a PFS lower than 12 months (47 patients), between 12 and 24 months (45 patients) or higher than 24 months from the time point of a second-line treatment, were 13.1, 20.3 and 44.6 months, respectively (p< 0.01). These findings indicate that the small subgroup of patients who relapse within 24 months after a fludarabine based treatment is characterized by a very poor prognosis.
Second-line treatment options for this subgroup of patients have been separately discussed. The evidence derived from subgroup analysis of comparative trials carried on relapsed or refractory patients was integrated by the EP with the results of phase II non RCTs. Stilgenbauer et al. reported an OR rate of 34% with a median PFS of 8 months in 103 fludarabine-refractory patients treated with alemtuzumab given as single agent. The OR rate of the 31 patients with del [17p] included in this study was 39% with a median PFS of 6 months. In a study presented in an abstract form at the 2010 ASH meeting by the same Author, alemtuzumab and dexamethasone combination was given to 23 fludarabine-refractory patients and to 12 patients with del [17p] treated in first relapse. The OR rate was 56% for the fludarabine-refractory patients and 75% for the relapsed patients with del [17p].
Recently, a new anti-CD20 monoclonal antibody, ofatumumab has been investigated by Wierda et al. in a non RCT including patients with CLL refractory to both fludarabine and alemtuzumab or refractory to fludarabine with bulky lymphadenopathy. The OR rates in the two groups were 58% and 47%, respectively. The median PFS and OS were 5.7 months and 13.7 months, respectively, for the first group, 5.9 and 15.4 months, respectively, for the second group. Survival parameters seemed to be higher than those reported from a historical assessment of other salvage therapies in a corresponding group of patients.
Recommendations
In patients requiring a second-line treatment, del [17p] and/or p53 mutations should be checked. In patients with no del [17p] and/or p53 mutations and relapsed after 24 months, the same front-line therapy including rituximab can be considered.
In patients with del [17p] and/or p53 mutations, in patients refractory or relapsed within 24 months from a fludarabine-based treatment, alemtuzumab containing regimens, or experimental treatment approaches within controlled trials should be given.
Furthermore, in poor prognosis younger patients with adequate fitness status and no significant co-morbidities, a treatment approach including an allogeneic SCT, from either a sibling or well-matched unrelated donor, should be offered after an appropriate cytoreductive treatment.
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