In a meeting in London yesterday listening to the young men argue and thinking, "What do they know?" I was shocked to find that they were over 50. When I was younger I wrote a short poem:
It will rain soon,
The wind has dropped a bit
And it is colder.
Fingering through
Anold notebook I find
That I am older.
It is supposed to say we get so involved in the things going on around us that we don't notice time passing.
The David Bowie song "Life on Mars"
And she's hooked to the silver screen,
But the film is sadd'ning bore
For she's lived it ten times or more.
She could spit in the eyes of fools
As they ask her to focus on
Sailors
Fighting in the dance hall.
Oh man!Look at those cavemen go.
It's the freakiest show.
Take a look at the lawman
Beating up the wrong guy.
Oh man!Wonder if he'll ever know
He's in the best selling show.
Is there life on Mars?
has given its name to a new TV show that is being remade for the American market.
A 21st Century detective has a car accident and wakes up to find himself back in 1973, complete with flares, crimpeline suits and police brutality. He's called Sam Tyler. The show is made by BBC Wales who have made the latest incarnation of Dr Who, whose young companion is Rose Tyler. Wat Tyler, was of course the leader of the Peasants Revolt against the Poll tax in 1381 in the reign of Richard the Second and was murdered by tthe Lord Mayor of London. Tyler became a symbol of the resurgence of ultra-left-wing political parties in the early 1990s in opposition to Margaret Thatchers's Poll Tax - itself mor properly named Community Charge, and attempt to address the unfairness of Household Rates, a local property tax levied on the size of the house, which were thought to be unfair to elderly pensioners living alone in large family houses without the income to sustain it.
In 1973 Watergate was simmering, the oil crisis was tempting Nixon to invade Iraq, the Tory government was being treatened by a sex scandal, and the miners were about to go on strike, Israel and the Arabs were at war, the Troubles were well under way in Northern ireland. The Left were rampant - old Labor would be elected for the last time in 1974.
Back in 1973 Sam finds himself at odds with policing style. Racism, sexism, no concern for the chain of evidence, institutionalised minor corruption ; confessions were obtained by beating up the suspect. It harks back to John Thaw's precious incarnation as Regan in The Sweeney (Cockney rhyming slang - Sweeney Todd = Flying Squad), even to the use of a Mark III Ford Cortina 2000E (though it falsely badged as a GXL). Rather than London, this crime drama is set in Manchester and even if they get a few things anachronistically wrong, they capture the atmosphere of the seventies. Much is made of the different attitude of then and now. Remember when all women were good for in the work place were to make the tea? When you could pinch a woman's bottom and she took it a compliment? When a black man would respond to a racist remark with a self-effacing joke to show he was one of the lads? When it was normal and expected for a police officer to receive free food and drinks from local businesses and even free sexual favors from prostitutes? Well, none of that was in my own experience, but it makes a nice contrast with the policing of today.
So we have the conflict of policing then and now, cultural attitudes then and now, fashion, then and now, pop music then and now (apart from Bowie it was Wings and the Who). Some viewers have been put off by the SciFi element. Is this time travel? Or is he dreaming while in a coma after his accident? Or is he really in 1973 and mad?
One of the things you do in the past is look up your mum and dad. Tyler's dad disappeared when he was a young boy. One episode concerns his search for his father. Interestingly, the name of Tyler's boss in 1973, the brutal chief inspector who beats up suspects, is Gene Hunt. (Incidentally, boss is right. TV police shows often have subordinates calling their superiors 'guv', but this was a London term. In Manchester in 1973 superiors were called 'boss')
If you haven't seen Life on Mars I recommend it. There will be only 16 episodes. The second and final series has just begun broadcasting. It is on BBC America and an American version of the concept is in pre-production.
Santayana said, "Those who cannot remember the past are condemned to repeat it."
Harold Wilson, leader of old Labor, swept to victory in the General Election of 1974, but retired in 1976 at the age of 60. Shortly afterwards he began showing the signs of Alzheimer's disease and withdrew from public life. He was buried in 1995, perhaps appropriately, on the Isles of Scilly. His family motto is Tempus Imperator Rerum (Time Commands All Things).
Thursday, February 22, 2007
Sunday, February 18, 2007
Psalm 99
Psalm 99 is an evocation of the character of God. It begins, "The LORD reigns."
This a something we seldom remember. Or we think of reigning as something the Queen of England does - a constitutional monarch who holds the ring, chairs the meetings, symbolizes the nation, but who has no power - or even as an American President who has power but must govern with consent. Our God is an absolute monarch. "Let the nations tremble; let the earth shake." He is a God to be held in awe. Remember CS Lewis description of Aslan. "Is he safe? No, He is not safe; but He is good." Our God is a Sovereign God. Not some trumped up despot who imagines he is a sovereign. Remember when Britain introduced the pound coin and it was nicknamed a thatcher. Because it was small and brassy and thought it was a sovereign. Our God really does control the Universe. He is eternal (Ps 90v2), omnipresent (Jer 23:24), unchanging (James 1:17), omniscient (1 John 33:20) and all powerful (Rev 19:1).
And He is not just a local god. (v2) "Great is the Lord in Zion" but "He is exalted above the nations." Last week at the BAFTAs the film editor Anne V Coates who edited Lawrence of Arabia and Becket, but also the new James Bond, Casino Royale, finished her thank you speech with the words, "May whatever god you worship bless you." As if there were gods to choose from. He is supreme. There is only one God. He is God of all the earth.
And He is holy (v3). Holiness is one of those words that has no context for the non-believer. Just as 'hepcidin' has no context except for hematologists. We have 'Holy Joes', guys into more religion than is good for them, but few could say what the difference between 'holy' and 'religious'. Holy first means separate; utterly other; not like us. But that could apply to any old alien that Captain Kirk would meet. It also means superior; above us. It means perfect; without flaw; spotless; unblemished. This is our God - perfect, unblemished, beyond our reach, superior, above us, unreachable, holy.
He loves justice (v4). Not only loves it but is empowered to put it into practice. "You have established equity". Inbuilt in us is a sense of fairness. How we complain when a referee misses an obvious penalty. Around a soccer pitch are 24 TV cameras viewing the match from every angle to spot the merest infringement; how can the referee compete? But our God sees everything, understands everything, knows every motive. As Abraham says when bargaining with God over Sodom, "Shall not the God of all the earth do right?" Yet we challenge his justice. We are unwilling to accept His decisions. As if the God of all the world was there for our comfort. Do we not realise who He is?
He is a wise God. His were the statutes and decrees that Moses kept (v7). From the microscopic to the telescopic he has created the universe (Ps 40:5; 104:25; Jer 51:15). His understanding is better than ours. The foolishness of God is greater than the wisdom of man. It is not a passive wisdom, but wisdom with a purpose (Eph 3:10-11). His purpose is that we should come and love Him and to this end he has made a way back to Him from the dark paths of sin.
He ia a loving God (v8). It was not because of any quality that we have that he loves us. He loves us because that is his character. While we were yet sinners He loved us, and sent his son to die for us (Rom 5:8). God is love, not a warm wishy-washy feeling that pervades the universe, but tough love, costly love, sacrificing love, saving love. Only when we perceive God's holiness and his justice can we recognize his love for what it is.
He is a Fatherly God. (v8) He certainly loves His children, but he 'punishes their misdeeds'. His purpose is that they should be holy as he is holy and like a father he applies loving corrective discipline. He will not spoil his child. "No discipline seems pleasant at the time, but painful,. Later on, however, it produces a harvest of righteousness and peace." (Heb 12:11) Yet this awesome holy God invites us to call Him 'abba': 'daddy'.
Our response to this awesome God? 'Let us praise you gtreat and awesome name' (v3). 'Exalt the LORD our God and worship at his footstall' (v5). 'Exalt the LORD our God and worship at his holy mountain' (v9).
This a something we seldom remember. Or we think of reigning as something the Queen of England does - a constitutional monarch who holds the ring, chairs the meetings, symbolizes the nation, but who has no power - or even as an American President who has power but must govern with consent. Our God is an absolute monarch. "Let the nations tremble; let the earth shake." He is a God to be held in awe. Remember CS Lewis description of Aslan. "Is he safe? No, He is not safe; but He is good." Our God is a Sovereign God. Not some trumped up despot who imagines he is a sovereign. Remember when Britain introduced the pound coin and it was nicknamed a thatcher. Because it was small and brassy and thought it was a sovereign. Our God really does control the Universe. He is eternal (Ps 90v2), omnipresent (Jer 23:24), unchanging (James 1:17), omniscient (1 John 33:20) and all powerful (Rev 19:1).
And He is not just a local god. (v2) "Great is the Lord in Zion" but "He is exalted above the nations." Last week at the BAFTAs the film editor Anne V Coates who edited Lawrence of Arabia and Becket, but also the new James Bond, Casino Royale, finished her thank you speech with the words, "May whatever god you worship bless you." As if there were gods to choose from. He is supreme. There is only one God. He is God of all the earth.
And He is holy (v3). Holiness is one of those words that has no context for the non-believer. Just as 'hepcidin' has no context except for hematologists. We have 'Holy Joes', guys into more religion than is good for them, but few could say what the difference between 'holy' and 'religious'. Holy first means separate; utterly other; not like us. But that could apply to any old alien that Captain Kirk would meet. It also means superior; above us. It means perfect; without flaw; spotless; unblemished. This is our God - perfect, unblemished, beyond our reach, superior, above us, unreachable, holy.
He loves justice (v4). Not only loves it but is empowered to put it into practice. "You have established equity". Inbuilt in us is a sense of fairness. How we complain when a referee misses an obvious penalty. Around a soccer pitch are 24 TV cameras viewing the match from every angle to spot the merest infringement; how can the referee compete? But our God sees everything, understands everything, knows every motive. As Abraham says when bargaining with God over Sodom, "Shall not the God of all the earth do right?" Yet we challenge his justice. We are unwilling to accept His decisions. As if the God of all the world was there for our comfort. Do we not realise who He is?
He is a wise God. His were the statutes and decrees that Moses kept (v7). From the microscopic to the telescopic he has created the universe (Ps 40:5; 104:25; Jer 51:15). His understanding is better than ours. The foolishness of God is greater than the wisdom of man. It is not a passive wisdom, but wisdom with a purpose (Eph 3:10-11). His purpose is that we should come and love Him and to this end he has made a way back to Him from the dark paths of sin.
He ia a loving God (v8). It was not because of any quality that we have that he loves us. He loves us because that is his character. While we were yet sinners He loved us, and sent his son to die for us (Rom 5:8). God is love, not a warm wishy-washy feeling that pervades the universe, but tough love, costly love, sacrificing love, saving love. Only when we perceive God's holiness and his justice can we recognize his love for what it is.
He is a Fatherly God. (v8) He certainly loves His children, but he 'punishes their misdeeds'. His purpose is that they should be holy as he is holy and like a father he applies loving corrective discipline. He will not spoil his child. "No discipline seems pleasant at the time, but painful,. Later on, however, it produces a harvest of righteousness and peace." (Heb 12:11) Yet this awesome holy God invites us to call Him 'abba': 'daddy'.
Our response to this awesome God? 'Let us praise you gtreat and awesome name' (v3). 'Exalt the LORD our God and worship at his footstall' (v5). 'Exalt the LORD our God and worship at his holy mountain' (v9).
Saturday, February 17, 2007
Health Care and the Uninsured
An interesting article by Karen Davis (President of the Commonwealth Fund; Head of Health Policy at the US Department of Health 1977-91) has appeared in the BMJ (17th February 2007 334:246-8) concerning the "uninsured" in America. It is a condensation of her 2006 Presidential address. I have seen figures of 30% or even 40% of Americans being not covered by health insurance. How true is this?
Strictly speaking there is 41% of the population who don't have health insurance: 54% have employer-based insurance and 5% individual insurance. But on top of that 12% are covered by the Federal Medicare program for those over 65 and those who have been disabled for 2 years or more. Then 13% are covered by State Medicaid programs, mainly children of low income families and in some cases their parents, as well as some long-term care programs, and some interaction with Medicare for low-income families. This leaves some 16% of the population without any cover, around 47 million people - about the same as the population of England and Wales.
Despite this, the United States spends far more on health per head of population than any other country - around $6100. In contrast Britain spends $2500, Australia $2800, Germany $3000, France and Canada $3100.
What does America get for the extra money? The 5 year survival for breast cancer in nearer 90% than the 80% that other countries achieve, but the life expectancy at the age of 60 is a year or two less than in most other countries, and whereas in most countries around 90% survive for 30 days after a heart attack, in the US it is closer to 85%.
I don't believe most of these outcome statistics that compare one country with another. Seldom are the statistics collected in the same way and apart from differences in disease definition (eg "hypotension" is a very common condition in Germany and consumes a large chunk of the drug budget even though it is virtually unknown in other countries), diseases like cancer have had artificial improvements in survival because of earlier diagnosis (breast screening and PSA). Nevertheless, it appears that America is spending an awful lot more money without a commensurate improvement in outcome.
This may be because outcomes are an average of superlative care for the insured and terrible care for the uninsured, but I would need to see some figures to convince me of this.
Those who don't have access to a Healthcare program are likely to be people between the ages of 18 and 64 in low-paid jobs. Healthcare insurance for a family is on average more than $11,000 per year: a large burden for a small employer to bear. It is a large burden for a big employer to bear and makes American industry less competitive. Accessing regular Healthcare options is more expensive for the uninsured who don't have the bulk-buying capabilities of the Insurance companies, though the uninsured would be well advised to shop around and negotiate.
Many of those who are uninsured are immigrants, often illegal immigrants, in casual jobs, often part of the 'black' economy; they are paid in cash with no questions asked. For health care they resort to Emergency Rooms in County Hospitals. They are likely to default on taking their medicines because they can't afford their prescription drugs. They are likely to take part in informal drug exchanges, swapping unused (sometimes out of date) drugs with others in the same predicament. Medicine cabinets of the recently deceased provide a constant supply: not a good omen.
I have seen statistics somewhere that the poorest 30 million Americans are no better off than they were 20 years ago: but it's not the same 30 million. People come to America to better themselves and most of them do. I hope it is not patronizing to say that it takes years for those coming from developing countries to free themselves from the lifestyles of their former abode and buy into the ways of a liberal democracy. America welcomes more immigrants than anywhere else. They come wanting what America can give and most of them will eventually get it. It should not be assumed that providing a 'free' health service to this group of the population will make the problems go away.
Britain has experienced unprecedented waves of immigration over the past few years. Apparently, London schoolteachers have to deal with children who speak 900 different languages. Healthcare is available free at the point of contact. Everybody is registered with a family practitioner.
For the past 3 years I have been privileged to attend at Kings College Hospital in South London. Kings is one of the world's top hospitals. The liver unit is world renowned for its pioneering work in hepatic transplantation; the neurology and hematology units are similarly famous. Kings sits in an area of South London rich in ethnic diversity - which is a euphemism for it's a mostly black area. Many of the patients I see there are illegals keeping their heads down. The area has recently been in the news because of a spate of teenage gun crime. I see at Kings diseases that had been almost eliminated when I was a young doctor and common disease appear in their late stages because they have been neglected. I previously practiced in Bournemouth, a middle class, mostly white, affluent community with an excellent health service, where we could worry about chipping off 0.1 per thousand from the infant mortality rate, where we could honestly say that we would not expect anybody to die from a stem cell autograft and that induction chemotherapy for acute leukemia was safe. The Hematology service at Kings is better than that; it takes on cases that middle class hospitals couldn't imagine.
Britain comes out bottom (with Ireland and Portugal) in the number of deaths before the age of 75 that would have been saved with appropriate medical treatment. These three countries (America is almost as bad) are almost twice as bad as France. I would put it down to lifestyle, but France is as boozy as Ireland and Portugal has a Mediterranean style diet. More likely this is an example of different methods of statistical collection or different definitions.
According to the statistics the French have one of the best health systems in the world. It is an insurance-based system like the American one. The French have a large immigrant population too, with many illegals. Why are they doing so much better? My suspicion is that they are manipulating the statistics (their figures on cirrhosis are notoriously unbelievable). But if not perhaps we should all be living on red wine, garlic and olive oil.
Strictly speaking there is 41% of the population who don't have health insurance: 54% have employer-based insurance and 5% individual insurance. But on top of that 12% are covered by the Federal Medicare program for those over 65 and those who have been disabled for 2 years or more. Then 13% are covered by State Medicaid programs, mainly children of low income families and in some cases their parents, as well as some long-term care programs, and some interaction with Medicare for low-income families. This leaves some 16% of the population without any cover, around 47 million people - about the same as the population of England and Wales.
Despite this, the United States spends far more on health per head of population than any other country - around $6100. In contrast Britain spends $2500, Australia $2800, Germany $3000, France and Canada $3100.
What does America get for the extra money? The 5 year survival for breast cancer in nearer 90% than the 80% that other countries achieve, but the life expectancy at the age of 60 is a year or two less than in most other countries, and whereas in most countries around 90% survive for 30 days after a heart attack, in the US it is closer to 85%.
I don't believe most of these outcome statistics that compare one country with another. Seldom are the statistics collected in the same way and apart from differences in disease definition (eg "hypotension" is a very common condition in Germany and consumes a large chunk of the drug budget even though it is virtually unknown in other countries), diseases like cancer have had artificial improvements in survival because of earlier diagnosis (breast screening and PSA). Nevertheless, it appears that America is spending an awful lot more money without a commensurate improvement in outcome.
This may be because outcomes are an average of superlative care for the insured and terrible care for the uninsured, but I would need to see some figures to convince me of this.
Those who don't have access to a Healthcare program are likely to be people between the ages of 18 and 64 in low-paid jobs. Healthcare insurance for a family is on average more than $11,000 per year: a large burden for a small employer to bear. It is a large burden for a big employer to bear and makes American industry less competitive. Accessing regular Healthcare options is more expensive for the uninsured who don't have the bulk-buying capabilities of the Insurance companies, though the uninsured would be well advised to shop around and negotiate.
Many of those who are uninsured are immigrants, often illegal immigrants, in casual jobs, often part of the 'black' economy; they are paid in cash with no questions asked. For health care they resort to Emergency Rooms in County Hospitals. They are likely to default on taking their medicines because they can't afford their prescription drugs. They are likely to take part in informal drug exchanges, swapping unused (sometimes out of date) drugs with others in the same predicament. Medicine cabinets of the recently deceased provide a constant supply: not a good omen.
I have seen statistics somewhere that the poorest 30 million Americans are no better off than they were 20 years ago: but it's not the same 30 million. People come to America to better themselves and most of them do. I hope it is not patronizing to say that it takes years for those coming from developing countries to free themselves from the lifestyles of their former abode and buy into the ways of a liberal democracy. America welcomes more immigrants than anywhere else. They come wanting what America can give and most of them will eventually get it. It should not be assumed that providing a 'free' health service to this group of the population will make the problems go away.
Britain has experienced unprecedented waves of immigration over the past few years. Apparently, London schoolteachers have to deal with children who speak 900 different languages. Healthcare is available free at the point of contact. Everybody is registered with a family practitioner.
For the past 3 years I have been privileged to attend at Kings College Hospital in South London. Kings is one of the world's top hospitals. The liver unit is world renowned for its pioneering work in hepatic transplantation; the neurology and hematology units are similarly famous. Kings sits in an area of South London rich in ethnic diversity - which is a euphemism for it's a mostly black area. Many of the patients I see there are illegals keeping their heads down. The area has recently been in the news because of a spate of teenage gun crime. I see at Kings diseases that had been almost eliminated when I was a young doctor and common disease appear in their late stages because they have been neglected. I previously practiced in Bournemouth, a middle class, mostly white, affluent community with an excellent health service, where we could worry about chipping off 0.1 per thousand from the infant mortality rate, where we could honestly say that we would not expect anybody to die from a stem cell autograft and that induction chemotherapy for acute leukemia was safe. The Hematology service at Kings is better than that; it takes on cases that middle class hospitals couldn't imagine.
Britain comes out bottom (with Ireland and Portugal) in the number of deaths before the age of 75 that would have been saved with appropriate medical treatment. These three countries (America is almost as bad) are almost twice as bad as France. I would put it down to lifestyle, but France is as boozy as Ireland and Portugal has a Mediterranean style diet. More likely this is an example of different methods of statistical collection or different definitions.
According to the statistics the French have one of the best health systems in the world. It is an insurance-based system like the American one. The French have a large immigrant population too, with many illegals. Why are they doing so much better? My suspicion is that they are manipulating the statistics (their figures on cirrhosis are notoriously unbelievable). But if not perhaps we should all be living on red wine, garlic and olive oil.
Wednesday, February 14, 2007
Cricket
The comment is a little late, but England have won a cricket match against Australia. Astonishingly, the team of no hopers have won the trophy. Reasons why? Michael Vaughan brought some captainsy skills to the party; this restored some confidence; some new blood given a chance; luck.
Tuesday, February 13, 2007
Consolidation therapy with Alemtuzumab
This is another section on consolidation therapy to follow on from the section on bone marrow transplantion.
An alternative approach with potentially less hazard is to attempt to consolidate the remission using monoclonal antibodies. Alemtuzumab is particularly suited to this task because it is able to kill CLL cells in a caspase-independent manner that is not inhibited by loss of p53 [10] and is therefore able to eliminate chemotherapy-resistant cells [11]. In a study [12] of 91 previously treated patients, 44 of whom were refractory to purine analogues, NCI defined [Cheson 1996 previously referenced] complete remissions were achieved in 32%, 56% of whom had no disease detectable by a four-color flow technique for detecting minimal residual disease (MRD)[13]. Those patients who became MRD negative had significantly longer treatment-free and overall survivals than those who did not.
In a prospective phase III study conducted in Germany [14] patients were randomized to receive or not receive Alemtuzumab 30mg intravenously thrice weekly for 12 weeks beginning a median of 67 days after the last dose of induction chemotherapy, which was fludarabine with or without cyclophosphamide. Although recruitment to this trial was halted because of severe infections in the Alemtuzumab arm, even with only 21 patients in the trial, those receiving Alemtuzumab had a significantly longer progression-free survival. Using a very sensitive PCR-based assay with sequence-specific primers to detect MRD, 5/6 patients tested became MRD negative.
A phase II study [15] of Alemtuzumab given in doses of 10mg subcutaneously three times a week for six weeks beginning not less than eight weeks after the discontinuation of fludarabine induction chemotherapy proved that this regimen was safer and capable of turning partial remissions into complete remissions. MRD was tested for using the less sensitive PCR technique with consensus primers, but using this, patients with mutated VH genes were more likely to become MRD negative than those with unmutated VH genes. Reactivation of cytomegalovirus occurred in 53% but was successfully treated with oral Ganciclovir. 53% of patients successfully underwent autologous stem cell transplantation, but no follow-up information is available.
At present, immunological consolidation with Alemtuzumab following chemotherapy appears safer than with allogeneic transplantation but we await a comparison of efficacy.
References
10. Mone AP, Cheney C, Banks AL et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia 2006; 20:272-9.
11. Lozanski G, Heerema NA, Flinn IW et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103:3278-81.
12. Moreton P, Kennedy B, Lucas G et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after Alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23:2971-9.
13. Rawstron AC, Kennedy B, Evans PA et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98:29-35.
14. Wedtner C-M, Ritgen M, Schweighofer CD et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLCG) Leukemia 2004; 18:1093-1101.
15. Montillo M, Tedeschi A, Miqueleiz S et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24:2337-42.
An alternative approach with potentially less hazard is to attempt to consolidate the remission using monoclonal antibodies. Alemtuzumab is particularly suited to this task because it is able to kill CLL cells in a caspase-independent manner that is not inhibited by loss of p53 [10] and is therefore able to eliminate chemotherapy-resistant cells [11]. In a study [12] of 91 previously treated patients, 44 of whom were refractory to purine analogues, NCI defined [Cheson 1996 previously referenced] complete remissions were achieved in 32%, 56% of whom had no disease detectable by a four-color flow technique for detecting minimal residual disease (MRD)[13]. Those patients who became MRD negative had significantly longer treatment-free and overall survivals than those who did not.
In a prospective phase III study conducted in Germany [14] patients were randomized to receive or not receive Alemtuzumab 30mg intravenously thrice weekly for 12 weeks beginning a median of 67 days after the last dose of induction chemotherapy, which was fludarabine with or without cyclophosphamide. Although recruitment to this trial was halted because of severe infections in the Alemtuzumab arm, even with only 21 patients in the trial, those receiving Alemtuzumab had a significantly longer progression-free survival. Using a very sensitive PCR-based assay with sequence-specific primers to detect MRD, 5/6 patients tested became MRD negative.
A phase II study [15] of Alemtuzumab given in doses of 10mg subcutaneously three times a week for six weeks beginning not less than eight weeks after the discontinuation of fludarabine induction chemotherapy proved that this regimen was safer and capable of turning partial remissions into complete remissions. MRD was tested for using the less sensitive PCR technique with consensus primers, but using this, patients with mutated VH genes were more likely to become MRD negative than those with unmutated VH genes. Reactivation of cytomegalovirus occurred in 53% but was successfully treated with oral Ganciclovir. 53% of patients successfully underwent autologous stem cell transplantation, but no follow-up information is available.
At present, immunological consolidation with Alemtuzumab following chemotherapy appears safer than with allogeneic transplantation but we await a comparison of efficacy.
References
10. Mone AP, Cheney C, Banks AL et al. Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism. Leukemia 2006; 20:272-9.
11. Lozanski G, Heerema NA, Flinn IW et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 2004; 103:3278-81.
12. Moreton P, Kennedy B, Lucas G et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after Alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 2005; 23:2971-9.
13. Rawstron AC, Kennedy B, Evans PA et al. Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy. Blood 2001; 98:29-35.
14. Wedtner C-M, Ritgen M, Schweighofer CD et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission – experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLCG) Leukemia 2004; 18:1093-1101.
15. Montillo M, Tedeschi A, Miqueleiz S et al. Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia. J Clin Oncol 2006; 24:2337-42.
Minimal residual disease
This is a concept that is confusing for most people, but it is vital if you are to understand the treatment of leukemia.
There are 1,000,000,000,000,000 cells in the body. 90% of them aren't even human, they're bacterial, but although you may be only 10% human by cell number, bacterial cells are so small that they make up only a trivial amount of your volume. It is impracticable to talk about a number with so many zeros, so in real life we talk about such large numbers as 10 to the power of 15; that is, a one with 15 zeros after it. It is usually written as a 10 with a tiny superscript 15 after it. Since I haven't worked our how to do superscripts on the blog, I shall refer to such numbers as 10 to ten power of whatever.
So in the human body there are 10 to the power of 14 human cells. In a patient with so much leukemia that they are just about to die there may be as many as 10 to the power of 13 leukemic cells; that is as many as 10% of the cells in the body are leukemic. When the disease presents there are typically about 10 to the power of eleven cells in the body. (Put the figure in your mind this way. 10 to the power 6 is a million. In America, 10 to the power 9 is a billion [in England it is a thousand million or milliard], 10 to the power 12 is a trillion [in England it's a billion]; so, 10 to the power of eleven is 100 billion in American money.
A complete remission in acute leukemia means that you can no longer detect leukemic cells in the bone marrow. This equates to less than a billion cells in the body (ten to the power of nine). It is normal to go on treating at this level (called consolidation treatment); it is hoped that by this time there are fewer than 10 to the power of 5 cells (one hundred thousand) left in the body. This is a stupendous result meaning that 99.9999% of the leukemic cells have been eliminated. We don't really know whether this is good enough. It is assumed that the body's defenses can handle small numbers of cells, and this seems to be true for some people some of the time.
Assays have been developed to test whether there is any disease left in the body - these are known as tests for minimal residual disease (MRD). Mostly these tests rely on one of two techniques: flow cytometry or the polymerase chain reaction PCR). Flow techniques rely on identifying a combination of antigens on the leukemic cells that is not on normal cells. For example CD2, CD7, CD19, and CD45. Flow techniques can be very sensitive, able to detect one cell in a thousand. PCR is generally more sensitive, detecting one cell in one hundred thousand. In acute leukemia, the PCR is used to detect a unique piece of DNA in the leukemia such as the DNA coding for the fusion protein generated by a chromosomal translocation.
In CLL a complete remission is less stringent than in acute leukemia. The NCI have defined a CR as all of the following being present for at least 2 months: absence of lymphadenopathy, hepatomegaly or splenomegaly by physical examination and appropriate imaging, absence of constitutional symptoms, polymorphs > 1500 per microlitre, platelets greater than 100,000 per microlitre, hemoglobin > 11.0 g/dL, bone marrow biopsy showing normal cellularity, fewer than 30% lymphocytes and no lymphoid nodules. Although patients with a CR have longer remissions than those who only get a partial response, most CRs can be shown to have residual disease by more sensitive tests.
In CLL there are usually no chromosomal translocations to use for a PCR test for MRD. The CLL cells are clonal and the DNA sequence of the immunoglobulin genes is the same in every cell. A PCR technique has been developed making use of this. Since in most cases nobody knows what this sequence is the PCR has to use what are called 'consensus primers' ie it will pick up any monoclonal population. It will detect MRD, but it is not very sensitive. It will detect one in a thousand cells. This means that if 10 thousand cells are loaded onto the PCR machine and among them are 10 the same, then it will pick it up, but if only 8 are the same then it won't. Some patients have had their immunoglobulin DNA sequenced to see if they were mutated or unmutated. If this has ben done then it is possible to design a PCR using sequence specific primers, and this makes the PCR much more sensitive picking up one cell in 100,000.
The alternative method is to use flow. Many people have hit upon the fact that CLL cells are CD5 and CD19 positive and have used this as a flow assay. Unfortunately this is neither sensitive nor specific - you get false positives and false negatives. This assay has been used in many famous units as a method of detecting MRD. Honestly, it is quite useless. Andy Rawstron developed a four color flow assay that was almost as sensitive as the best PCR technique. Using antibodies against CD19/CD5/CD20/CD79b he was able to detect somewhere between 2 and 5 cells in 100,000. This assay won't do for patients who have been treated with rituximab, and for these he has devised another assay employing antibodies against CD81/CD22/CD19/CD5.
These assays work in practice. In a study employing Campath to remove MRD, MRD negative patients had longer treatment-free and overall survivals than those whose CRs were MRD positive. The actuarial figures were startling; at 7 years only 20% of the MRD negative patients had require retreating, whereas patients with MRD positive CRs needed retreatment after a median 20 months and those with PRs after a median 13 months. Achieving an MRD negative CR led to an overall survival of 80% at 7 years. Not achieving an MRD negative CR led to an overall median survival of 19 months. However of those who became MRD negative, half had become MRD positive again by 28 months. This does not mean that Campath is a wonder treatment. Only 20% of those treated became MRD negative, and this may have more to do with the nature of the CLL than the fact that they had Campath. Campath may just be a good, if expensive way, of picking winners.
There are 1,000,000,000,000,000 cells in the body. 90% of them aren't even human, they're bacterial, but although you may be only 10% human by cell number, bacterial cells are so small that they make up only a trivial amount of your volume. It is impracticable to talk about a number with so many zeros, so in real life we talk about such large numbers as 10 to the power of 15; that is, a one with 15 zeros after it. It is usually written as a 10 with a tiny superscript 15 after it. Since I haven't worked our how to do superscripts on the blog, I shall refer to such numbers as 10 to ten power of whatever.
So in the human body there are 10 to the power of 14 human cells. In a patient with so much leukemia that they are just about to die there may be as many as 10 to the power of 13 leukemic cells; that is as many as 10% of the cells in the body are leukemic. When the disease presents there are typically about 10 to the power of eleven cells in the body. (Put the figure in your mind this way. 10 to the power 6 is a million. In America, 10 to the power 9 is a billion [in England it is a thousand million or milliard], 10 to the power 12 is a trillion [in England it's a billion]; so, 10 to the power of eleven is 100 billion in American money.
A complete remission in acute leukemia means that you can no longer detect leukemic cells in the bone marrow. This equates to less than a billion cells in the body (ten to the power of nine). It is normal to go on treating at this level (called consolidation treatment); it is hoped that by this time there are fewer than 10 to the power of 5 cells (one hundred thousand) left in the body. This is a stupendous result meaning that 99.9999% of the leukemic cells have been eliminated. We don't really know whether this is good enough. It is assumed that the body's defenses can handle small numbers of cells, and this seems to be true for some people some of the time.
Assays have been developed to test whether there is any disease left in the body - these are known as tests for minimal residual disease (MRD). Mostly these tests rely on one of two techniques: flow cytometry or the polymerase chain reaction PCR). Flow techniques rely on identifying a combination of antigens on the leukemic cells that is not on normal cells. For example CD2, CD7, CD19, and CD45. Flow techniques can be very sensitive, able to detect one cell in a thousand. PCR is generally more sensitive, detecting one cell in one hundred thousand. In acute leukemia, the PCR is used to detect a unique piece of DNA in the leukemia such as the DNA coding for the fusion protein generated by a chromosomal translocation.
In CLL a complete remission is less stringent than in acute leukemia. The NCI have defined a CR as all of the following being present for at least 2 months: absence of lymphadenopathy, hepatomegaly or splenomegaly by physical examination and appropriate imaging, absence of constitutional symptoms, polymorphs > 1500 per microlitre, platelets greater than 100,000 per microlitre, hemoglobin > 11.0 g/dL, bone marrow biopsy showing normal cellularity, fewer than 30% lymphocytes and no lymphoid nodules. Although patients with a CR have longer remissions than those who only get a partial response, most CRs can be shown to have residual disease by more sensitive tests.
In CLL there are usually no chromosomal translocations to use for a PCR test for MRD. The CLL cells are clonal and the DNA sequence of the immunoglobulin genes is the same in every cell. A PCR technique has been developed making use of this. Since in most cases nobody knows what this sequence is the PCR has to use what are called 'consensus primers' ie it will pick up any monoclonal population. It will detect MRD, but it is not very sensitive. It will detect one in a thousand cells. This means that if 10 thousand cells are loaded onto the PCR machine and among them are 10 the same, then it will pick it up, but if only 8 are the same then it won't. Some patients have had their immunoglobulin DNA sequenced to see if they were mutated or unmutated. If this has ben done then it is possible to design a PCR using sequence specific primers, and this makes the PCR much more sensitive picking up one cell in 100,000.
The alternative method is to use flow. Many people have hit upon the fact that CLL cells are CD5 and CD19 positive and have used this as a flow assay. Unfortunately this is neither sensitive nor specific - you get false positives and false negatives. This assay has been used in many famous units as a method of detecting MRD. Honestly, it is quite useless. Andy Rawstron developed a four color flow assay that was almost as sensitive as the best PCR technique. Using antibodies against CD19/CD5/CD20/CD79b he was able to detect somewhere between 2 and 5 cells in 100,000. This assay won't do for patients who have been treated with rituximab, and for these he has devised another assay employing antibodies against CD81/CD22/CD19/CD5.
These assays work in practice. In a study employing Campath to remove MRD, MRD negative patients had longer treatment-free and overall survivals than those whose CRs were MRD positive. The actuarial figures were startling; at 7 years only 20% of the MRD negative patients had require retreating, whereas patients with MRD positive CRs needed retreatment after a median 20 months and those with PRs after a median 13 months. Achieving an MRD negative CR led to an overall survival of 80% at 7 years. Not achieving an MRD negative CR led to an overall median survival of 19 months. However of those who became MRD negative, half had become MRD positive again by 28 months. This does not mean that Campath is a wonder treatment. Only 20% of those treated became MRD negative, and this may have more to do with the nature of the CLL than the fact that they had Campath. Campath may just be a good, if expensive way, of picking winners.
Sunni and Cher
As I was thinking about Iraq today I found myself humming. "I got you, Babe". No, it was not just the wakeup call on Groundhog Day - another day; another bomb. Sonny and Cher - Sunni and Shi'a - seem to be two sides of the same coin.
Cheryl Sarkisian LaPiere was the daughter of John Sarkisian, himself half-Iranian. A truck-driver who left her mother early in their marriage, he was, of course, neither Sunni nor Shi'a, but an Armenian Christian, part of the Armenian oppression by Otterman Turks. (Just as the Iranians deny the Holocaust, so the Turks deny the Armenian genocide.) Sarkisian was briefly reconciled to her mother, Georgia Holt (herself part-Cherokee, Irish, German and English, such is the melting pot of America), when Cher was eleven, and he died in 1985
Cher married the older Sonny Bono and together they formed one of the most successful singing duos the pop-world has seen. When their marriage fell apart Sonny had to give up being a celebrity and was demoted to being a US congressman. I liked his comment on illegal immigrants, "What can I say; they're illegal." He died a spectacular death and was buried in the same cemetery as Frank Sinatra. Cher, meantime, remains a superstar. With an Oscar.
What does this tell us about Iraq and Iran - Sunni and Shi'a? Probably that they need each other. Bang, Bang, my baby shot me down.
Cheryl Sarkisian LaPiere was the daughter of John Sarkisian, himself half-Iranian. A truck-driver who left her mother early in their marriage, he was, of course, neither Sunni nor Shi'a, but an Armenian Christian, part of the Armenian oppression by Otterman Turks. (Just as the Iranians deny the Holocaust, so the Turks deny the Armenian genocide.) Sarkisian was briefly reconciled to her mother, Georgia Holt (herself part-Cherokee, Irish, German and English, such is the melting pot of America), when Cher was eleven, and he died in 1985
Cher married the older Sonny Bono and together they formed one of the most successful singing duos the pop-world has seen. When their marriage fell apart Sonny had to give up being a celebrity and was demoted to being a US congressman. I liked his comment on illegal immigrants, "What can I say; they're illegal." He died a spectacular death and was buried in the same cemetery as Frank Sinatra. Cher, meantime, remains a superstar. With an Oscar.
What does this tell us about Iraq and Iran - Sunni and Shi'a? Probably that they need each other. Bang, Bang, my baby shot me down.
Monday, February 12, 2007
Bone marrow transplantation for CLL
This is the next section in the article that I am writing in the Lancet.
In leukemia, remissions are traditionally consolidated with high dose chemotherapy, sometimes with autologous stem cell rescue. Using this approach the German group were able to eliminate minimal residual disease (MRD) and produce prolonged remissions in patients whose CLL had mutated VH genes, but for those with unmutated VH genes molecular relapse was inevitable and clinical relapse almost so by 4 years follow-up [1]. However, even this, less-than-encouraging, outcome may be better than what is achievable with more conventional chemotherapy according to a comparison with matched historical controls [2]. Moreover, a stem cell harvest is only possible in about two thirds of cases [3] and there is a worryingly high incidence of secondary myelodysplastic syndrome [3, 4]
In an attempt to gain immunological control over the CLL by using the graft-versus-leukemia effect, stem cell allografts have been employed. As might have been expected with a largely elderly population, myeloablative conditioning leads to an unacceptably high treatment-related mortality of between 40% and 50% [4, 5]. To combat this toxicity, allotransplantation with reduced intensity conditioning, often followed by donor lymphocyte infusion, has become popular. However, early results do not yet show an improvement in event-free survival compared to myeloablative transplants [6-8]. In every series there is a high incidence of chronic graft-versus host disease. Nevertheless, in patients with poor risk prognostic markers, and especially those with 17p13 deletions, sustained remissions without molecular relapse are achievable [9].
1. Ritgen M, Lange A, Stilgenbauer S et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. 2003;101:2049-53.
2. Dreger P, Stilgenbauer S, Benner A et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood. 2004103:2850-8.
3. Milligan DW, Fernandes S, Dasgupta R et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood. 2005;105:397-404.
4. Gribben JG, Zahrieh D, Stephens K et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005;106:4389-96.
5. Paneesha S, Milligan DW. Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol. 2005;128:145-52..
6. Dreger P, Brand R, Milligan D et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005;19:1029-33.
7. Brown JR, Kim-HT, Li S et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2006;12:1056-64.
That is very much a brief summary because I have limited space, but here are the figures in detail for allos and mini-allos:
John Gribben et al (Dana Farber)Blood 2005;106:4389-96. 25 sibling donor myeloablative allotransplants aged 28-55. Treatment related mortality was 24%. Overall survival at 6 years was 58%. Median progression free survival 2 years. 6 year progression-free survival was 24%.
Peter Dreger et al. (EBMT) Leukemia 2005; 19:1029-33. 82 myeloablative allografts (MA) and 73 with reduced intensity conditioning (RIC). At 2 years actuarial follow up there was no significant difference between MCA and RIC transplants in terms of treatment related mortality, event-free survival and overall survival, but there were fewer relapses in those receiving full dose conditioning (28% v 11%); but when other adverse prognostic factors were taken into consideration, treatment related mortality was less for the RIC patients by a factor of 0.4. Significantly, relapse was more likely if chronic graft-versus-host disease (GVHD)did not occur.
Jennifer Brown et al. (Dana Farber) Biol Blood Marrow Transplant. 2006;12:1056-64. 46 patients RIC allografts either sibling or matched unrelated donors. Age 35-67. Treatment related mortality was 17%, relapse at 2 years was 48%, 1 year progression-free survival was 44% and 2-year progression-free survival was 34%. One-year overall survival was 66% and two-year overall survival was 54%. This was a mixed bag of patients who had mostly relapsed after both chlorambucil and fludarabine therapy, although very few had p53 deletions. Better results were obtained in patients who entered their transplant with fewer than 5% CLL cells in their marrow, but only 11% of those with poor risk cytogenetics were still in remission at 2 years.
Julia Delgado et al. (UK transplant group). Blood 2006; 107:1724-30. 41 Campath-based mini-allos in patients aged 37-67. Transplant-related mortality 26%. Overall survival at 2 years 51%. Acute GVHD in 41%, chronic GVHD in 33%. Of 11 patients refractory to fludarabine, 2 remain alive in CR, one alive with molecular relapse, one alive with graft failure and 7 are dead. Donor lymphocyte infusions were tried in 9 relapsing patients but produced a sustained response in only 3.
Mohamed Sorror et al (Seattle) J Clin Oncol 2005; 23:3819-29. 64 patients received RIC allografts. Mortality at 2 years was 40%, half due to treatment; half due to relapse; 2-year relapse free survival was 52% and overall survival 60%. Chronic GVHD occurred in 39%.
Dolores Caballaro et al (Spain). Clin Cancer Res 2005; 11:7757-63. 30 patients aged 35-67 receiving RIC allos. Of the 30 patients, 2 died early, 6 more died in the first 2 years without relapsing, 22 patients (72%)remain alive and in remission at 4 years. These results are better than in other series; are there any factors that explain this? Eight patients had del 11q and 6 has del 17p. These patients seem to have done as well as the others. Having had more than two lines of treatment before transplant was an adverse factor. The conditioning regimen was fludarabine 150mg plus melphalan 140 mg (both per sq meter) in the majority of cases.
My conclusions on bone marrow transplantation for CLL are as follows: All transplant procedures on CLL patients are experimental procedures. Granted that it is only applied to patients with the poorest risk, but in most series 40% of patients are dead within 2 years of receiving the transplant. Stem cell autografting works well with patients with mutated VH genes (who may not really need it) but poorly in patients with unmutated VH genes (though perhaps better than conventional chemotherapy would. For these patients an immunological approach might be better.
Originally, allografting was restricted to very young patients so that it had little application in CLL. However, reduced intensity conditioning has extended the age range (up to 67) and made unrelated donor transplants feasible. Nevertheless the mortality associated with the procedure is still around 40% at two years, and in those patients who survive there is a high incidence of chronic GVHD. If it is restricted to patients who are refractory to other treatments, the outcome is even worse, but still probably better than with most other treatments. Were it used earlier in the disease would the outcome be better? That is one of the questions that needs to be tested in clinical trials.
In leukemia, remissions are traditionally consolidated with high dose chemotherapy, sometimes with autologous stem cell rescue. Using this approach the German group were able to eliminate minimal residual disease (MRD) and produce prolonged remissions in patients whose CLL had mutated VH genes, but for those with unmutated VH genes molecular relapse was inevitable and clinical relapse almost so by 4 years follow-up [1]. However, even this, less-than-encouraging, outcome may be better than what is achievable with more conventional chemotherapy according to a comparison with matched historical controls [2]. Moreover, a stem cell harvest is only possible in about two thirds of cases [3] and there is a worryingly high incidence of secondary myelodysplastic syndrome [3, 4]
In an attempt to gain immunological control over the CLL by using the graft-versus-leukemia effect, stem cell allografts have been employed. As might have been expected with a largely elderly population, myeloablative conditioning leads to an unacceptably high treatment-related mortality of between 40% and 50% [4, 5]. To combat this toxicity, allotransplantation with reduced intensity conditioning, often followed by donor lymphocyte infusion, has become popular. However, early results do not yet show an improvement in event-free survival compared to myeloablative transplants [6-8]. In every series there is a high incidence of chronic graft-versus host disease. Nevertheless, in patients with poor risk prognostic markers, and especially those with 17p13 deletions, sustained remissions without molecular relapse are achievable [9].
1. Ritgen M, Lange A, Stilgenbauer S et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. 2003;101:2049-53.
2. Dreger P, Stilgenbauer S, Benner A et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood. 2004103:2850-8.
3. Milligan DW, Fernandes S, Dasgupta R et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood. 2005;105:397-404.
4. Gribben JG, Zahrieh D, Stephens K et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005;106:4389-96.
5. Paneesha S, Milligan DW. Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol. 2005;128:145-52..
6. Dreger P, Brand R, Milligan D et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005;19:1029-33.
7. Brown JR, Kim-HT, Li S et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2006;12:1056-64.
That is very much a brief summary because I have limited space, but here are the figures in detail for allos and mini-allos:
John Gribben et al (Dana Farber)Blood 2005;106:4389-96. 25 sibling donor myeloablative allotransplants aged 28-55. Treatment related mortality was 24%. Overall survival at 6 years was 58%. Median progression free survival 2 years. 6 year progression-free survival was 24%.
Peter Dreger et al. (EBMT) Leukemia 2005; 19:1029-33. 82 myeloablative allografts (MA) and 73 with reduced intensity conditioning (RIC). At 2 years actuarial follow up there was no significant difference between MCA and RIC transplants in terms of treatment related mortality, event-free survival and overall survival, but there were fewer relapses in those receiving full dose conditioning (28% v 11%); but when other adverse prognostic factors were taken into consideration, treatment related mortality was less for the RIC patients by a factor of 0.4. Significantly, relapse was more likely if chronic graft-versus-host disease (GVHD)did not occur.
Jennifer Brown et al. (Dana Farber) Biol Blood Marrow Transplant. 2006;12:1056-64. 46 patients RIC allografts either sibling or matched unrelated donors. Age 35-67. Treatment related mortality was 17%, relapse at 2 years was 48%, 1 year progression-free survival was 44% and 2-year progression-free survival was 34%. One-year overall survival was 66% and two-year overall survival was 54%. This was a mixed bag of patients who had mostly relapsed after both chlorambucil and fludarabine therapy, although very few had p53 deletions. Better results were obtained in patients who entered their transplant with fewer than 5% CLL cells in their marrow, but only 11% of those with poor risk cytogenetics were still in remission at 2 years.
Julia Delgado et al. (UK transplant group). Blood 2006; 107:1724-30. 41 Campath-based mini-allos in patients aged 37-67. Transplant-related mortality 26%. Overall survival at 2 years 51%. Acute GVHD in 41%, chronic GVHD in 33%. Of 11 patients refractory to fludarabine, 2 remain alive in CR, one alive with molecular relapse, one alive with graft failure and 7 are dead. Donor lymphocyte infusions were tried in 9 relapsing patients but produced a sustained response in only 3.
Mohamed Sorror et al (Seattle) J Clin Oncol 2005; 23:3819-29. 64 patients received RIC allografts. Mortality at 2 years was 40%, half due to treatment; half due to relapse; 2-year relapse free survival was 52% and overall survival 60%. Chronic GVHD occurred in 39%.
Dolores Caballaro et al (Spain). Clin Cancer Res 2005; 11:7757-63. 30 patients aged 35-67 receiving RIC allos. Of the 30 patients, 2 died early, 6 more died in the first 2 years without relapsing, 22 patients (72%)remain alive and in remission at 4 years. These results are better than in other series; are there any factors that explain this? Eight patients had del 11q and 6 has del 17p. These patients seem to have done as well as the others. Having had more than two lines of treatment before transplant was an adverse factor. The conditioning regimen was fludarabine 150mg plus melphalan 140 mg (both per sq meter) in the majority of cases.
My conclusions on bone marrow transplantation for CLL are as follows: All transplant procedures on CLL patients are experimental procedures. Granted that it is only applied to patients with the poorest risk, but in most series 40% of patients are dead within 2 years of receiving the transplant. Stem cell autografting works well with patients with mutated VH genes (who may not really need it) but poorly in patients with unmutated VH genes (though perhaps better than conventional chemotherapy would. For these patients an immunological approach might be better.
Originally, allografting was restricted to very young patients so that it had little application in CLL. However, reduced intensity conditioning has extended the age range (up to 67) and made unrelated donor transplants feasible. Nevertheless the mortality associated with the procedure is still around 40% at two years, and in those patients who survive there is a high incidence of chronic GVHD. If it is restricted to patients who are refractory to other treatments, the outcome is even worse, but still probably better than with most other treatments. Were it used earlier in the disease would the outcome be better? That is one of the questions that needs to be tested in clinical trials.
Saturday, February 10, 2007
As Time Goes By
For the past 6 weeks our TV watching has just about been confined to the DVDs of As Time Goes By. We bought the whole series for Christmas. For those who don't know it, the stars are Judi Dench and Geoffrey Palmer. It is the story of a young subaltern and a young nurse who fall in love in 1952. He is sent to the Korean War and because a letter goes astray they lose touch. They meet again 38 years later and rekindle their romance. In 1992 when the series was first shown Geoffrey Palmer was 65 playing 58 and Judi Dench was 57 playing 55. When the last show was made in 2005 he was 78 and she 70.
What was so good about the series is how well it captured the mores of people of my age. Lionel is a grumpy old man who believes people should mind their own business but he has a sentimental streak. Jean is warm hearted but insatiably curious about other people. She fanatsises in every situation, he keeps his feet on the ground, even buried in the ground. They are surrounded by zany characters. Alistair, Lionel's publisher, has a superman complex and an incomprehensible mod vocabulary, and is courting Jean's daughter Judi - twice divorced and looking for commitment - not exactly Alistair's middle name. Jean's beautiful young secretary, Sandy, moves in with the old couple, which leads to problems over a shared bathroom, but gives Jean another lost sheep to care for. Sandy falls for a young policeman but has difficulty in keeping his mind off rugby. Penny, Jean's first husband's selfish and domineering sister, and her monumentally boring dentist-husband threaten to move next door. Rocky, Lionel's eccentric father decides to marry the even more eccentric Madge, who drives about in a pink Cadillac with bull horns. These parts were played by Frank Middlemass and Joan Sims, both sadly now dead.
Gentle, clean, and genuinely funny. If you haven't seen it buy the recordings.
What was so good about the series is how well it captured the mores of people of my age. Lionel is a grumpy old man who believes people should mind their own business but he has a sentimental streak. Jean is warm hearted but insatiably curious about other people. She fanatsises in every situation, he keeps his feet on the ground, even buried in the ground. They are surrounded by zany characters. Alistair, Lionel's publisher, has a superman complex and an incomprehensible mod vocabulary, and is courting Jean's daughter Judi - twice divorced and looking for commitment - not exactly Alistair's middle name. Jean's beautiful young secretary, Sandy, moves in with the old couple, which leads to problems over a shared bathroom, but gives Jean another lost sheep to care for. Sandy falls for a young policeman but has difficulty in keeping his mind off rugby. Penny, Jean's first husband's selfish and domineering sister, and her monumentally boring dentist-husband threaten to move next door. Rocky, Lionel's eccentric father decides to marry the even more eccentric Madge, who drives about in a pink Cadillac with bull horns. These parts were played by Frank Middlemass and Joan Sims, both sadly now dead.
Gentle, clean, and genuinely funny. If you haven't seen it buy the recordings.
Tuesday, February 06, 2007
Reading
It has been a long time since I posted what I have been reading. Rest assured I have been reading. I am almost up to date on the Terry Goodkind Sword of Truth series. I am just starting Book ten. The last one Chain Fire postulates a single individual being removed from history. All references to her are removed; only her husband remembers her. Slowly, but progressively, his world and their world diverge. I guess the message is that every individual makes a difference; everybody counts.
Alex Cross is played by Morgan Freeman in the movies, but he was created by James Patterson. I have read the first three Alex Cross thrillers since Christmas - there are sven more; have I been hooked into another reading marathon? They are cleverly plotted, but very violent. I wouldn't like to have to think of murders like that for a living. On the thriller front I have also read the latest Rebus, the latest Harry Bosch, and the latest Reacher, since Christmas.
Alexander McCall Smith is famous for his gentle Ladies Detective Agency books, set in Botswana. These seem to have dried up for the moment so I have read his Professor Dr Von Igelfeld series. These are short farces about three, rather pompous, German professors of philology. The situations that they get into are almost believable and spring from the characteristics of the three professors. If you are wondering where you have heard about philology before, the hero of CS Lewis's science fiction trilogy was a philologist. It is the study of the origin of words and language.
I have related the plots of these books to my friends and we can't stop giggling. However, when I read them they only cause mild amusement. They are the sort of stories that improve in the telling but lose something on the printed page.
My Christian reading has been concerned with a large tome of intense theology, 'The King of God's Kingdom' by David Secombe, Principal of George Whitfield College in Cape Town. It is a sort of harmonization of the synoptic gospels centering around teh phrase 'the Kingdom of God'. I am close to the end now and about to start on 'John's Wisdom' by Ben Witherington III, Professor of New Testament Interpretation at Asbury Theological Seminary, Wilmore, Kentucky. As a taster, he believes that the fourth gospel was written by Lazarus.
Alex Cross is played by Morgan Freeman in the movies, but he was created by James Patterson. I have read the first three Alex Cross thrillers since Christmas - there are sven more; have I been hooked into another reading marathon? They are cleverly plotted, but very violent. I wouldn't like to have to think of murders like that for a living. On the thriller front I have also read the latest Rebus, the latest Harry Bosch, and the latest Reacher, since Christmas.
Alexander McCall Smith is famous for his gentle Ladies Detective Agency books, set in Botswana. These seem to have dried up for the moment so I have read his Professor Dr Von Igelfeld series. These are short farces about three, rather pompous, German professors of philology. The situations that they get into are almost believable and spring from the characteristics of the three professors. If you are wondering where you have heard about philology before, the hero of CS Lewis's science fiction trilogy was a philologist. It is the study of the origin of words and language.
I have related the plots of these books to my friends and we can't stop giggling. However, when I read them they only cause mild amusement. They are the sort of stories that improve in the telling but lose something on the printed page.
My Christian reading has been concerned with a large tome of intense theology, 'The King of God's Kingdom' by David Secombe, Principal of George Whitfield College in Cape Town. It is a sort of harmonization of the synoptic gospels centering around teh phrase 'the Kingdom of God'. I am close to the end now and about to start on 'John's Wisdom' by Ben Witherington III, Professor of New Testament Interpretation at Asbury Theological Seminary, Wilmore, Kentucky. As a taster, he believes that the fourth gospel was written by Lazarus.
Monday, February 05, 2007
The label came off
I feel ambivalent about pharmaceutical companies at the present time. There is no doubt that they have contributed greatly in the fight against disease; without them we would not have a fraction of the drugs that we do. However, we are not allies in the fight against CLL, we are co-belligerents. We are certainly fighting the same enemy, but I would not want to be associated with some of the methods they are using.
We have a different regulatory framework in the UK to that in the US. The FDA examines a drug to see if it is efficacious and safe. It is a balancing act. Efficacious drugs are not always safe. Even an aspirin can kill you. The FDA has to balance the good that they might do with the harm that they might do. They may put restrictions on their use. In the UK a body known as the MHRA does the same thing.
In making this assessment the FDA relies on the pharmaceutical company releasing to it all the information concerning efficacy and toxicity. As we have learned in recent times Big Pharma sometimes withholds information about toxicity, or seeks to belittle it. It is also possible to talk up the efficacy of an agent. A recent analysis of a new drug for CLL demonstrated an effect in a subset of patients. This was not an effect that the trial had been designed to detect, but one that emerged from data dredging. Subset analysis is a valid methodology, but the statistical tests that are applied to it have to be more stringent. We cannot accept that P<0.05 is significant. After all if you dredge through 20 subsets of data you are bound to find something with a 5% chance of being significant. For example, you have 20 schoolboys. Your hypothesis is that Peter is taller than the others. You have a 1 in 20 chance of being right. However if your hypothesis is one boy is taller than the others, you are almost bound to be right. In the recent British CLL trial subset analysis suggests that overall survival for patients with mutated IgVH genes is better if they are treated with chlorambucil than if they are treated with fludarabine. But that comparison is invalid, because it wasn't one of the things that the trial was designed to detect. It would have needed many more patients to be randomized. It was just this sort of analysis that the manufacturer (not of chlorambucil, I hasten to add) attempted to swing on the FDA. To their credit, the FDA spotted what was going on and refused to license the drug.
Another trick is to use the comparator drug at a lower than optimal dose. For years I have been using chlorambucil at a dose of 10mg a day for two weeks in every four. That's 140 mg per month. The average person is 1.72 sq meters in surface area, so on average I was giving 81 mg/sq m/month. Why am I not surprised when I turn to the pivotal trial for fludarabine and find that patients in the chlorambucil arm received only 40 mg/sq m/month. When I examine the Campath trial which has just shown Campath to be better than chlorambucil as first line therapy, I find that the same rather low dose of chlorambucil has been used. It's not a wrong dose of chlorambucil, but it sets the winning post a little easier to reach.
In the UK we have an organization called NICE that I have referred to before. Its job is to inform the government which drugs are cost-effective and should therefore be paid for by the NHS. It is not perfect, but it tries hard. Not every drug is examined by NICE, but when drugs are not examined, the local health purchaser has to make a decision, and it is likely to be a deal more arbitrary than the one NICE makes. In the US once a drug is licensed it can be prescribed by any doctor as long as the patient can find someone to pay for it. Very often the third party funder will look at the decision that NICE has made in the UK.
Of course the licensing does not cover every possible use a particular drug. Doctors will experiment. For example, Daunorubicin, which has been the mainstay of treatment for acute myeloid leukemia since the 1960s, but for a long period it did not have a license for this use in the UK. In India, a cardiologist who knew a bit about physiology reasoned that sildenafil would be a very useful drug for the treatment of congenital pulmonary hypertension. You can imagine the outrage at a doctor giving Viagra off-license to new-born babies. But he was right and the lives of many babies were saved by his courage.
However, pharmaceutical companies are not allowed to promote their drug for unlicensed conditions. You can imagine why the FDA was outraged to discover that 70% of prescriptions for one popular monoclonal antibody were for conditions outside the licensed indications.
Which brings me to a warning letter sent to a certain pharmaceutical company by the FDA. This is an old letter dating from 7 years ago so I shan’t name the company who no doubt have put their house in order by now. The point of the warning letter was to suggest that the company had violated the terms of the license: “statements or implications by you that this product may indeed be safe and efficacious in the treatment of diseases or patient populations beyond that approved in your application may be considered a violation of the promotional provisions of the Act.” In particular the company was accused of promoting the drug for indications beyond its license. As it happens we now know that that particular drug was useful for that particular indication, and it has become the standard treatment. Nonetheless, it was a transgression.
Pharmaceutical companies are naturally keen to get their product to market and they often have very large sums of money tied up in the success of any particular product. In the past when I have asked drug company reps about a particular unlicensed use of their product, they will say straight away, I am not allowed to promote that use. But if I press them for information they will have the documentation favoring that use handy. It’s just a question of pushing the right buttons. If challenged would say that they were just being helpful in my quest for knowledge. All very well if the doctor reads and judges the paper himself, rather than relying on the company’s interpretation of it.
In my previous post I reviewed the clinical trials of treatments for CLL. You may have noticed that there was nothing about Revlimid there. This is because I don’t want to encourage its use outside its license. This is what I have written previously about Revlimid:
Revlimid has not been licensed for use in CLL and neither has thalidomide. However in small phase II trials both have been shown to have some activity in CLL. Do not be persuaded to take either of these drugs unlicensed, except in the context of a clinical trial. Clinical trials have to be assessed by ethical committees. They will regard any trial as unethical if the risk to the patient is greater for taking the drug rather than avoiding it. Therefore there will be strict entry criteria for these trials, and patients entered into the trials will be closely monitored. Ideally these trials should be randomized phase III trials.
This is still true.
At ASH last year there were two abstracts on the use of Revlimid in CLL. In the first, from MD Anderson the abstract was accompanied by a statement that Revlimid had been approved for use in 5q- MDS and myeloma, and that its use in CLL should be considered off-label. Among 22 relapsed and refractory patients 7 had a response and one a CR. The major toxicity was bone marrow suppression and one patient died of a fungal infection. Tumor flare (sudden tender enlargement of lymph nodes, liver or spleen, rash and fever) occurred in 6, fatigue in 13, nausea in 10, itching in 7 and diarrhea in 5. In the other trial which was from Roswell Park, 45 relapsed and refractory patients were treated, the overall response rate was 42% with 9% CR. Similar side effects were seen as in the Houston experience, but in addition tumor lysis syndrome occurred in two.
My conclusion is that this treatment is no picnic, but because it acts in different ways to most anti-CLL treatment, it may have a role in CLL. We need more information on whether it is able to help patients with p53 deletions and whether it might synergise with existing therapies.
We have a different regulatory framework in the UK to that in the US. The FDA examines a drug to see if it is efficacious and safe. It is a balancing act. Efficacious drugs are not always safe. Even an aspirin can kill you. The FDA has to balance the good that they might do with the harm that they might do. They may put restrictions on their use. In the UK a body known as the MHRA does the same thing.
In making this assessment the FDA relies on the pharmaceutical company releasing to it all the information concerning efficacy and toxicity. As we have learned in recent times Big Pharma sometimes withholds information about toxicity, or seeks to belittle it. It is also possible to talk up the efficacy of an agent. A recent analysis of a new drug for CLL demonstrated an effect in a subset of patients. This was not an effect that the trial had been designed to detect, but one that emerged from data dredging. Subset analysis is a valid methodology, but the statistical tests that are applied to it have to be more stringent. We cannot accept that P<0.05 is significant. After all if you dredge through 20 subsets of data you are bound to find something with a 5% chance of being significant. For example, you have 20 schoolboys. Your hypothesis is that Peter is taller than the others. You have a 1 in 20 chance of being right. However if your hypothesis is one boy is taller than the others, you are almost bound to be right. In the recent British CLL trial subset analysis suggests that overall survival for patients with mutated IgVH genes is better if they are treated with chlorambucil than if they are treated with fludarabine. But that comparison is invalid, because it wasn't one of the things that the trial was designed to detect. It would have needed many more patients to be randomized. It was just this sort of analysis that the manufacturer (not of chlorambucil, I hasten to add) attempted to swing on the FDA. To their credit, the FDA spotted what was going on and refused to license the drug.
Another trick is to use the comparator drug at a lower than optimal dose. For years I have been using chlorambucil at a dose of 10mg a day for two weeks in every four. That's 140 mg per month. The average person is 1.72 sq meters in surface area, so on average I was giving 81 mg/sq m/month. Why am I not surprised when I turn to the pivotal trial for fludarabine and find that patients in the chlorambucil arm received only 40 mg/sq m/month. When I examine the Campath trial which has just shown Campath to be better than chlorambucil as first line therapy, I find that the same rather low dose of chlorambucil has been used. It's not a wrong dose of chlorambucil, but it sets the winning post a little easier to reach.
In the UK we have an organization called NICE that I have referred to before. Its job is to inform the government which drugs are cost-effective and should therefore be paid for by the NHS. It is not perfect, but it tries hard. Not every drug is examined by NICE, but when drugs are not examined, the local health purchaser has to make a decision, and it is likely to be a deal more arbitrary than the one NICE makes. In the US once a drug is licensed it can be prescribed by any doctor as long as the patient can find someone to pay for it. Very often the third party funder will look at the decision that NICE has made in the UK.
Of course the licensing does not cover every possible use a particular drug. Doctors will experiment. For example, Daunorubicin, which has been the mainstay of treatment for acute myeloid leukemia since the 1960s, but for a long period it did not have a license for this use in the UK. In India, a cardiologist who knew a bit about physiology reasoned that sildenafil would be a very useful drug for the treatment of congenital pulmonary hypertension. You can imagine the outrage at a doctor giving Viagra off-license to new-born babies. But he was right and the lives of many babies were saved by his courage.
However, pharmaceutical companies are not allowed to promote their drug for unlicensed conditions. You can imagine why the FDA was outraged to discover that 70% of prescriptions for one popular monoclonal antibody were for conditions outside the licensed indications.
Which brings me to a warning letter sent to a certain pharmaceutical company by the FDA. This is an old letter dating from 7 years ago so I shan’t name the company who no doubt have put their house in order by now. The point of the warning letter was to suggest that the company had violated the terms of the license: “statements or implications by you that this product may indeed be safe and efficacious in the treatment of diseases or patient populations beyond that approved in your application may be considered a violation of the promotional provisions of the Act.” In particular the company was accused of promoting the drug for indications beyond its license. As it happens we now know that that particular drug was useful for that particular indication, and it has become the standard treatment. Nonetheless, it was a transgression.
Pharmaceutical companies are naturally keen to get their product to market and they often have very large sums of money tied up in the success of any particular product. In the past when I have asked drug company reps about a particular unlicensed use of their product, they will say straight away, I am not allowed to promote that use. But if I press them for information they will have the documentation favoring that use handy. It’s just a question of pushing the right buttons. If challenged would say that they were just being helpful in my quest for knowledge. All very well if the doctor reads and judges the paper himself, rather than relying on the company’s interpretation of it.
In my previous post I reviewed the clinical trials of treatments for CLL. You may have noticed that there was nothing about Revlimid there. This is because I don’t want to encourage its use outside its license. This is what I have written previously about Revlimid:
Revlimid has not been licensed for use in CLL and neither has thalidomide. However in small phase II trials both have been shown to have some activity in CLL. Do not be persuaded to take either of these drugs unlicensed, except in the context of a clinical trial. Clinical trials have to be assessed by ethical committees. They will regard any trial as unethical if the risk to the patient is greater for taking the drug rather than avoiding it. Therefore there will be strict entry criteria for these trials, and patients entered into the trials will be closely monitored. Ideally these trials should be randomized phase III trials.
This is still true.
At ASH last year there were two abstracts on the use of Revlimid in CLL. In the first, from MD Anderson the abstract was accompanied by a statement that Revlimid had been approved for use in 5q- MDS and myeloma, and that its use in CLL should be considered off-label. Among 22 relapsed and refractory patients 7 had a response and one a CR. The major toxicity was bone marrow suppression and one patient died of a fungal infection. Tumor flare (sudden tender enlargement of lymph nodes, liver or spleen, rash and fever) occurred in 6, fatigue in 13, nausea in 10, itching in 7 and diarrhea in 5. In the other trial which was from Roswell Park, 45 relapsed and refractory patients were treated, the overall response rate was 42% with 9% CR. Similar side effects were seen as in the Houston experience, but in addition tumor lysis syndrome occurred in two.
My conclusion is that this treatment is no picnic, but because it acts in different ways to most anti-CLL treatment, it may have a role in CLL. We need more information on whether it is able to help patients with p53 deletions and whether it might synergise with existing therapies.
Treatment of CLL
I am in the midle of writing a review of CLL for the Lancet Oncology.
Here is a first draft of the section on treatment. The finished article will probably be nothing like this, but I wrote this to summarize the evidence from clinical trials.
The majority of patients with CLL present without symptoms or signs, simply because a blood test has been requested for an unrelated reason. Many of these patients never progress. Clearly, there is no need to treat such patients, but those who do need treatment often present in the same way. Several trials have asked whether it is safe to delay treatment until progression occurs. A meta-analysis of 2048 such patients in 7 trials randomised between immediate or deferred treatment with chlorambucil (with or without prednisolone) suggested no benefit for either arm. [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] In a French study, [Dighiero G, Maloum K, Desablens B et al. Chlorambucil in indolent chronic lymphocytic leukaemia. N Engl J Med, 1998, 338, 1506-14] 51% of patients allocated to the deferred treatment arm eventually required treatment, and 27% eventually died of a cause related to CLL.
Standard management for CLL therefore includes a period of watchful waiting until features of progression occur. These features have been codified by a working group sponsored by the American National Cancer Institute [Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7] (Table 1).
With the appearance of more effective treatments than chlorambucil and better ways of determining which patients are unlikely to progress this question should be revisited, and randomized trials of early versus delayed therapy for patients with poor-risk prognostic markers are planned or under way in Germany, the US and the UK.
Several trials have evaluated the effect of adding an anthracycline to alkylating agents in more advanced cases. A meta-analysis of 10 trials involving 2035 stage B and C patients [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] showed that the presence of an anthracycline in the combination does not affect the outcome.
Purine analogues
Although the purine analogue, fludarabine, has not been approved by the National Institute for Clinical Excellence for first line use in CLL in England and Wales, its use, either alone or in combination, has become the standard of care in most other countries. A meta-analysis [Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R; on behalf of the Cochrane Haematologic Malignancies Group.Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. Cancer Treat Rev. 2006 ;32:377-89] looked at five trials with 1838 patients randomized between an alkylator-based regimen and a purine analogue. Patients treated with a purine analogue had significantly higher overall and complete response rates, and longer progression-free survivals, that those treated with alkylator-based regimens, but overall survival was not significantly different. Three further large trials had not been evaluated at the time of analysis and we may yet see a difference in overall survival as more data accumulate. However, because patients failing one regimen may respond very well to the other arm of the study, this question may never be resolved. Because of this, because and because the natural history of CLL is so long, those conducting clinical trials have adopted ‘progression-free-survival’ as a surrogate for overall survival as the primary trial end-point. However, with such a strategy there is a danger of being misled [Cavo M, Baccarani M. The changing landscape of myeloma therapy.
N Engl J Med. 2006;354:1076-8].
The situation is further complicated by trials in which a higher dose of chlorambucil is used (70 mg/m2/month rather than 40). Response rates and progression-free survivals not significantly different from those of fludarabine may be achieved with less toxicity [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL nay be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)].
Combinations of purine analogues and alkylating agents have been tested in three randomized trials. In the American Intergroup trial [Rai KR, Peterson BL NEJM 2000; 343:1750-7] the fludarabine plus chlorambucil arm had to be abandoned as too toxic. The German CLL4 trial [Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jager U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Dohner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885-91] compared fludarabine with fludarabine plus cyclophosphamide (FC) in 375 patients under the age of 66. The British CLL4 trial [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL may be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)]
conducted a similar comparison in 390 patients without age restriction. Both found the combination significantly better in terms of overall and complete response rates and progression free survival, but there was no significant difference in overall survival. In both trials the combination was significantly more toxic.
In the British CLL4 trial the effect of prognostic markers on outcome was evaluated prospectively [Oscier DG, Wade R … Prognostic factors in the UK LRF CLL4 trial Blood 2006; 108: (suppl 1): 92a (abstract 299)]. Importantly, the prognostic factors had a greater effect on overall survival than the choice of therapy. Patients with del 17p in >20% of cells had a very short median survival, and those with mutated VH genes had a significantly longer survival than those with unmutated VH genes, no matter which treatment they were given. This clear distinction emphasises how difficult it is to compare the results of phase II trials that have taken place at different times and different places, yet it is on just such information that off-license treatment of CLL with monoclonal antibodies has become so widespread.
Another purine analogue, cladribine, has been evaluated in a three-way randomized phase III study, comparing it with its combination with cyclophosphamide or cyclophosphamide plus mitoxantrone [Robak T, Blonski JZ … Blood 2006; 108:473-9]. The three-drug combination produced significantly more responses and CR at the expense of more marrow toxicity. There were no significant differences in either progression-free or overall survival.
Immunochemotherapy
Rituximab, the chimeric, monoclonal anti-CD20, is only moderately active as a first line agent in CLL [Hainsworth JD, Litchy S,. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-51] with an overall response rate of 51% and a CR rate of only 4%. However, when added to fludarabine or FC impressive responses have been reported.
In a randomised phase II study [Byrd JC, Peterson BL… Blood 2003; 101:6-14] rituximab added to fludarabine produced higher responses when given concurrently than given sequentially. An analysis of VH mutational status and FISH for del 11q23 and del 17p13 stressed the importance of these prognostic markers in evaluating trial results [Byrd JC, Gribben JG …. J Clin Oncol 2006; 24:437-43]. The patients enrolled on this trial were compared with matched historical controls selected from the fludarabine arm a previous Cancer and Leukemia Group B trial. In a multivariate analysis controlling for pre-treatment characteristics (but not for modern prognostic markers) the addition of rituximab appeared to improve significantly progression-free and overall survival [Byrd JC, Rai K …. Blood 2005;105:49-53].
The combination of fludarabine, cyclophosphamide and rituximab (FCR) has been tested in the front-line and the relapsed and refractory setting. As first line therapy [Keating MJ, O’Brien S… J Clin Oncol 2005;23:4079-88], overall response rates of 95% with complete remissions (CR) in 70%. The same group produced overall response rates of 88% with 35% CR in historical controls treated with FC. However, only 33% of the FCR-treated patients were Rai stage III and IV, compared with 50% of the FC-treated patients, and no modern prognostic markers have been reported for either of these phase II trials.
In the relapsed and refractory setting [Wierda W, O’Brien S…. J Clin Oncol 2005; 23:4070-8; Wierda W, O’Brien S .... Cancer 2006; 106:337-45] FCR can also produce high response rates (73%) and CR (25%). Again, comparison with historical controls suggests that FCR is superior to FC or to fludarabine alone, but although the multivariate analysis included serum 2-microglobulin levels interphase cytogenetics and VH mutational status were not studied.
Another purine analogue, pentostatin, has been evaluated in combination with cyclophosphamide and rituximab in a phase II trial of previously untreated patients [Kay NE, Geyer SM …. Blood 2007; 109:405-11]. This trial is valuable in that the prognostic markers, VH gene mutations, CD38 expression, ZAP-70 expression and interphase cytogenetics were reported. The overall response rate was 91% with 41% CR. Patients with p53 anomalies had poor responses. The authors claimed that this regimen is less toxic than FCR.
In a phase II study the addition of mitoxantrone to FCR appeared to add only toxicity rather than increased efficacy [Faderl S, Wierda W… Blood 2006; 108 (suppl 1):803a (abstract 2836)].
Alemtuzumab appears to be one of the few agents capable of killing CLL cells with mutated or deleted p53 genes. It has been used as first-line therapy in a phase III trial in which it was compared with chlorambucil at a dose of 40 mg/m2/month. Overall response rate and progression-free survival were significantly better for Alemtuzumab [Hillmen P Skotnicki A …. Blood 2006; 108 (suppl 1):93a (abstract 301)].
Drug-resistant CLL
Most effective therapies for CLL require an intact p53 pathway. High dose methyl prednisolone produced an overall response rate of 77% in a cohort of patients with advanced refractory CLL [ThorntonPD, Matutes E …. Ann Hematol 2003;82:759-65] and Alemtuzumab is also able to produce high levels of response in p53 deleted CLL [Stilgenbauer S, Blood 2004; 104: (Suppl 1) 140a (abstract 478)]. The combination of these agents produced 100% response with 60% CR in a small cohort of patients with p53 defects [Petit AR, Matutes E, Oscier D. Alemtuzumab in combination with high-dosemethylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 2006; 20:1441-5].
Flavoperidol, a cyclin-dependent kinase inhibitor, has proved a very effective killer of p53 deleted CLL cells in vitro, but was almost completely ineffective in vivo because it was so highly bound to human serum albumin. By altering the infusion schedule it has been possible to obtain partial remissions of long duration in 42% of CLLs with p53 deletions [Byrd JC, Lin TS… Blood 2007; 109:399-404]
Table 1
NCI guidelines for beginning treatment
At least one of these must be present
1. At least one of the following disease-related symptoms must be present
a. Weight loss of > 10% of body weight in the previous 6 months;
b. Extreme fatigue so that the patient cannot work of perform usual activities;
c. Fevers of greater than 38°C for at least 2 weeks without evidence of infection;
d. Night sweats without evidence of infection.
2. Evidence of bone marrow failure shown by the development of, or worsening of, anemia or thrombocytopenia.
3. Autoimmune hemolytic anemia and/or thrombocytopenia poorly responsive to corticosteroids.
4. Massive (>6cm below the costal margin) or progrtessive splenomegaly.
5. Massive lymph nodes or clusters of nodes (>10 cm in longest diameter) or progressive lymphadenopathy.
6. Increase in lymphocyte count by >50% over two months or an anticipated doubling time of <6 months.
Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for
beginning therapy, nor is any particular level of lymphocyte count.
Here is a first draft of the section on treatment. The finished article will probably be nothing like this, but I wrote this to summarize the evidence from clinical trials.
The majority of patients with CLL present without symptoms or signs, simply because a blood test has been requested for an unrelated reason. Many of these patients never progress. Clearly, there is no need to treat such patients, but those who do need treatment often present in the same way. Several trials have asked whether it is safe to delay treatment until progression occurs. A meta-analysis of 2048 such patients in 7 trials randomised between immediate or deferred treatment with chlorambucil (with or without prednisolone) suggested no benefit for either arm. [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] In a French study, [Dighiero G, Maloum K, Desablens B et al. Chlorambucil in indolent chronic lymphocytic leukaemia. N Engl J Med, 1998, 338, 1506-14] 51% of patients allocated to the deferred treatment arm eventually required treatment, and 27% eventually died of a cause related to CLL.
Standard management for CLL therefore includes a period of watchful waiting until features of progression occur. These features have been codified by a working group sponsored by the American National Cancer Institute [Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, Rai KR. National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996; 87:4990-7] (Table 1).
With the appearance of more effective treatments than chlorambucil and better ways of determining which patients are unlikely to progress this question should be revisited, and randomized trials of early versus delayed therapy for patients with poor-risk prognostic markers are planned or under way in Germany, the US and the UK.
Several trials have evaluated the effect of adding an anthracycline to alkylating agents in more advanced cases. A meta-analysis of 10 trials involving 2035 stage B and C patients [CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst, 1999, 91, 861-8] showed that the presence of an anthracycline in the combination does not affect the outcome.
Purine analogues
Although the purine analogue, fludarabine, has not been approved by the National Institute for Clinical Excellence for first line use in CLL in England and Wales, its use, either alone or in combination, has become the standard of care in most other countries. A meta-analysis [Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R; on behalf of the Cochrane Haematologic Malignancies Group.Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. Cancer Treat Rev. 2006 ;32:377-89] looked at five trials with 1838 patients randomized between an alkylator-based regimen and a purine analogue. Patients treated with a purine analogue had significantly higher overall and complete response rates, and longer progression-free survivals, that those treated with alkylator-based regimens, but overall survival was not significantly different. Three further large trials had not been evaluated at the time of analysis and we may yet see a difference in overall survival as more data accumulate. However, because patients failing one regimen may respond very well to the other arm of the study, this question may never be resolved. Because of this, because and because the natural history of CLL is so long, those conducting clinical trials have adopted ‘progression-free-survival’ as a surrogate for overall survival as the primary trial end-point. However, with such a strategy there is a danger of being misled [Cavo M, Baccarani M. The changing landscape of myeloma therapy.
N Engl J Med. 2006;354:1076-8].
The situation is further complicated by trials in which a higher dose of chlorambucil is used (70 mg/m2/month rather than 40). Response rates and progression-free survivals not significantly different from those of fludarabine may be achieved with less toxicity [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL nay be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)].
Combinations of purine analogues and alkylating agents have been tested in three randomized trials. In the American Intergroup trial [Rai KR, Peterson BL NEJM 2000; 343:1750-7] the fludarabine plus chlorambucil arm had to be abandoned as too toxic. The German CLL4 trial [Eichhorst BF, Busch R, Hopfinger G, Pasold R, Hensel M, Steinbrecher C, Siehl S, Jager U, Bergmann M, Stilgenbauer S, Schweighofer C, Wendtner CM, Dohner H, Brittinger G, Emmerich B, Hallek M; German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885-91] compared fludarabine with fludarabine plus cyclophosphamide (FC) in 375 patients under the age of 66. The British CLL4 trial [Catovsky D, Else M, Richards S, Hillmen P. The lack of survival differences in randomized clinical trials in CLL may be related to the effect of second line therapies. A report from the LRF CLL4 trial. Blood 2006; 108: suppl1: 94a (abstract 304)]
conducted a similar comparison in 390 patients without age restriction. Both found the combination significantly better in terms of overall and complete response rates and progression free survival, but there was no significant difference in overall survival. In both trials the combination was significantly more toxic.
In the British CLL4 trial the effect of prognostic markers on outcome was evaluated prospectively [Oscier DG, Wade R … Prognostic factors in the UK LRF CLL4 trial Blood 2006; 108: (suppl 1): 92a (abstract 299)]. Importantly, the prognostic factors had a greater effect on overall survival than the choice of therapy. Patients with del 17p in >20% of cells had a very short median survival, and those with mutated VH genes had a significantly longer survival than those with unmutated VH genes, no matter which treatment they were given. This clear distinction emphasises how difficult it is to compare the results of phase II trials that have taken place at different times and different places, yet it is on just such information that off-license treatment of CLL with monoclonal antibodies has become so widespread.
Another purine analogue, cladribine, has been evaluated in a three-way randomized phase III study, comparing it with its combination with cyclophosphamide or cyclophosphamide plus mitoxantrone [Robak T, Blonski JZ … Blood 2006; 108:473-9]. The three-drug combination produced significantly more responses and CR at the expense of more marrow toxicity. There were no significant differences in either progression-free or overall survival.
Immunochemotherapy
Rituximab, the chimeric, monoclonal anti-CD20, is only moderately active as a first line agent in CLL [Hainsworth JD, Litchy S,. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol. 2003;21:1746-51] with an overall response rate of 51% and a CR rate of only 4%. However, when added to fludarabine or FC impressive responses have been reported.
In a randomised phase II study [Byrd JC, Peterson BL… Blood 2003; 101:6-14] rituximab added to fludarabine produced higher responses when given concurrently than given sequentially. An analysis of VH mutational status and FISH for del 11q23 and del 17p13 stressed the importance of these prognostic markers in evaluating trial results [Byrd JC, Gribben JG …. J Clin Oncol 2006; 24:437-43]. The patients enrolled on this trial were compared with matched historical controls selected from the fludarabine arm a previous Cancer and Leukemia Group B trial. In a multivariate analysis controlling for pre-treatment characteristics (but not for modern prognostic markers) the addition of rituximab appeared to improve significantly progression-free and overall survival [Byrd JC, Rai K …. Blood 2005;105:49-53].
The combination of fludarabine, cyclophosphamide and rituximab (FCR) has been tested in the front-line and the relapsed and refractory setting. As first line therapy [Keating MJ, O’Brien S… J Clin Oncol 2005;23:4079-88], overall response rates of 95% with complete remissions (CR) in 70%. The same group produced overall response rates of 88% with 35% CR in historical controls treated with FC. However, only 33% of the FCR-treated patients were Rai stage III and IV, compared with 50% of the FC-treated patients, and no modern prognostic markers have been reported for either of these phase II trials.
In the relapsed and refractory setting [Wierda W, O’Brien S…. J Clin Oncol 2005; 23:4070-8; Wierda W, O’Brien S .... Cancer 2006; 106:337-45] FCR can also produce high response rates (73%) and CR (25%). Again, comparison with historical controls suggests that FCR is superior to FC or to fludarabine alone, but although the multivariate analysis included serum 2-microglobulin levels interphase cytogenetics and VH mutational status were not studied.
Another purine analogue, pentostatin, has been evaluated in combination with cyclophosphamide and rituximab in a phase II trial of previously untreated patients [Kay NE, Geyer SM …. Blood 2007; 109:405-11]. This trial is valuable in that the prognostic markers, VH gene mutations, CD38 expression, ZAP-70 expression and interphase cytogenetics were reported. The overall response rate was 91% with 41% CR. Patients with p53 anomalies had poor responses. The authors claimed that this regimen is less toxic than FCR.
In a phase II study the addition of mitoxantrone to FCR appeared to add only toxicity rather than increased efficacy [Faderl S, Wierda W… Blood 2006; 108 (suppl 1):803a (abstract 2836)].
Alemtuzumab appears to be one of the few agents capable of killing CLL cells with mutated or deleted p53 genes. It has been used as first-line therapy in a phase III trial in which it was compared with chlorambucil at a dose of 40 mg/m2/month. Overall response rate and progression-free survival were significantly better for Alemtuzumab [Hillmen P Skotnicki A …. Blood 2006; 108 (suppl 1):93a (abstract 301)].
Drug-resistant CLL
Most effective therapies for CLL require an intact p53 pathway. High dose methyl prednisolone produced an overall response rate of 77% in a cohort of patients with advanced refractory CLL [ThorntonPD, Matutes E …. Ann Hematol 2003;82:759-65] and Alemtuzumab is also able to produce high levels of response in p53 deleted CLL [Stilgenbauer S, Blood 2004; 104: (Suppl 1) 140a (abstract 478)]. The combination of these agents produced 100% response with 60% CR in a small cohort of patients with p53 defects [Petit AR, Matutes E, Oscier D. Alemtuzumab in combination with high-dosemethylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects. Leukemia 2006; 20:1441-5].
Flavoperidol, a cyclin-dependent kinase inhibitor, has proved a very effective killer of p53 deleted CLL cells in vitro, but was almost completely ineffective in vivo because it was so highly bound to human serum albumin. By altering the infusion schedule it has been possible to obtain partial remissions of long duration in 42% of CLLs with p53 deletions [Byrd JC, Lin TS… Blood 2007; 109:399-404]
Table 1
NCI guidelines for beginning treatment
At least one of these must be present
1. At least one of the following disease-related symptoms must be present
a. Weight loss of > 10% of body weight in the previous 6 months;
b. Extreme fatigue so that the patient cannot work of perform usual activities;
c. Fevers of greater than 38°C for at least 2 weeks without evidence of infection;
d. Night sweats without evidence of infection.
2. Evidence of bone marrow failure shown by the development of, or worsening of, anemia or thrombocytopenia.
3. Autoimmune hemolytic anemia and/or thrombocytopenia poorly responsive to corticosteroids.
4. Massive (>6cm below the costal margin) or progrtessive splenomegaly.
5. Massive lymph nodes or clusters of nodes (>10 cm in longest diameter) or progressive lymphadenopathy.
6. Increase in lymphocyte count by >50% over two months or an anticipated doubling time of <6 months.
Marked hypogammaglobulinemia or the development of a monoclonal protein in the absence of any of the above criteria for active disease is not sufficient for
beginning therapy, nor is any particular level of lymphocyte count.
Friday, February 02, 2007
Military matters
Today I have posted in full from Hansard a speech on military matters by Tobias Ellwood, who is my local MP. He seems to know a thing or two about military matters
I pay tribute to the hon. Member for Plymouth, Sutton (Linda Gilroy) for her commitment to Devonport. Unfortunately, such is the state of the Navy that there is competition between the three main service bases as to which will remain intact. That is a debate for another day, but the hon. Lady spoke about her constituency with commitment and intellect.
We have had a frank, open and educational debate, which has rightly focused on Iraq and Afghanistan, as those are the areas in which we are heavily involved. The backdrop to the debate is the Prime Minister's comment on board HMS Albion on Friday 12 January:
"Britain has to choose whether to be on the front line of the global fight against terrorism or to retreat to a peacekeeping role."
Perhaps we should mention that choice to our NATO allies. We have committed more than 7,000 troops to Iraq and 5,700 to Afghanistan. Unfortunately, however, the Prime Minister's words stand in stark contrast to our military capability because, since 1997, there has been a dramatic fall in the size of our Army, Navy and Air Force and the procurement process has changed drastically: the number of aircraft carriers has been cut from three to two; the number of T-45 destroyers from 12 to six; the number of infantry regiments from 40 to 36; and the number of Eurofighters has been reduced, too. Will the Minister make a commitment to maintain the Red Arrows, as there is a shadow hanging over the pride and joy of the British skies? Will he assure the nation that there is a future for that important asset in his winding-up speech? There has been a great deal of discussion about the procurement process and its effect on equipment, notably the Snatch Land Rovers, which are inadequate in both Afghanistan and Iraq, so perhaps the Minister would be gracious enough to comment on that, too.
We are approaching the fourth anniversary of the invasion of Iraq, and I am afraid that I do not agree with the glossy picture that has been painted in an effort to suggest that things are going well. I am pleased that General Dannatt was able to expose the reality of the situation, because only three of the 18 provinces in Iraq have been handed over to Iraqi control. Depending on which figures one uses, about 600,000 people have been killed since the 2003 invasion, and an average of 3,500 individuals are killed every month, according to a recent UN report. In fact, Baghdad has built a second morgue that can accept 250 bodies a day. That is the state of affairs in Iraq: we face civil war, so we must address the problem.
I have said many times that I never supported the war itself, which was a distraction from the real concern—Afghanistan. However, we are where we are. We have heard important voices such as Carne Ross, the former first secretary of the British delegation to the UN, who testified to the Butler inquiry that there were no weapons of mass destruction. We heard, too, from 52 diplomats, including former ambassadors to Baghdad and Tel Aviv, who questioned the Government's middle east policy, which has caused us to endure many problems. A fundamental flaw in our ability to deal with Iraq stemmed from the fact that the previous Secretary of State for International Development, the right hon. Member for Birmingham, Ladywood (Clare Short), refused to participate in post-conflict work. We therefore missed the opportunity to win over hearts and minds and begin work on the reconstruction projects that were very much needed in the first few months after the main conflict.
The second fundamental error was the disbandment of the Ba'ath party. I intervened on the Defence Secretary and I was pleased that he finally acknowledged that that was a schoolboy error. It should not have been done. We immediately got rid of the army and the police force, but 80 per cent. of the current army and police force are former members of the Ba'ath party. Not only that—we also got rid of all the doctors, nurses and teachers. They all went home because they were not allowed to work, yet the majority of them wanted nothing to do with Saddam Hussein. They were simply working as best they could in the environment that existed then.
The biggest problem is the friction between the Shi'ites and the Sunnis. The bombing on 22 February last year of the al-Askari shrine, the Shi'ites' most holy site, was the tipping point. Since then, Sunnis and Shi'a have found it harder and harder to work together. There is a growing insurgency. Many of the political groupings are linked to militias, and that is taking the country further into civil war.
Will the Minister comment on the growth of the militias, particularly the Mahdi army, which is one of the largest? I cannot see the leaders in Iraq disbanding these groups. First, they do not have the power, and secondly, the militias are helping them to remain in power. On 6 October last year, an entire Iraqi police brigade was taken out of service because it had links with death squads and looting, turning a blind eye to such activities.
On training, we were supposed to have reached a target now, four years after the invasion, of 400,000 trained Iraqi security personnel. We are not even close to 275,000. The Pentagon has stopped releasing assessments of the number of trained Iraqi soldiers, because they are not accurate and the numbers are in decline.
The blueprint that we have for Iraq is wrong. The US is in a quagmire, and erroneous assumptions have been made about the readiness of the Iraq Government to take over. We are in denial if we believe that. There is corruption and looting, and al-Maliki has little interest in disarming the warring factions. We are not winning hearts and minds, as we should do, and there is a growing opinion that ethnic tensions have gone too far.
We are obsessed with keeping the original borders. Tens of billions have been spent to try and avoid civil war, but that has failed. We could easily move a third of the population of 28 million, build houses, roads and all the infrastructure that is required for towns and villages, and divide the country in three on a model similar to the United Arab Emirates. We have a choice. We can change the blueprint and consider that option, or we can continue as we are doing and end up with a divided country anyway, but one divided by war.
I conclude with some comments about Afghanistan. Iraq played a huge role in what is going on there. Too few troops went in—30,000 to begin with. Only four years later, in 2005, did we get to the heart of the Taliban's operations in Helmand province. Even now, in neighbouring Nimruz province, there is not a single NATO soldier. I ask the Minister to shout to our allies, "Where are you? Why are you not with us fighting the battles out there? Please come and join us in Afghanistan, but leave your caveats behind." The British are doing most of the work, along with our colleagues, such as the Canadians and the Americans, but where are the French, the Germans and the Turks? We will not win in Afghanistan unless we have more troops there and a more co-ordinated effort.
My final point relates to the shortage of diamorphine in the United Kingdom. It seems ironic that when we have G8 responsibility for counter-narcotics in Afghanistan, a shortage in the UK of a commodity that is made from poppies, and responsibility for Helmand province, where a third of the world's narcotics come from, we cannot come up with a solution that involves licensing the poppy crops and preventing the terrorists from gaining from that income.
I pay tribute to the hon. Member for Plymouth, Sutton (Linda Gilroy) for her commitment to Devonport. Unfortunately, such is the state of the Navy that there is competition between the three main service bases as to which will remain intact. That is a debate for another day, but the hon. Lady spoke about her constituency with commitment and intellect.
We have had a frank, open and educational debate, which has rightly focused on Iraq and Afghanistan, as those are the areas in which we are heavily involved. The backdrop to the debate is the Prime Minister's comment on board HMS Albion on Friday 12 January:
"Britain has to choose whether to be on the front line of the global fight against terrorism or to retreat to a peacekeeping role."
Perhaps we should mention that choice to our NATO allies. We have committed more than 7,000 troops to Iraq and 5,700 to Afghanistan. Unfortunately, however, the Prime Minister's words stand in stark contrast to our military capability because, since 1997, there has been a dramatic fall in the size of our Army, Navy and Air Force and the procurement process has changed drastically: the number of aircraft carriers has been cut from three to two; the number of T-45 destroyers from 12 to six; the number of infantry regiments from 40 to 36; and the number of Eurofighters has been reduced, too. Will the Minister make a commitment to maintain the Red Arrows, as there is a shadow hanging over the pride and joy of the British skies? Will he assure the nation that there is a future for that important asset in his winding-up speech? There has been a great deal of discussion about the procurement process and its effect on equipment, notably the Snatch Land Rovers, which are inadequate in both Afghanistan and Iraq, so perhaps the Minister would be gracious enough to comment on that, too.
We are approaching the fourth anniversary of the invasion of Iraq, and I am afraid that I do not agree with the glossy picture that has been painted in an effort to suggest that things are going well. I am pleased that General Dannatt was able to expose the reality of the situation, because only three of the 18 provinces in Iraq have been handed over to Iraqi control. Depending on which figures one uses, about 600,000 people have been killed since the 2003 invasion, and an average of 3,500 individuals are killed every month, according to a recent UN report. In fact, Baghdad has built a second morgue that can accept 250 bodies a day. That is the state of affairs in Iraq: we face civil war, so we must address the problem.
I have said many times that I never supported the war itself, which was a distraction from the real concern—Afghanistan. However, we are where we are. We have heard important voices such as Carne Ross, the former first secretary of the British delegation to the UN, who testified to the Butler inquiry that there were no weapons of mass destruction. We heard, too, from 52 diplomats, including former ambassadors to Baghdad and Tel Aviv, who questioned the Government's middle east policy, which has caused us to endure many problems. A fundamental flaw in our ability to deal with Iraq stemmed from the fact that the previous Secretary of State for International Development, the right hon. Member for Birmingham, Ladywood (Clare Short), refused to participate in post-conflict work. We therefore missed the opportunity to win over hearts and minds and begin work on the reconstruction projects that were very much needed in the first few months after the main conflict.
The second fundamental error was the disbandment of the Ba'ath party. I intervened on the Defence Secretary and I was pleased that he finally acknowledged that that was a schoolboy error. It should not have been done. We immediately got rid of the army and the police force, but 80 per cent. of the current army and police force are former members of the Ba'ath party. Not only that—we also got rid of all the doctors, nurses and teachers. They all went home because they were not allowed to work, yet the majority of them wanted nothing to do with Saddam Hussein. They were simply working as best they could in the environment that existed then.
The biggest problem is the friction between the Shi'ites and the Sunnis. The bombing on 22 February last year of the al-Askari shrine, the Shi'ites' most holy site, was the tipping point. Since then, Sunnis and Shi'a have found it harder and harder to work together. There is a growing insurgency. Many of the political groupings are linked to militias, and that is taking the country further into civil war.
Will the Minister comment on the growth of the militias, particularly the Mahdi army, which is one of the largest? I cannot see the leaders in Iraq disbanding these groups. First, they do not have the power, and secondly, the militias are helping them to remain in power. On 6 October last year, an entire Iraqi police brigade was taken out of service because it had links with death squads and looting, turning a blind eye to such activities.
On training, we were supposed to have reached a target now, four years after the invasion, of 400,000 trained Iraqi security personnel. We are not even close to 275,000. The Pentagon has stopped releasing assessments of the number of trained Iraqi soldiers, because they are not accurate and the numbers are in decline.
The blueprint that we have for Iraq is wrong. The US is in a quagmire, and erroneous assumptions have been made about the readiness of the Iraq Government to take over. We are in denial if we believe that. There is corruption and looting, and al-Maliki has little interest in disarming the warring factions. We are not winning hearts and minds, as we should do, and there is a growing opinion that ethnic tensions have gone too far.
We are obsessed with keeping the original borders. Tens of billions have been spent to try and avoid civil war, but that has failed. We could easily move a third of the population of 28 million, build houses, roads and all the infrastructure that is required for towns and villages, and divide the country in three on a model similar to the United Arab Emirates. We have a choice. We can change the blueprint and consider that option, or we can continue as we are doing and end up with a divided country anyway, but one divided by war.
I conclude with some comments about Afghanistan. Iraq played a huge role in what is going on there. Too few troops went in—30,000 to begin with. Only four years later, in 2005, did we get to the heart of the Taliban's operations in Helmand province. Even now, in neighbouring Nimruz province, there is not a single NATO soldier. I ask the Minister to shout to our allies, "Where are you? Why are you not with us fighting the battles out there? Please come and join us in Afghanistan, but leave your caveats behind." The British are doing most of the work, along with our colleagues, such as the Canadians and the Americans, but where are the French, the Germans and the Turks? We will not win in Afghanistan unless we have more troops there and a more co-ordinated effort.
My final point relates to the shortage of diamorphine in the United Kingdom. It seems ironic that when we have G8 responsibility for counter-narcotics in Afghanistan, a shortage in the UK of a commodity that is made from poppies, and responsibility for Helmand province, where a third of the world's narcotics come from, we cannot come up with a solution that involves licensing the poppy crops and preventing the terrorists from gaining from that income.
Thursday, February 01, 2007
LIST
This a list of the notable things about Britain in no particular order.
The discovery of the DNA code by Francis Crick
Smallpox vaccination by Edward Jenner
Monty Python
Godfrey Hounsfield's CT scanner
The old course at St Andrews
Baden-Powell's boy scouts
Rudyard Kipling
The Archers
Frank Whittle and the jet engine
The Tollpuddle martyrs and the birth of Trades Union
Dolly the sheep
The ss Queen Mary
Michael Faraday
The Medical Research Council and the randomised clinical trial
Isambard Kingdom Brunel
The 1611 translation of the Bible
The link between cigarette smoking and lung cancer
The British Council
The eccentric scientist working alone (viz. Peter Mitchell)
John Wesley and Methodism
Brighton Pavilion
James Black's designer drugs
God's Englishman, Oliver Cromwell
Manchester United
The Royal Mail
The National Trust
William Harvey and the circulation of blood
The New Forest
The Spitfire
Lister's antiseptic surgery
The Lake District
Handel's Messiah
Public hanging at Tyburn
Ronald Ross's discovery of how malaria is transmitted
Poets' corner
Jarrow marchers
Charles Rennie Mackintosh
Cranmer's book of common prayer
The 11-plus
Ration books
Sir Christopher Wren
Driving on the left
The Broad Street Pump incident
The Royal Society
The cathedral choir
The miners' strike
English cheeses
The parish council
Speakers' corner
Shirley Bassey
Yorkshire pudding
Hampden Court Maze
The E type Jaguar
The playing fields of Eton
Blackpool Tower and Pleasure beach
The Times crossword puzzle
Earl Grey tea
The blitz
The Raj
Mary Shelley's Frankenstein
The Flying Scotsman
Dan Dare and the Mekon
Ballroom dancing
Coarse fishing
The London sewers
Dinosaurs in Dorset
The Arsenal offside trap
The Lancet
Lords
Waterloo (the battle not the station)
"Brief Encounter"
Morris dancers+
The Notting Hill Carnival
Mary Jones' Bible (Bala)
Understatement
Polo
Sun headlines
The Royal Aircraft Establishment at Farnborough
The smell at Lipton's and the Home and Colonial
Double Decker buses
Old English Marmalade
Real tennis
Litotes
The leg-before-wicket law
The Goons
The six wives of Henry VIII
Sherlock Holmes
Twickenham
The list is not exhaustive
The discovery of the DNA code by Francis Crick
Smallpox vaccination by Edward Jenner
Monty Python
Godfrey Hounsfield's CT scanner
The old course at St Andrews
Baden-Powell's boy scouts
Rudyard Kipling
The Archers
Frank Whittle and the jet engine
The Tollpuddle martyrs and the birth of Trades Union
Dolly the sheep
The ss Queen Mary
Michael Faraday
The Medical Research Council and the randomised clinical trial
Isambard Kingdom Brunel
The 1611 translation of the Bible
The link between cigarette smoking and lung cancer
The British Council
The eccentric scientist working alone (viz. Peter Mitchell)
John Wesley and Methodism
Brighton Pavilion
James Black's designer drugs
God's Englishman, Oliver Cromwell
Manchester United
The Royal Mail
The National Trust
William Harvey and the circulation of blood
The New Forest
The Spitfire
Lister's antiseptic surgery
The Lake District
Handel's Messiah
Public hanging at Tyburn
Ronald Ross's discovery of how malaria is transmitted
Poets' corner
Jarrow marchers
Charles Rennie Mackintosh
Cranmer's book of common prayer
The 11-plus
Ration books
Sir Christopher Wren
Driving on the left
The Broad Street Pump incident
The Royal Society
The cathedral choir
The miners' strike
English cheeses
The parish council
Speakers' corner
Shirley Bassey
Yorkshire pudding
Hampden Court Maze
The E type Jaguar
The playing fields of Eton
Blackpool Tower and Pleasure beach
The Times crossword puzzle
Earl Grey tea
The blitz
The Raj
Mary Shelley's Frankenstein
The Flying Scotsman
Dan Dare and the Mekon
Ballroom dancing
Coarse fishing
The London sewers
Dinosaurs in Dorset
The Arsenal offside trap
The Lancet
Lords
Waterloo (the battle not the station)
"Brief Encounter"
Morris dancers+
The Notting Hill Carnival
Mary Jones' Bible (Bala)
Understatement
Polo
Sun headlines
The Royal Aircraft Establishment at Farnborough
The smell at Lipton's and the Home and Colonial
Double Decker buses
Old English Marmalade
Real tennis
Litotes
The leg-before-wicket law
The Goons
The six wives of Henry VIII
Sherlock Holmes
Twickenham
The list is not exhaustive
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