The one who sent me is with me; he has not left me alone, for I always do what pleases him.” Even as he spoke, many believed in him.
So much of John's gospel emphasises the intimate relationship between the different persons of the Trinity. Even though the word "Trinity" is not mentioned in the Bible, you would have to be wilfully blind not to see it in John's Gospel.
No wonder many believed in him.
Tuesday, December 06, 2011
Lying
Two recent news items have drawn me to the idea of truth. We know that Pilate asked "What is Truth?" but he was talking about how truth is relative and we might all see it from our own viewpoint. No, what I am taking about is blatant lying.
The first incident concerned a convicted murderer; a farmer who had killed his wife and buried her and then sworn at his trial that he was innocent. Now some years later he had confessed and shown the police where the body was buried. At his trial he had just told lies under oath. Nevertheless he had a wedge of supporters who were crying about a miscarriage of justice.
The second case concerned a railway station manager in the New Forrest who had broken the safety regulations at a level crossing and been dismissed from his job. He was now seeking unfair dismissal in view of the fact that someone had left a shopping trolley on the line, and he had had to remove it. I remember the case on the Local TV news and it garnered a lot of public sympathy. We now hear (though not on TV) that this was a tissue of lies. There was no shopping trolley. Case dismissed.
A news item tells us that only 22% of BBC employees claim to be Christians. The largest group are atheists. I imagine that most who claim Christianity are tea-ladies and cleaners. The intellectual elite there are secular humanists. That being so, what is the point of them giving evidence under oath? In days past people feared fro their immortal soul. Nowadays they don't believe they have a soul.
What is the absolute standard of truthfulness? A man's word? Recent happenings have putrefied the word of politicians (expenses scandal), journalists (Levenson enquiry), the police (Stephen Lawrence case) civil servants (economical with the truth), celebrities (X-Factor), businessmen (Financial disasters) and scientists (global warming). The same can be extended to priests, who openly declare that they are taking office (and stipends) when they do not believe in God, and doctors who hide the truth from dying patients.
We know that eye-witnesses can be mistaken, photographs can be Photo shopped, and DNA can be contaminated. Criminals can beat lie-detector tests. Experienced judges have a higher conviction rate than lay-juries. Are they less gullible or more cynical?
Should we believe anyome?
The first incident concerned a convicted murderer; a farmer who had killed his wife and buried her and then sworn at his trial that he was innocent. Now some years later he had confessed and shown the police where the body was buried. At his trial he had just told lies under oath. Nevertheless he had a wedge of supporters who were crying about a miscarriage of justice.
The second case concerned a railway station manager in the New Forrest who had broken the safety regulations at a level crossing and been dismissed from his job. He was now seeking unfair dismissal in view of the fact that someone had left a shopping trolley on the line, and he had had to remove it. I remember the case on the Local TV news and it garnered a lot of public sympathy. We now hear (though not on TV) that this was a tissue of lies. There was no shopping trolley. Case dismissed.
A news item tells us that only 22% of BBC employees claim to be Christians. The largest group are atheists. I imagine that most who claim Christianity are tea-ladies and cleaners. The intellectual elite there are secular humanists. That being so, what is the point of them giving evidence under oath? In days past people feared fro their immortal soul. Nowadays they don't believe they have a soul.
What is the absolute standard of truthfulness? A man's word? Recent happenings have putrefied the word of politicians (expenses scandal), journalists (Levenson enquiry), the police (Stephen Lawrence case) civil servants (economical with the truth), celebrities (X-Factor), businessmen (Financial disasters) and scientists (global warming). The same can be extended to priests, who openly declare that they are taking office (and stipends) when they do not believe in God, and doctors who hide the truth from dying patients.
We know that eye-witnesses can be mistaken, photographs can be Photo shopped, and DNA can be contaminated. Criminals can beat lie-detector tests. Experienced judges have a higher conviction rate than lay-juries. Are they less gullible or more cynical?
Should we believe anyome?
Bereavement
I have been watching the Danish thriller, The Killing, continuing my exploration of Continental dramas with subtitles. What has particularly impressed me has been the acting of Bjarne Henriksen, who plays the father of the murdered girl. Whether or not he turns out to be involved, I know not, but the way he has dealt with the emotion of grief has been impressive. On Sunday, I watched the latest episode of Garrow's Law on BBC1 where Garrow says that he understands what a woman feels who has just lost her father. She protests that no-one could. But Garrow has just been bereaved of his friend and fellow-lawyer, Southouse, and is able to eloquently describe the feelings of grief.
The words sounded familiar and, of course they are very reminiscent of Shadowlands, the story of the bereavement of CS Lewis, when his wife Joy died. I recommend both versions, either with Anthony Hopkins or Joss Ackland. Both are based on the little book "A Grief Observed" finally published posthumously under his own name. "A Grief Observed comprises the reflections of the great scholar and Christian apologist on the death of his wife after only a few short years of marriage. Painfully honest in its dissection of his thoughts and feelings, this is a book that details his paralysing grief, bewilderment and sense of loss in simple and moving prose." says the blurb and it is very accurate.
In The Killing, the Lutheran Pastor makes the crass statement to the mother of the murdered girl, "At least she is now with the Angels." To which the mother angrily replies, "She shouldn't be with the Angels; she should be with me!" It ill betides any doctor or Pastor to meddle with a person's grief.
Very few doctors or pastors have no trouble with their own mortality. I know the Scriptures on this, and I had my moment of reconciliation with God more than 35 years ago when my father died, but I felt the pastoral counselling that I received then pretty useless.
I know a few old ladies who grieve terribly for their lost husbands of more than 30 years ago. It would be easy to say that they should put it aside now. That if theirs was a true faith that they would lost that burden at the foot of the cross, but I would never make that judgment. People are always different. There were many who waited for that long and longer for Jesus to take away that burden.
Anna, the daughter of Phanuel, had lived with her husband for seven years and then was a widow until she was 84. She never left the Temple but worshipped night and day, fasting and praying, waiting for the Christ Child.
Grief is unpredictable and although wew can remember to give a sympathetic hug, very few of us can find the correct form of gentle words to assuage it.
The words sounded familiar and, of course they are very reminiscent of Shadowlands, the story of the bereavement of CS Lewis, when his wife Joy died. I recommend both versions, either with Anthony Hopkins or Joss Ackland. Both are based on the little book "A Grief Observed" finally published posthumously under his own name. "A Grief Observed comprises the reflections of the great scholar and Christian apologist on the death of his wife after only a few short years of marriage. Painfully honest in its dissection of his thoughts and feelings, this is a book that details his paralysing grief, bewilderment and sense of loss in simple and moving prose." says the blurb and it is very accurate.
In The Killing, the Lutheran Pastor makes the crass statement to the mother of the murdered girl, "At least she is now with the Angels." To which the mother angrily replies, "She shouldn't be with the Angels; she should be with me!" It ill betides any doctor or Pastor to meddle with a person's grief.
Very few doctors or pastors have no trouble with their own mortality. I know the Scriptures on this, and I had my moment of reconciliation with God more than 35 years ago when my father died, but I felt the pastoral counselling that I received then pretty useless.
I know a few old ladies who grieve terribly for their lost husbands of more than 30 years ago. It would be easy to say that they should put it aside now. That if theirs was a true faith that they would lost that burden at the foot of the cross, but I would never make that judgment. People are always different. There were many who waited for that long and longer for Jesus to take away that burden.
Anna, the daughter of Phanuel, had lived with her husband for seven years and then was a widow until she was 84. She never left the Temple but worshipped night and day, fasting and praying, waiting for the Christ Child.
Grief is unpredictable and although wew can remember to give a sympathetic hug, very few of us can find the correct form of gentle words to assuage it.
health news
I have finally heard from the Cancer drug fund. The news came through at about 5-45 this evening (Monday). The monoclonal antibody has been approved and I should be able to get it this week.
First I have arranged for my ascites to be tapped this week which should be able to relieve me from the abdominal pressure that I have been increasingly suffering from.
First I have arranged for my ascites to be tapped this week which should be able to relieve me from the abdominal pressure that I have been increasingly suffering from.
Sunday, December 04, 2011
John 8:28. Crucifixion is coming
So Jesus said, “When you have lifted up the Son of Man, then you will know that I am he and that I do nothing on my own but speak just what the Father has taught me.
Jesus knew how he was to die. Here he predicted it. The crucifixion is coming. They will know the answer then if they will only open their eyes.
Jesus knew how he was to die. Here he predicted it. The crucifixion is coming. They will know the answer then if they will only open their eyes.
Remembrance 2011
Gary Speed, MBE: the young men stand with red knees glowing
Perplexed as they applaud at Cardiff, Liverpool and Leeds.
He had it all; fame, kids, nice wife and home, success; still showing
Despite their grief, that these will never satisfy their needs.
Eleven eleven eleven; time to remember the dead and missing.
Black garbed crows with ribbons, wreaths and sticks
March fearlessly this time, ignoring boos and bitter hissing
Of the Muslims, students, and mad anarchists thrown in the mix.
We are not saved by this display of silent drinking and eating
Of scraps of desiccated bread and cups of inferior wine.
The precious act that we remember was totally sin-defeating
And it demolished yours just as it forever abolished mine
Perplexed as they applaud at Cardiff, Liverpool and Leeds.
He had it all; fame, kids, nice wife and home, success; still showing
Despite their grief, that these will never satisfy their needs.
Eleven eleven eleven; time to remember the dead and missing.
Black garbed crows with ribbons, wreaths and sticks
March fearlessly this time, ignoring boos and bitter hissing
Of the Muslims, students, and mad anarchists thrown in the mix.
We are not saved by this display of silent drinking and eating
Of scraps of desiccated bread and cups of inferior wine.
The precious act that we remember was totally sin-defeating
And it demolished yours just as it forever abolished mine
Saturday, December 03, 2011
John 8:26-27: tell them about the father
“I have much to say in judgment of you. But he who sent me is trustworthy, and what I have heard from him I tell the world.” They did not understand that he was telling them about his Father.
Isn't it dangerous to be guided by the blind? Much of the Christian church is guided by the blind or at very least the near-sighted. Visionaries like John Stott, Jim Packer, Alec Moyteer, Billy Graham, Michael Green and Dick Lucas are old men now, but read their writings. Look out for Michael Ots our own home-grown evangelist if we are hear the truth about God.
We are all to be witnesses but some are called to be evangelists.
Isn't it dangerous to be guided by the blind? Much of the Christian church is guided by the blind or at very least the near-sighted. Visionaries like John Stott, Jim Packer, Alec Moyteer, Billy Graham, Michael Green and Dick Lucas are old men now, but read their writings. Look out for Michael Ots our own home-grown evangelist if we are hear the truth about God.
We are all to be witnesses but some are called to be evangelists.
Up-to-date news.
I am sitting in my office looking out on a beautiful day. The sun is shining and although it is not hot, we have a temperature of about 53 degrees F and a soft SW breeze. The leaves on the trees are yellow and gold and the sky is light blue with small patches of white.
My wife is polishing the wood block floor and there is a delicious smell of polish mingled with a beef casserole in the oven.
I should hear about the monoclonal antibody on Monday afternoon. The delay has been because the chairman of the Committee (don't you hate that word) has been on annual leave and nobody has been brave enough to take the decision until he returns.
I was told by a patient who was an Insurance man that taking out Private Medical Insurance in the UK was not cost effective. Companies like PPP and BUPA were frauds against the general public. You can get a good deal through a company scheme, but if you have to fund it yourself, you would find it more cost effective to put your money in Unit Trusts via a PEP or ISA scheme that shields the growth from tax and draw on it when you need it. This is what I shall do if the answer on Monday is NO.
Talking of medical insurance, it seems to me that NICE has taken a strange view of what medication it should be supporting. If it were dealing with car insurance rather than medical insurance it would not be funding low cost items. We all have an excess on our car policies. The first £350 of damages incurred in an accident I pay myself so as not to lose my no-claims benefit. I can afford to pay that myself. It's the £10,000 write off bill and the £1 million damages when the other driver loses a limb that I want help with. So it should be with medical expenses. I can buy my own indigestion medicine, I need help with long term treatment for a handicapped child or maintenance therapy for cystic fibrosis or for cancer therapy.
My general health is quite good though I have to be careful only to eat small meals. My main problem is ascites - fluid secreted by the cancer and accumulating in the peritoneum between loops of bowel. At some stage this will need to be drained away with a thin plastic tube under ultrasound guidance.
My daughter the hematology registrar is on-call in Oxford this weekend. Among her patients is one who has a very difficult lymphoma with translocations on both chromosome 14s at the site of the promoter for the Ig heavy chain gene. On one chromosome the translocation is to BCL-2 and on the other to c-myc. This is a very rare combination and in the literature there are no long term survivors. It is ironic that I described the first such case back in the early 1980s.
My son, the F1 engineer, has finished his globe trotting to Grand Prix and in future will be in charge of procuring and providing at AP Racing. He has been thrown in the deep end with a computer glitch which he has sorted much to the approval of the CEO.
My older son, will be emigrating to New Zealand on Jan 7th. He has been head-hunted to do healthcare risk management there. Apparently his Visa came through in two days, so keen were they to have him. He is glad to leave the CQC which has become mired in an internecine dispute engineered by a two supposed whistleblowers. One is a passed over inspector, not clever enough to advance in her division (she can't grasp Bayesian statistics) and now angling for 'constructive dismissal' and the other is a Board Member who was appointed for her special interest in mental disease; her special interest being that she had suffered from it and was getting increasingly disturbed as the year went on.
My older daughter took voluntary redundancy earlier in the year and has set up her own company doing business analysis. In the meantime she is in partnership with her step-son in an arts and crafts business which is making and selling objets-arts around Christmas time.
I ought to explain what the monoclonal antibody does:
Every cell in the body needs to either grow or die. This is as true for normal cells as cancer cells. Each cell receives a growth signal from a growth factor which reacts with a growth factor receptor on the cell surface. This message is then transmitted to the nucleus where a transcription factor sets the cell dividing at its set rate. This will be different for a skin cell compared to a blood cell compared to a brain cell. Cancer cells will tend to divide faster.
The message must be taken from the cell surface to the nucleus by a series of second messengers. Mistakes (mutations) can take place in the growth factor, the growth factor receptor, any of the second messengers or the transcription factors. A common mistake is in the second messenger k-ras and it is known that these monoclonal antibodies, which block the epidermal growth factor receptor do not work very well if k-ras is mutated. Happily mine is not.
In view of the fact that my disease is very indolent (in its metastatic form it has been present for over 3 years) the cancer does not seem to be carrying too many mutations and I have every hope that EGFR blockade with this monoclonal will be successful.
In the football it is an important weekend for the Premier League. Chelsea have just beaten Newcastle and later today Man U play Aston Villa, Spurs play Bolton, and Man C play Norwich. These are all games that could go either way and the Champions will come from this group of clubs. England were fortunate with the draw for the European Championships and will not have to meet a really top team until Wayne Rooney returns from suspension.
In the News today is a report which suggests that 3000 women in Britain are suffering from so-called "honor beatings" from family members because of the alien "shame culture" brought into Britain by (mostly) Muslims. And Jacques DeLors, the instigator of the Euro, has admitted that it was badly introduced since most countries, including Germany, broke the entry rules.
For all Biblical Creation Society members who may be reading this blog, thank you for your prayers. Another explanation for why my cancer has taken so long to kill me is that I am being sustained by the prayers of Christians all over the world, and because in response to those prayers the Holy Spirit still finds me useful where I am am rather than in taking me home. If that is the case would you pray that he keeps me free from pain and keeps making innovative suggestions on how I may more easily bear this period of difficulty. In particular I should like wisdom on when it would be right to tap the ascites.
It has been a very eventful week with fillings falling out, dishwasher delays, eyesight tests, earwax bothers, monoclonal hold-ups, bad days, good days, CT scan, visits from children and grandchildren, reading too late some nights, sleeping too long some mornings, a fall down stairs, and difficult decisions; but the Lord has brought me through all this and does sustain me in the worst of times.
I have discovered that the nicer you are to other people the nicer they are to you.
My wife is polishing the wood block floor and there is a delicious smell of polish mingled with a beef casserole in the oven.
I should hear about the monoclonal antibody on Monday afternoon. The delay has been because the chairman of the Committee (don't you hate that word) has been on annual leave and nobody has been brave enough to take the decision until he returns.
I was told by a patient who was an Insurance man that taking out Private Medical Insurance in the UK was not cost effective. Companies like PPP and BUPA were frauds against the general public. You can get a good deal through a company scheme, but if you have to fund it yourself, you would find it more cost effective to put your money in Unit Trusts via a PEP or ISA scheme that shields the growth from tax and draw on it when you need it. This is what I shall do if the answer on Monday is NO.
Talking of medical insurance, it seems to me that NICE has taken a strange view of what medication it should be supporting. If it were dealing with car insurance rather than medical insurance it would not be funding low cost items. We all have an excess on our car policies. The first £350 of damages incurred in an accident I pay myself so as not to lose my no-claims benefit. I can afford to pay that myself. It's the £10,000 write off bill and the £1 million damages when the other driver loses a limb that I want help with. So it should be with medical expenses. I can buy my own indigestion medicine, I need help with long term treatment for a handicapped child or maintenance therapy for cystic fibrosis or for cancer therapy.
My general health is quite good though I have to be careful only to eat small meals. My main problem is ascites - fluid secreted by the cancer and accumulating in the peritoneum between loops of bowel. At some stage this will need to be drained away with a thin plastic tube under ultrasound guidance.
My daughter the hematology registrar is on-call in Oxford this weekend. Among her patients is one who has a very difficult lymphoma with translocations on both chromosome 14s at the site of the promoter for the Ig heavy chain gene. On one chromosome the translocation is to BCL-2 and on the other to c-myc. This is a very rare combination and in the literature there are no long term survivors. It is ironic that I described the first such case back in the early 1980s.
My son, the F1 engineer, has finished his globe trotting to Grand Prix and in future will be in charge of procuring and providing at AP Racing. He has been thrown in the deep end with a computer glitch which he has sorted much to the approval of the CEO.
My older son, will be emigrating to New Zealand on Jan 7th. He has been head-hunted to do healthcare risk management there. Apparently his Visa came through in two days, so keen were they to have him. He is glad to leave the CQC which has become mired in an internecine dispute engineered by a two supposed whistleblowers. One is a passed over inspector, not clever enough to advance in her division (she can't grasp Bayesian statistics) and now angling for 'constructive dismissal' and the other is a Board Member who was appointed for her special interest in mental disease; her special interest being that she had suffered from it and was getting increasingly disturbed as the year went on.
My older daughter took voluntary redundancy earlier in the year and has set up her own company doing business analysis. In the meantime she is in partnership with her step-son in an arts and crafts business which is making and selling objets-arts around Christmas time.
I ought to explain what the monoclonal antibody does:
Every cell in the body needs to either grow or die. This is as true for normal cells as cancer cells. Each cell receives a growth signal from a growth factor which reacts with a growth factor receptor on the cell surface. This message is then transmitted to the nucleus where a transcription factor sets the cell dividing at its set rate. This will be different for a skin cell compared to a blood cell compared to a brain cell. Cancer cells will tend to divide faster.
The message must be taken from the cell surface to the nucleus by a series of second messengers. Mistakes (mutations) can take place in the growth factor, the growth factor receptor, any of the second messengers or the transcription factors. A common mistake is in the second messenger k-ras and it is known that these monoclonal antibodies, which block the epidermal growth factor receptor do not work very well if k-ras is mutated. Happily mine is not.
In view of the fact that my disease is very indolent (in its metastatic form it has been present for over 3 years) the cancer does not seem to be carrying too many mutations and I have every hope that EGFR blockade with this monoclonal will be successful.
In the football it is an important weekend for the Premier League. Chelsea have just beaten Newcastle and later today Man U play Aston Villa, Spurs play Bolton, and Man C play Norwich. These are all games that could go either way and the Champions will come from this group of clubs. England were fortunate with the draw for the European Championships and will not have to meet a really top team until Wayne Rooney returns from suspension.
In the News today is a report which suggests that 3000 women in Britain are suffering from so-called "honor beatings" from family members because of the alien "shame culture" brought into Britain by (mostly) Muslims. And Jacques DeLors, the instigator of the Euro, has admitted that it was badly introduced since most countries, including Germany, broke the entry rules.
For all Biblical Creation Society members who may be reading this blog, thank you for your prayers. Another explanation for why my cancer has taken so long to kill me is that I am being sustained by the prayers of Christians all over the world, and because in response to those prayers the Holy Spirit still finds me useful where I am am rather than in taking me home. If that is the case would you pray that he keeps me free from pain and keeps making innovative suggestions on how I may more easily bear this period of difficulty. In particular I should like wisdom on when it would be right to tap the ascites.
It has been a very eventful week with fillings falling out, dishwasher delays, eyesight tests, earwax bothers, monoclonal hold-ups, bad days, good days, CT scan, visits from children and grandchildren, reading too late some nights, sleeping too long some mornings, a fall down stairs, and difficult decisions; but the Lord has brought me through all this and does sustain me in the worst of times.
I have discovered that the nicer you are to other people the nicer they are to you.
Friday, December 02, 2011
Abortion and cytotoxic drugs
One of the things on my conscience concerns abortion. I have always held strict opinions about it and would opt out of being concerned in any matter to do with it. The only grounds that I could see for abortion would be if the baby had little chance of surviving the pregnancy. To ask a prenant woman with an anencephalic child to wait 9 months to deliver a baby that would die immediately seems to me too cruel to contemplate.
There was one occasion when I was faced with this. A young married woman with polycythemia was being treated by me with hydoxyurea (hydroxycarbamide). She was taking this during the first trimester of her pregnancy. She came to me worried that the baby would be affected by the carcinogenic/teratogenic drug.
Now I have always taken the view that hydroxyurea is a safe drug from this respect, and have believed that it is safe to use this drug in young people. But it is a fact that patients with polycythemia do tend to develop acute leukemia after about 13 years follow up. My opinion is that this is part of the nature of the disease rather than because of hydroxyurea since sickle cell patients who receive hydroxyurea to increase their HbF production do not develop acute leukemia. (There are only 2 cases in the literature - probably a chance encounter.)
However I could not be absolutely sure. (On one occasion a patient of mine in this situation switched from hydroxyurea to venesection when she moved to a different part of the country and promptly had a severe stroke.) In the UK it is necessary for 2 doctors to sign a form to permit the abortion to go ahead. I could have passed the buck, but it was really my decision to make, and I signed the form - the only occasion that I have.
Now there is a report in JCO (2011; 29:2410-5) which suggests that I was right all along and could have refused with a clear conscience. (Well not exactly clear, because I would also have to deal with a weeping woman who was very frightened.) The Swedish Chronic Myeloproliferative Neoplasm Study Group has reported on 11039 patients and concluded that despite a 35 fold higher risk of patients with Myeloproliferative conditions developing MDS/AML, there is no higher risk for those who have only received hydroxyurea as chemotherapy. Of course, I am talking about carcinogenicity here not teratogenicity, but they tend to go together.
This was a judgment call that I may have got wrong.
There was one occasion when I was faced with this. A young married woman with polycythemia was being treated by me with hydoxyurea (hydroxycarbamide). She was taking this during the first trimester of her pregnancy. She came to me worried that the baby would be affected by the carcinogenic/teratogenic drug.
Now I have always taken the view that hydroxyurea is a safe drug from this respect, and have believed that it is safe to use this drug in young people. But it is a fact that patients with polycythemia do tend to develop acute leukemia after about 13 years follow up. My opinion is that this is part of the nature of the disease rather than because of hydroxyurea since sickle cell patients who receive hydroxyurea to increase their HbF production do not develop acute leukemia. (There are only 2 cases in the literature - probably a chance encounter.)
However I could not be absolutely sure. (On one occasion a patient of mine in this situation switched from hydroxyurea to venesection when she moved to a different part of the country and promptly had a severe stroke.) In the UK it is necessary for 2 doctors to sign a form to permit the abortion to go ahead. I could have passed the buck, but it was really my decision to make, and I signed the form - the only occasion that I have.
Now there is a report in JCO (2011; 29:2410-5) which suggests that I was right all along and could have refused with a clear conscience. (Well not exactly clear, because I would also have to deal with a weeping woman who was very frightened.) The Swedish Chronic Myeloproliferative Neoplasm Study Group has reported on 11039 patients and concluded that despite a 35 fold higher risk of patients with Myeloproliferative conditions developing MDS/AML, there is no higher risk for those who have only received hydroxyurea as chemotherapy. Of course, I am talking about carcinogenicity here not teratogenicity, but they tend to go together.
This was a judgment call that I may have got wrong.
Another attempt to get FCA up front
This is not quite the right trial, but it is an attempt by the Dutch group to introduce alemtuzumab up front in high risk patients. The other arm should have been FCR not FC and they were wrong to include trisomy 12 in the high risk group.
290 Immunochemotherapy with Low-Dose Subcutaneous Alemtuzumab (A) Plus Oral Fludarabine and Cyclophosphamide (FC) Is Safe and Induces More and Deeper Complete Remissions in Untreated Patients with High-Risk Chronic Lymphocytic Leukemia (CLL) Than Chemotherapy with FC Alone. An Early Analysis of the Randomized Phase-III HOVON68 CLL Trial
In CLL unmutated immunoglobulin heavy chain (IGH) genes, deletions of chromosome 17p or 11q and trisomy 12 are associated with an unfavorable outcome. At the outset of the present trial, phase II studies had shown promising results of immunochemotherapy with FC + rituximab, but the optimal immunochemotherapy regimen was not known, especially not for high-risk CLL patients. The aim of this trial was to improve the outcome of high-risk CLL by the addition of the monoclonal antibody alemtuzumab to the currently best known chemotherapy FC. Because of the recognized immunosuppressant activity of both treatment modalities, a low-dose alemtuzumab approach was chosen and vigilance and prophylaxis towards infection upheld throughout the study.
Previously untreated, fit patients up to 75 years of age with high-risk CLL in need of treatment according to the NCI/IWCLL guidelines were randomized to either oral FC (F 40 mg/m2 D1-3 and C 250 mg/m2 D1-3) or AFC: oral FC + subcutaneous (sc.) alemtuzumab 30 mg, in cycle 1 day -1 to +1, in cycles 2-6 30 mg day 1 only. Responses and endpoints were defined according to NCI/IWCLL guidelines. The primary endpoint was progression-free survival (PFS) on intent-to-treat with progression defined as no response after three cycles of induction treatment, progression of disease, relapse or death whichever occurred first. Secondary endpoints included the rate of complete remission (CR) and the rate of MRD – negative CR (by PCR or flow cytometry), overall survival (OS) and toxicity. We assumed that the addition of alemtuzumab to FC could increase the CR rate from the estimated 20% to 40% and the median PFS from 30 to 42 months.
The study population of 281 patients was included 2006-2010. As of July 2011 262 patients (93%) were evaluable, 129 in the AFC arm and 133 in the FC arm with a median follow-up of 30 months (range 2-63 months). The median age was 60 years (range 27-75) and 75% were males. Twelve % had Binet stage A, 54% stage B and 34% stage C. Beta-2-microglobulin was increased in the majority of the patients (median 3.7 g/ml). Eighty-nine % had unmutated IGH genes and FISH revealed 27% with del 11q, 18% with trisomy 12 and 11% with del 17p according to the hierarchical model. All risk parameters were well balanced between the two arms. Sixty-three% completed all six cycles in each arm, 73% completed at least 5 cýcles AFC while 66% completed 5 cycles FC.
The overall response to AFC and FC was 88% and 80% respectively (NS), the CR rates were 57% and 45% respectively (P=0.049), and the rates of MRD-negative CR were 29% and 17% respectively (P=0.02). The median PFS following AFC and FC was 37 and 31 months respectively (P=0.08). The median OS has not been reached. In the subgroups with 17p deletions, 11q deletions, trisomy 12 or unmutated IGH genes a trend of improved PFS following AFC was seen, but this did not reach significance due to small numbers. There were no differences in response or PFS between treatment arms according to Binet stage or beta-2-microglobulin level.
Severe adverse events, mostly grade 3, were significantly more frequent following AFC than FC: 145 vs 90 (P=0.0001), including flu-like syndrome due to the antibody (27 vs. 2), opportunistic infections (25 vs 11), and organ affection (34 vs 14). The numbers of neutropenic and other infections did not differ. Six treatment related deaths were reported in each arm to a total treatment related mortality of 4%.
In this selected high-risk CLL population, the addition of low-dose sc. alemtuzumab to FC induced a higher rate and higher quality of complete remission than FC alone, which, however, in this early analysis, did not yet translate into significantly prolonged PFS or OS. As expected, the combination is more immuno-suppressant than chemotherapy alone, leading to a higher number of opportunistic infections. With proper vigilance and prophylactic measures, these infections were manageable and did not lead to any excess mortality.
290 Immunochemotherapy with Low-Dose Subcutaneous Alemtuzumab (A) Plus Oral Fludarabine and Cyclophosphamide (FC) Is Safe and Induces More and Deeper Complete Remissions in Untreated Patients with High-Risk Chronic Lymphocytic Leukemia (CLL) Than Chemotherapy with FC Alone. An Early Analysis of the Randomized Phase-III HOVON68 CLL Trial
In CLL unmutated immunoglobulin heavy chain (IGH) genes, deletions of chromosome 17p or 11q and trisomy 12 are associated with an unfavorable outcome. At the outset of the present trial, phase II studies had shown promising results of immunochemotherapy with FC + rituximab, but the optimal immunochemotherapy regimen was not known, especially not for high-risk CLL patients. The aim of this trial was to improve the outcome of high-risk CLL by the addition of the monoclonal antibody alemtuzumab to the currently best known chemotherapy FC. Because of the recognized immunosuppressant activity of both treatment modalities, a low-dose alemtuzumab approach was chosen and vigilance and prophylaxis towards infection upheld throughout the study.
Previously untreated, fit patients up to 75 years of age with high-risk CLL in need of treatment according to the NCI/IWCLL guidelines were randomized to either oral FC (F 40 mg/m2 D1-3 and C 250 mg/m2 D1-3) or AFC: oral FC + subcutaneous (sc.) alemtuzumab 30 mg, in cycle 1 day -1 to +1, in cycles 2-6 30 mg day 1 only. Responses and endpoints were defined according to NCI/IWCLL guidelines. The primary endpoint was progression-free survival (PFS) on intent-to-treat with progression defined as no response after three cycles of induction treatment, progression of disease, relapse or death whichever occurred first. Secondary endpoints included the rate of complete remission (CR) and the rate of MRD – negative CR (by PCR or flow cytometry), overall survival (OS) and toxicity. We assumed that the addition of alemtuzumab to FC could increase the CR rate from the estimated 20% to 40% and the median PFS from 30 to 42 months.
The study population of 281 patients was included 2006-2010. As of July 2011 262 patients (93%) were evaluable, 129 in the AFC arm and 133 in the FC arm with a median follow-up of 30 months (range 2-63 months). The median age was 60 years (range 27-75) and 75% were males. Twelve % had Binet stage A, 54% stage B and 34% stage C. Beta-2-microglobulin was increased in the majority of the patients (median 3.7 g/ml). Eighty-nine % had unmutated IGH genes and FISH revealed 27% with del 11q, 18% with trisomy 12 and 11% with del 17p according to the hierarchical model. All risk parameters were well balanced between the two arms. Sixty-three% completed all six cycles in each arm, 73% completed at least 5 cýcles AFC while 66% completed 5 cycles FC.
The overall response to AFC and FC was 88% and 80% respectively (NS), the CR rates were 57% and 45% respectively (P=0.049), and the rates of MRD-negative CR were 29% and 17% respectively (P=0.02). The median PFS following AFC and FC was 37 and 31 months respectively (P=0.08). The median OS has not been reached. In the subgroups with 17p deletions, 11q deletions, trisomy 12 or unmutated IGH genes a trend of improved PFS following AFC was seen, but this did not reach significance due to small numbers. There were no differences in response or PFS between treatment arms according to Binet stage or beta-2-microglobulin level.
Severe adverse events, mostly grade 3, were significantly more frequent following AFC than FC: 145 vs 90 (P=0.0001), including flu-like syndrome due to the antibody (27 vs. 2), opportunistic infections (25 vs 11), and organ affection (34 vs 14). The numbers of neutropenic and other infections did not differ. Six treatment related deaths were reported in each arm to a total treatment related mortality of 4%.
In this selected high-risk CLL population, the addition of low-dose sc. alemtuzumab to FC induced a higher rate and higher quality of complete remission than FC alone, which, however, in this early analysis, did not yet translate into significantly prolonged PFS or OS. As expected, the combination is more immuno-suppressant than chemotherapy alone, leading to a higher number of opportunistic infections. With proper vigilance and prophylactic measures, these infections were manageable and did not lead to any excess mortality.
Second-line treatment after CLL8
What do the early relapsers from CLL8 actually get as second line treatment and does it work? The information in this German ASH abstract tells us and the results are rather surprising.
2863 Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)
The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts.
The combination CHOP-R was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse less than 24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent Alemtuzumab(A) (20 pts) or Bendamustine (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/-R and B+/-R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/-R (16 and 18 months respectively) when compared to FC+/-R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months).
Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/-R and B+/-R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/-R and B+/-R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR.
2863 Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)
The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts.
The combination CHOP-R was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse less than 24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent Alemtuzumab(A) (20 pts) or Bendamustine (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/-R and B+/-R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/-R (16 and 18 months respectively) when compared to FC+/-R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months).
Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/-R and B+/-R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/-R and B+/-R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR.
Should we CT scan all new Rai stage 0 patients?
2837 Inclusion of Total BODY Computed Tomography (TB-CT) SCANS In the INITIAL WORK-up of Binet STAGE A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS On CLINICAL Grounds: PRELIMINARY RESULTS of the Prospective, MULTICENTER O-CLL1- GISL STUDY 
Rai and Binet staging systems are not devoid of some limitations, including the lack of evaluation of thoracic and abdominal lymphadenopathies. The widely-used IWCLL guidelines do not incorporate use of TB-CT scan in the diagnostic algorithm. In the present study, we investigated whether TB-CT scans could up-stage Binet stage A CLL patients included in the prospective multicenter O-CLL01 GISL study and whether this subgroup presented differences in prognostic markers and in progression-free survival (PFS).
To date, 454 patients have been enrolled and TB-CT scans were available in 238 patients. The median age was 60 years (range, 33-71) and 136 (57%) were male. According to Rai, 180 patients were at low risk (stage 0) and 58 at intermediate risk (stages I-II). b2-microglobulin was elevated in 35.5% of cases. Seventy-eight patients (32%) were IgVH unmutated, 108 patients (45%) had a high ZAP-70 expression, 45 patients (19%) were CD38 positive (>30%). FISH data were available in 226/238 cases; the most frequent abnormality was del(13)(q14) (105 pts, 46.5%), followed by trisomy 12 (24 pts, 10.6%), del(11q22.3) (13 pts 5.5%), del(17p13) (4 pts 1.8%) while 80 cases (35.4%) cytogenetics were normal. Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low (del(13q14) and normal), intermediate (trisomy 12) and high risk (del(11q22) and del(17p13)]. Two hundred six out of 238 patients had a minimum follow-up of 6 months and were evaluable for PFS.
Considering TB-CT scan, 54 out of 238 analyzed (22.7%) patients converted into Binet stage B. Notably, 63% were male, b2-microglobulin was elevated in 50% of cases, 42.6% were IgVH unmutated, 48.1% had a high ZAP-70 expression, 27.8% were CD38 positive, and 17.6% showed a high-risk FISH. Binet B patients showed a statistically higher rate of cases with high risk cytogenetic abnormalities than Binet A patients (17.6% vs 4.6%; p=0.032). While, no statistically different distribution of gender, age, B2-microglobulin, IgVH mutational status, CD38 or ZAP-70 expression were observed between the two subgroups. After a median follow-up of 24 months 46/206 (22%) evaluable cases showed disease progression. Binet B patients showed a PFS significantly shorter than those with a normal TB-CT (2-years PFS probability, 85.6% vs 68.5%; p=0.0001). According to the Rai classification 102/180 (56.7%) low risk patients were re-defined as intermediate risk with the integration of TB-CT scan. This subset of patients showed a statistically higher rate of cases with elevated ZAP-70 (51.5% vs 35.9%; p=0.049) and CD38 (22.5% vs 10.3%; p=0.045) than patients at low risk. After a median follow-up of 25 months, 23/154 (15%) of evaluable cases showed disease progression. Patients with an intermediate risk Rai stage showed a PFS significantly shorter than those with a low risk (2-years PFS probability, 82% vs 96%; p=0.002). In this setting 70 cases met the diagnostic criteria of monoclonal B-lymphocytosis (less than 5 × 10e9/L B-lymphocytes in the blood). With the integration of TB-CT scan 30/70 (42.9%) monoclonal B-lymphocytosis patients were re-defined as intermediate risk according the Rai classification. No statistically different distribution of clinical and biological parameters were observed between cases who remained in the low risk stage and those who became at intermediate risk. After a median follow-up of 28 months 4/57 cases evaluable for PFS showed a disease progression (2 cases for each subgroup). Considering low risk Rai stage, no statistical difference in PFS was observed among non CT-upstaged MBL, CT-upstaged MBL, non CT-upstaged Rai 0, while CT-upstaged Rai 0 cases showed a statistically shorter PFS (p<.0001) than the other groups (Figure 1). Finally, TB-CT scan allowed the early identification of a second neoplasia in 2 cases (lung cancer 1 pt, renal cell carcinoma 1 pt).
Our preliminary data indicate that the integration of TB-CT scans in the clinical staging allows for an effective clinical discrimination of Binet A CLL cases in approximately 23% of cases at more advanced stages, predicting a worse clinical outcome. However, the use of TB-CT scanning for upstaging is not beneficial for predicting PFS in MBL cases. A longer follow-up will demonstrate whether the inclusion of TB-CT scan in the initial work-up of patients with early-stage CLL will provide clinically relevant prognostic information.
Clearly there is prognostic information to be had in scanning all new cases of stage o CLL; but all previous prognostic information in the literature would have to be ditched.
Rai and Binet staging systems are not devoid of some limitations, including the lack of evaluation of thoracic and abdominal lymphadenopathies. The widely-used IWCLL guidelines do not incorporate use of TB-CT scan in the diagnostic algorithm. In the present study, we investigated whether TB-CT scans could up-stage Binet stage A CLL patients included in the prospective multicenter O-CLL01 GISL study and whether this subgroup presented differences in prognostic markers and in progression-free survival (PFS).
To date, 454 patients have been enrolled and TB-CT scans were available in 238 patients. The median age was 60 years (range, 33-71) and 136 (57%) were male. According to Rai, 180 patients were at low risk (stage 0) and 58 at intermediate risk (stages I-II). b2-microglobulin was elevated in 35.5% of cases. Seventy-eight patients (32%) were IgVH unmutated, 108 patients (45%) had a high ZAP-70 expression, 45 patients (19%) were CD38 positive (>30%). FISH data were available in 226/238 cases; the most frequent abnormality was del(13)(q14) (105 pts, 46.5%), followed by trisomy 12 (24 pts, 10.6%), del(11q22.3) (13 pts 5.5%), del(17p13) (4 pts 1.8%) while 80 cases (35.4%) cytogenetics were normal. Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low (del(13q14) and normal), intermediate (trisomy 12) and high risk (del(11q22) and del(17p13)]. Two hundred six out of 238 patients had a minimum follow-up of 6 months and were evaluable for PFS.
Considering TB-CT scan, 54 out of 238 analyzed (22.7%) patients converted into Binet stage B. Notably, 63% were male, b2-microglobulin was elevated in 50% of cases, 42.6% were IgVH unmutated, 48.1% had a high ZAP-70 expression, 27.8% were CD38 positive, and 17.6% showed a high-risk FISH. Binet B patients showed a statistically higher rate of cases with high risk cytogenetic abnormalities than Binet A patients (17.6% vs 4.6%; p=0.032). While, no statistically different distribution of gender, age, B2-microglobulin, IgVH mutational status, CD38 or ZAP-70 expression were observed between the two subgroups. After a median follow-up of 24 months 46/206 (22%) evaluable cases showed disease progression. Binet B patients showed a PFS significantly shorter than those with a normal TB-CT (2-years PFS probability, 85.6% vs 68.5%; p=0.0001). According to the Rai classification 102/180 (56.7%) low risk patients were re-defined as intermediate risk with the integration of TB-CT scan. This subset of patients showed a statistically higher rate of cases with elevated ZAP-70 (51.5% vs 35.9%; p=0.049) and CD38 (22.5% vs 10.3%; p=0.045) than patients at low risk. After a median follow-up of 25 months, 23/154 (15%) of evaluable cases showed disease progression. Patients with an intermediate risk Rai stage showed a PFS significantly shorter than those with a low risk (2-years PFS probability, 82% vs 96%; p=0.002). In this setting 70 cases met the diagnostic criteria of monoclonal B-lymphocytosis (less than 5 × 10e9/L B-lymphocytes in the blood). With the integration of TB-CT scan 30/70 (42.9%) monoclonal B-lymphocytosis patients were re-defined as intermediate risk according the Rai classification. No statistically different distribution of clinical and biological parameters were observed between cases who remained in the low risk stage and those who became at intermediate risk. After a median follow-up of 28 months 4/57 cases evaluable for PFS showed a disease progression (2 cases for each subgroup). Considering low risk Rai stage, no statistical difference in PFS was observed among non CT-upstaged MBL, CT-upstaged MBL, non CT-upstaged Rai 0, while CT-upstaged Rai 0 cases showed a statistically shorter PFS (p<.0001) than the other groups (Figure 1). Finally, TB-CT scan allowed the early identification of a second neoplasia in 2 cases (lung cancer 1 pt, renal cell carcinoma 1 pt).
Our preliminary data indicate that the integration of TB-CT scans in the clinical staging allows for an effective clinical discrimination of Binet A CLL cases in approximately 23% of cases at more advanced stages, predicting a worse clinical outcome. However, the use of TB-CT scanning for upstaging is not beneficial for predicting PFS in MBL cases. A longer follow-up will demonstrate whether the inclusion of TB-CT scan in the initial work-up of patients with early-stage CLL will provide clinically relevant prognostic information.
Clearly there is prognostic information to be had in scanning all new cases of stage o CLL; but all previous prognostic information in the literature would have to be ditched.
A role for ras genes in chlorambucil resistance?
From this Italian ASH abstract it seems that Chlorambucil-rituximab is a promising regimen in CLL patients over-65. Those who respond have molecular differences to those who don't. ras genes seem to be important.
294 Rituximab Plus Chlorambucil As Initial Treatment for Elderly Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Pre-Treatment Biological Characteristics and Gene Expression Patterns on Response to Treatment Robin Foa, Stefania Ciolli, Francesco Di Raimondo, Giovanni Del Poeta, Francesco Lauria, Francesco Forconi, Antonio Cuneo, Agostino Cortelezzi, Francesco Nobile, Vincenzo Callea, Maura Brugiatelli, Massimo Massaia, Stefano Molica, Livio Trentin, Rita Rizzi, Giorgina Specchia, Lorella Orsucci, Achille Ambrosetti, Marco Montillo, Pier Luigi Zinzani, Felicetto Ferrara, Fortunato Morabito, Maria Angela Mura, Silvia Soriani, Marilisa Marinelli, Maria Stefania De Propris, Alessandra Alietti, Eva J. Runggaldier, Enrica Gamba, Ilaria Del Giudice, Silvia Bonina1, Francesca Romana Mauro, Sabina Chiaretti and Anna Guarini.
Rituximab plus fludarabine/cyclophosphamide (R-FC) is currently the standard of care for fit patients with untreated or relapsed CLL. However, patients with CLL are predominantly an elderly population and many of these patients may have comorbidities that make them less suitable to receive fludarabine-containing therapy. Chlorambucil-based treatments are frequently used for these patients despite the fact that clinical benefits are limited. There is a need for well-tolerated and more efficacious treatment regimens for these patients.
The ML21445 study evaluated the combination of rituximab and chlorambucil (R-chlorambucil) as first-line treatment for patients with CLL considered ineligible for treatment with the current standard of care, R-FC. Patients aged >65 years (or 60–65 years and ineligible for fludarabine) were treated with eight 28-day cycles of chlorambucil (8 mg/m2/day Days 1–7) with rituximab administered on Day 1 of cycle 3 (375 mg/m2) and cycles 4–8 (500 mg/m2). Patients with a response at the end of induction were randomized to rituximab maintenance therapy (375 mg/m2 every 8 weeks for 2 years) or observation. The induction phase of the study is complete while the maintenance phase is still ongoing.
This is a rather low dose for chlorambucil. 10mg/m2/day for 10 days would be equivalent to what patients got in LRF CLL4
The overall response rate (ORR) in 85 patients who received at least one dose of rituximab during induction was 81.2% (n = 69) with 16.5% (n = 14) achieving a complete response (CR) and 2.4% (n = 2) a CR with incomplete bone marrow recovery (CRi). ORR and CR rates were similar across the different Binet stages (ORR: Binet A 86.4%, Binet B 79.6%, Binet C 78.6%) and age categories (ORR: 60–64 years 84.6%, 65–69 years 85.2%, 70–74 years 75.0%, ≥75 years 81.0%). Two of four patients aged ≥80 years responded to induction treatment.
ORR of 81% is excellent for a chlorambucil containing regimen.
Logistic regression analysis revealed no correlation between known biological prognostic factors – CD38, cytogenetics, IGHV mutational status, ZAP-70, thymidine kinase, soluble CD23, and beta-2 microglobulin – and response to treatment. To further investigate possible factors influencing response, pre-treatment patterns of gene expression were analyzed in different patient subgroups. Material was available for 62 patients, including 16 with CR/CRi, 41 partial responders and 5 non-responders. In an exploratory analysis, mRNA expression was examined using Affymetrix® Human Genome U133 microarrays. This revealed marked differences in pre-treatment gene expression profiles between response groups. Non-responders showed a homogeneous gene expression signature involving up-modulation of transcripts involved in anti-apoptotic and pro-proliferative pathways, including K-ras and N-ras. CR/CRi patients also showed a homogeneous pattern of gene expression that was clearly distinct from non-responding patients, while patients with a partial response showed a more heterogeneous pattern of gene expression before treatment.
Apart from TP-53 effects response rates usually do not vary with rituximab containing regimens, but PFS does.
These initial findings reflect the heterogeneity of CLL and suggest that microarray analysis of gene expression may be useful in predicting response to R-chlorambucil in elderly patients with CLL.
294 Rituximab Plus Chlorambucil As Initial Treatment for Elderly Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Pre-Treatment Biological Characteristics and Gene Expression Patterns on Response to Treatment Robin Foa, Stefania Ciolli, Francesco Di Raimondo, Giovanni Del Poeta, Francesco Lauria, Francesco Forconi, Antonio Cuneo, Agostino Cortelezzi, Francesco Nobile, Vincenzo Callea, Maura Brugiatelli, Massimo Massaia, Stefano Molica, Livio Trentin, Rita Rizzi, Giorgina Specchia, Lorella Orsucci, Achille Ambrosetti, Marco Montillo, Pier Luigi Zinzani, Felicetto Ferrara, Fortunato Morabito, Maria Angela Mura, Silvia Soriani, Marilisa Marinelli, Maria Stefania De Propris, Alessandra Alietti, Eva J. Runggaldier, Enrica Gamba, Ilaria Del Giudice, Silvia Bonina1, Francesca Romana Mauro, Sabina Chiaretti and Anna Guarini.
Rituximab plus fludarabine/cyclophosphamide (R-FC) is currently the standard of care for fit patients with untreated or relapsed CLL. However, patients with CLL are predominantly an elderly population and many of these patients may have comorbidities that make them less suitable to receive fludarabine-containing therapy. Chlorambucil-based treatments are frequently used for these patients despite the fact that clinical benefits are limited. There is a need for well-tolerated and more efficacious treatment regimens for these patients.
The ML21445 study evaluated the combination of rituximab and chlorambucil (R-chlorambucil) as first-line treatment for patients with CLL considered ineligible for treatment with the current standard of care, R-FC. Patients aged >65 years (or 60–65 years and ineligible for fludarabine) were treated with eight 28-day cycles of chlorambucil (8 mg/m2/day Days 1–7) with rituximab administered on Day 1 of cycle 3 (375 mg/m2) and cycles 4–8 (500 mg/m2). Patients with a response at the end of induction were randomized to rituximab maintenance therapy (375 mg/m2 every 8 weeks for 2 years) or observation. The induction phase of the study is complete while the maintenance phase is still ongoing.
This is a rather low dose for chlorambucil. 10mg/m2/day for 10 days would be equivalent to what patients got in LRF CLL4
The overall response rate (ORR) in 85 patients who received at least one dose of rituximab during induction was 81.2% (n = 69) with 16.5% (n = 14) achieving a complete response (CR) and 2.4% (n = 2) a CR with incomplete bone marrow recovery (CRi). ORR and CR rates were similar across the different Binet stages (ORR: Binet A 86.4%, Binet B 79.6%, Binet C 78.6%) and age categories (ORR: 60–64 years 84.6%, 65–69 years 85.2%, 70–74 years 75.0%, ≥75 years 81.0%). Two of four patients aged ≥80 years responded to induction treatment.
ORR of 81% is excellent for a chlorambucil containing regimen.
Logistic regression analysis revealed no correlation between known biological prognostic factors – CD38, cytogenetics, IGHV mutational status, ZAP-70, thymidine kinase, soluble CD23, and beta-2 microglobulin – and response to treatment. To further investigate possible factors influencing response, pre-treatment patterns of gene expression were analyzed in different patient subgroups. Material was available for 62 patients, including 16 with CR/CRi, 41 partial responders and 5 non-responders. In an exploratory analysis, mRNA expression was examined using Affymetrix® Human Genome U133 microarrays. This revealed marked differences in pre-treatment gene expression profiles between response groups. Non-responders showed a homogeneous gene expression signature involving up-modulation of transcripts involved in anti-apoptotic and pro-proliferative pathways, including K-ras and N-ras. CR/CRi patients also showed a homogeneous pattern of gene expression that was clearly distinct from non-responding patients, while patients with a partial response showed a more heterogeneous pattern of gene expression before treatment.
Apart from TP-53 effects response rates usually do not vary with rituximab containing regimens, but PFS does.
These initial findings reflect the heterogeneity of CLL and suggest that microarray analysis of gene expression may be useful in predicting response to R-chlorambucil in elderly patients with CLL.
More outrage in Nigeria
From Open Doors
Over 150 people have been killed and 10 churches demolished in a carefully planned attack on the Christian community in Damaturu.
More than 200 heavily armed Boko Haram members invaded the community of New Jerusalem after Friday prayers on 4 November, detonating bombs in churches and shooting any believer in sight. Carrying sophisticated guns, explosives and knives, and chanting "Allahu Akbar", the Islamists began to shoot passers by who could not recite any Islamic verses - the only condition for survival. All the Christians who were trapped were either shot or slaughtered with knives. Boko Haram spent about four hours killing and demolishing churches without hindrance from police or security personnel. At least 17 military and police were killed during the attack and both the new and old Police Headquarters were demolished.
Concentrated in northern Nigeria, the extreme Islamist sect is openly agitating for the full implementation of Sharia throughout the country. "War on the church of Jesus Christ" A new settlement of believers in the New Jerusalem area of Damaturu has been described as a haven of churches and Christians - one with which extremist Muslims are not happy. "We are dumbfounded by this attack. It is a war on the church of Jesus Christ," said Rev. Garba Idi, pastor of the ECWA Gospel Church that suffered a bloody blast during the attack. "Boko Haram is out to destroy the church," he concluded while inspecting his damaged church. "Their plan was to kill all of us, but the Lord has spared us. We have a great challenge as a church in this part of the world. We are living on the mercy of God, because they promised to come back and destroy our homes."
Mrs. Grace Samaila, 30, newly married in June, saw her husband shot in the head in front of their church. "We were on my husband's motorbike just outside the gate of the church. The Muslim militants stopped us and asked my husband if he was a Muslim. He said, ‘No, I am a Christian.' In my heart I knew that calamity will soon befall, so I was praying. They asked me to get down from the bike and go my way [although] I asked them to allow my husband [to go] so that he could take me home. They shouted at me and pushed me with a stick as my husband was pleading with them to allow me [to go]. "They asked him to accept Islam and he said no. So they shouted at him to keep going. As soon as he moved some meters away from them, they shot him in the head. He fell from the bike [and died next to the road]. "I could not sleep, and every day the scene of the incident appears to me," she said. "I want God to take away my life, to join my husband."
The present situation
Believers in Damaturu remain fearful. Many have fled the city, convinced that the few security men deployed in the area are insufficient to contain the situation. Local church leaders tried to meet with His Royal Highness the emir of Damaturu, but they were denied an audience by the palace attendants.
In claiming responsibility for the attacks in Damaturu, the spokesperson for Boko Haram, Abu Qaqa, threatened to launch more attacks all across northern Nigeria. With the intention of imposing full Sharia, this Islamic sect has apparently designed a plan to eliminate all churches throughout the northern cities and villages. About 10 people have been arrested in connection with the attacks; further investigation is underway, according to the state police commissioner.
Please pray:
For comfort and healing for Christians caught up in these attacks
For protection, strength and wisdom for Open Doors co-workers seeking to encourage our persecuted brothers and sisters in situations such as this
That God would reveal Himself to the leaders of Boko Haram and change their hatred to love.
Over 150 people have been killed and 10 churches demolished in a carefully planned attack on the Christian community in Damaturu.
More than 200 heavily armed Boko Haram members invaded the community of New Jerusalem after Friday prayers on 4 November, detonating bombs in churches and shooting any believer in sight. Carrying sophisticated guns, explosives and knives, and chanting "Allahu Akbar", the Islamists began to shoot passers by who could not recite any Islamic verses - the only condition for survival. All the Christians who were trapped were either shot or slaughtered with knives. Boko Haram spent about four hours killing and demolishing churches without hindrance from police or security personnel. At least 17 military and police were killed during the attack and both the new and old Police Headquarters were demolished.
Concentrated in northern Nigeria, the extreme Islamist sect is openly agitating for the full implementation of Sharia throughout the country. "War on the church of Jesus Christ" A new settlement of believers in the New Jerusalem area of Damaturu has been described as a haven of churches and Christians - one with which extremist Muslims are not happy. "We are dumbfounded by this attack. It is a war on the church of Jesus Christ," said Rev. Garba Idi, pastor of the ECWA Gospel Church that suffered a bloody blast during the attack. "Boko Haram is out to destroy the church," he concluded while inspecting his damaged church. "Their plan was to kill all of us, but the Lord has spared us. We have a great challenge as a church in this part of the world. We are living on the mercy of God, because they promised to come back and destroy our homes."
Mrs. Grace Samaila, 30, newly married in June, saw her husband shot in the head in front of their church. "We were on my husband's motorbike just outside the gate of the church. The Muslim militants stopped us and asked my husband if he was a Muslim. He said, ‘No, I am a Christian.' In my heart I knew that calamity will soon befall, so I was praying. They asked me to get down from the bike and go my way [although] I asked them to allow my husband [to go] so that he could take me home. They shouted at me and pushed me with a stick as my husband was pleading with them to allow me [to go]. "They asked him to accept Islam and he said no. So they shouted at him to keep going. As soon as he moved some meters away from them, they shot him in the head. He fell from the bike [and died next to the road]. "I could not sleep, and every day the scene of the incident appears to me," she said. "I want God to take away my life, to join my husband."
The present situation
Believers in Damaturu remain fearful. Many have fled the city, convinced that the few security men deployed in the area are insufficient to contain the situation. Local church leaders tried to meet with His Royal Highness the emir of Damaturu, but they were denied an audience by the palace attendants.
In claiming responsibility for the attacks in Damaturu, the spokesperson for Boko Haram, Abu Qaqa, threatened to launch more attacks all across northern Nigeria. With the intention of imposing full Sharia, this Islamic sect has apparently designed a plan to eliminate all churches throughout the northern cities and villages. About 10 people have been arrested in connection with the attacks; further investigation is underway, according to the state police commissioner.
Please pray:
For comfort and healing for Christians caught up in these attacks
For protection, strength and wisdom for Open Doors co-workers seeking to encourage our persecuted brothers and sisters in situations such as this
That God would reveal Himself to the leaders of Boko Haram and change their hatred to love.
What's going on with Occupy London?
This from Today's Times:
It was supposed to be a protest against the evils of capitalism, among other things, but the St Paul’s Cathedral campers have been spending as much of their time on their own economic affairs as on the global financial system. It was on Tuesday evening, after the campers had gathered for a meeting about money in their unofficial conference space, a Starbucks, that the equal people first came to blows with those who, to some minds, are more equal than others. While some Occupy London demonstrators cradled cappuccinos and others drank nothing because they considered the coffee house to be a “symbol of capitalism”, heated exchanges took place over the state of the financial system — the one within the campsite.
The self-appointed finance committee, angry voices among the protesters have since claimed, had turned into an all-powerful and unaccountable force comparable to the ruling elite in George Orwell’s political satire Animal Farm. Yesterday, amid a growing row over transparency and allocation of funds, the committee, which consists of between four and six people, stood down en masse. One of its key members, Tess Jones, 25, from New York, said, however, that she would stay on and help to form an interim committee after receiving a vote of confidence.
During Tuesday’s meeting, the camp’s first aid team and “tranquillity” team, which is responsible for welfare and night patrols, had asked the committee for £1,200 to buy equipment including walkie-talkies and trauma kits for treating stab and gunshot wounds. (Delusions of grandeur, methinks - are they that afrais of jeremy Clarkson?) The request came after what protesters described as threats and safety concerns at the site. The committee was accused of dithering and withholding money, putting campers at risk. It was claimed that it reduced funds for food, while other working groups such as the technology tent were able to buy expensive equipment.
Last week, the committee said that a drop in donations meant that it would have to be “stricter” about funding. The camp’s bank balance was £12,000, Ms Jones said yesterday, including £8,000 in an account held by the London Camp for Climate Change and £4,000 cash in a secure location off site. She added that about £25,000 has been donated to the camp by well-wishers since it formed seven weeks ago. As tensions rose at the meeting, Ms Jones was implicitly accused of using the donations to fund flights to New York, prompting her to storm out in exasperation at the “wild rumours”. The first aiders and the tranquillity group stood down in protest at their treatment by the “elitist” committee, though both have since reformed.
Yesterday, Ms Jones, who did a master’s degree in sociology at the London School of Economics, said that the allegation was completely untrue and that she and her mother had paid for the flights in question. After The Times was contacted by a whistleblower and made inquiries, the committee announced its disbandment. Ms Jones said: “We had a public meeting, and there was support and faith in the finance group. We decided that the working group will no longer be doing the finances . . . We are now trying to move forward, and deal with rumours and negativity.” She said that the maximum balance ever held by the camp was £17,000, but an anonymous whistleblower said: “About two weeks ago we had £21,000 in donations and there must have been more now but they said there would be no more money for the food tent or the tranquillity tent and that the legal team couldn’t use taxis or buy stationery.
“We want to know where all the money has gone. The people who made the donations thought it was going to feed us but one younger mother has had to leave because they said there was not enough food. “It is becoming a nightmare and people are starting to leave. It is becoming intimidating. If you don’t agree with what the leaders say they shout at you and can be quite aggressive. We are now being ruled by an elite inner circle. They are telling us what to think.” She said the two main leaders were two veteran anarchists in their 40s or 50s, and three people in their 20s. “Paul [in his 40s or 50s] has written a charter which gives all the power to a tiny group of people,” she added. “We are all calling it the Animal Farm manifesto. They are always smartly dressed. I don’t know how they manage it when we are all camping, and they go off and have these secret meetings at Starbucks. A small number have decided they are more equal and are controlling the rest of us.”
Which occupiers have gone the distance?
Occupy Wall Street Evicted from Zuccotti Park after nearly two months on November 15. Activists are planning their next move.
Occupy Oakland Evicted from Frank H. Ogawa Plaza on November 14 and from smaller camps by November 21. Demonstrations continue.
Occupy LA Earlier this week, the two-month old encampment outside City Hall was cleared by 1,400 police with 300 arrests.
Occupy Philadelphia At 1am on Wednesday, 100 protesters were cleared from their camp by police. Occupy Bristol Protesters are still camped at College Green and aim to stay into the new year.
Occupy Exeter A camp of about 18 tents remains outside Exeter Cathedral. A second camp was set up on Wednesday in Totnes.
Occupy Edinburgh The continuing occupation of St Andrew Square was recognised by the City Council on November 24.
Occupy Toronto Came to a peaceful end after a month on November 23.
Occupy Berlin The Bundespressestrand, near the government district, has been occupied by 50 protesters since November 9.
Occupy Bournemouth was disbanded a couple of weeks ago. It comprised a couple of dozen beggars, drug addicts and publicity seekers. they has reassembled in a back alley, out of public view.
It was supposed to be a protest against the evils of capitalism, among other things, but the St Paul’s Cathedral campers have been spending as much of their time on their own economic affairs as on the global financial system. It was on Tuesday evening, after the campers had gathered for a meeting about money in their unofficial conference space, a Starbucks, that the equal people first came to blows with those who, to some minds, are more equal than others. While some Occupy London demonstrators cradled cappuccinos and others drank nothing because they considered the coffee house to be a “symbol of capitalism”, heated exchanges took place over the state of the financial system — the one within the campsite.
The self-appointed finance committee, angry voices among the protesters have since claimed, had turned into an all-powerful and unaccountable force comparable to the ruling elite in George Orwell’s political satire Animal Farm. Yesterday, amid a growing row over transparency and allocation of funds, the committee, which consists of between four and six people, stood down en masse. One of its key members, Tess Jones, 25, from New York, said, however, that she would stay on and help to form an interim committee after receiving a vote of confidence.
During Tuesday’s meeting, the camp’s first aid team and “tranquillity” team, which is responsible for welfare and night patrols, had asked the committee for £1,200 to buy equipment including walkie-talkies and trauma kits for treating stab and gunshot wounds. (Delusions of grandeur, methinks - are they that afrais of jeremy Clarkson?) The request came after what protesters described as threats and safety concerns at the site. The committee was accused of dithering and withholding money, putting campers at risk. It was claimed that it reduced funds for food, while other working groups such as the technology tent were able to buy expensive equipment.
Last week, the committee said that a drop in donations meant that it would have to be “stricter” about funding. The camp’s bank balance was £12,000, Ms Jones said yesterday, including £8,000 in an account held by the London Camp for Climate Change and £4,000 cash in a secure location off site. She added that about £25,000 has been donated to the camp by well-wishers since it formed seven weeks ago. As tensions rose at the meeting, Ms Jones was implicitly accused of using the donations to fund flights to New York, prompting her to storm out in exasperation at the “wild rumours”. The first aiders and the tranquillity group stood down in protest at their treatment by the “elitist” committee, though both have since reformed.
Yesterday, Ms Jones, who did a master’s degree in sociology at the London School of Economics, said that the allegation was completely untrue and that she and her mother had paid for the flights in question. After The Times was contacted by a whistleblower and made inquiries, the committee announced its disbandment. Ms Jones said: “We had a public meeting, and there was support and faith in the finance group. We decided that the working group will no longer be doing the finances . . . We are now trying to move forward, and deal with rumours and negativity.” She said that the maximum balance ever held by the camp was £17,000, but an anonymous whistleblower said: “About two weeks ago we had £21,000 in donations and there must have been more now but they said there would be no more money for the food tent or the tranquillity tent and that the legal team couldn’t use taxis or buy stationery.
“We want to know where all the money has gone. The people who made the donations thought it was going to feed us but one younger mother has had to leave because they said there was not enough food. “It is becoming a nightmare and people are starting to leave. It is becoming intimidating. If you don’t agree with what the leaders say they shout at you and can be quite aggressive. We are now being ruled by an elite inner circle. They are telling us what to think.” She said the two main leaders were two veteran anarchists in their 40s or 50s, and three people in their 20s. “Paul [in his 40s or 50s] has written a charter which gives all the power to a tiny group of people,” she added. “We are all calling it the Animal Farm manifesto. They are always smartly dressed. I don’t know how they manage it when we are all camping, and they go off and have these secret meetings at Starbucks. A small number have decided they are more equal and are controlling the rest of us.”
Which occupiers have gone the distance?
Occupy Wall Street Evicted from Zuccotti Park after nearly two months on November 15. Activists are planning their next move.
Occupy Oakland Evicted from Frank H. Ogawa Plaza on November 14 and from smaller camps by November 21. Demonstrations continue.
Occupy LA Earlier this week, the two-month old encampment outside City Hall was cleared by 1,400 police with 300 arrests.
Occupy Philadelphia At 1am on Wednesday, 100 protesters were cleared from their camp by police. Occupy Bristol Protesters are still camped at College Green and aim to stay into the new year.
Occupy Exeter A camp of about 18 tents remains outside Exeter Cathedral. A second camp was set up on Wednesday in Totnes.
Occupy Edinburgh The continuing occupation of St Andrew Square was recognised by the City Council on November 24.
Occupy Toronto Came to a peaceful end after a month on November 23.
Occupy Berlin The Bundespressestrand, near the government district, has been occupied by 50 protesters since November 9.
Occupy Bournemouth was disbanded a couple of weeks ago. It comprised a couple of dozen beggars, drug addicts and publicity seekers. they has reassembled in a back alley, out of public view.
John 8:25-26. No excuses
“Who are you?” they asked. “Just what I have been telling you from the beginning,” Jesus replied. “I have much to say in judgment of you. But he who sent me is trustworthy, and what I have heard from him I tell the world.”
The sin is unbelief. If we refuse to believe God, what hope is there for us?
How do we know what God is saying? Paul tells us in Romans Ch 1 "What may be known about God is plain. For since the creation of the world God's invisible qualities - his eternal power and divine nature - have been clearly seen, being understood from what he has made, so that men are without excuse.
We can look at nature. But since the 19th Century men have thought up theories about how these could be self-generating - not that these theories are convincing - the arguments were all demolished in the nineteenth century - but so that they might find an excuse for not believing in God.
Others will point to the tradition of the Church that there is a God, but I admit that this is hearsay evidence and often wild and poorly attested. But we have better evidence than that. God sent his son. And we have the evidence of those who met him and heard his testimony. That which was heard and seen has been written down by those witnesses within 20 years of the actual event and that actual event included the death and resurrection of Jesus.
I don't know about you, but I can recall actual conversations that I had 30 years ago which were much less stupendous than this: conversations with colleagues, administrators and patients. And we have the benefit of many witnesses and detailed researchers who went about asking questions: "How do you remember that?" asked Luke of Peter, John Mark, Mary and the other women and many others.
WE have Scripture, and according to Scripture we have the Holy Spirit.
So we really are without excuse when we do not believe.
The sin is unbelief. If we refuse to believe God, what hope is there for us?
How do we know what God is saying? Paul tells us in Romans Ch 1 "What may be known about God is plain. For since the creation of the world God's invisible qualities - his eternal power and divine nature - have been clearly seen, being understood from what he has made, so that men are without excuse.
We can look at nature. But since the 19th Century men have thought up theories about how these could be self-generating - not that these theories are convincing - the arguments were all demolished in the nineteenth century - but so that they might find an excuse for not believing in God.
Others will point to the tradition of the Church that there is a God, but I admit that this is hearsay evidence and often wild and poorly attested. But we have better evidence than that. God sent his son. And we have the evidence of those who met him and heard his testimony. That which was heard and seen has been written down by those witnesses within 20 years of the actual event and that actual event included the death and resurrection of Jesus.
I don't know about you, but I can recall actual conversations that I had 30 years ago which were much less stupendous than this: conversations with colleagues, administrators and patients. And we have the benefit of many witnesses and detailed researchers who went about asking questions: "How do you remember that?" asked Luke of Peter, John Mark, Mary and the other women and many others.
WE have Scripture, and according to Scripture we have the Holy Spirit.
So we really are without excuse when we do not believe.
Aid to India. Even they are embarrassed and have asked us to stop it next year.
I don't believe everything I read in the Daily Mail. It is a right-wing tabloid with an agenda. But here is what Sue Reid writes after a visit to India. A genuine grass-roots investigation or a gathering of evidence to illustrate her point?
At the Rolls-Royce showroom, behind imposing iron gates off dusty Ashoka Road, the chief salesman is pleased with his latest sale of a £600,000 Phantom to a billionaire Delhi businessman. Thirty-five Phantoms, the biggest and most expensive Rolls-Royce, have been bought in India already in 2011. By the end of the year, another 35 will be sold to Indian tycoons and Bollywood film stars. ‘There’s always someone here with enough cash to buy a Rolls-Royce, even though the import tax doubles the price,’ the sharp-suited salesman says with pride.
Ferrari, Aston Martin and Land Rover have each opened up showrooms here. On sale too is the king of supercars, the Bugatti Veyron, with an eye-watering price tag of almost £1.5 million. The country is racing up the league of rich nations. Indeed, its soaring economy will outstrip the UK’s by 2022. According to financial advisers Merrill Lynch, India has 153,000 dollar-millionaires — a 20 per cent rise in a year, compared with Britain’s own paltry increase of less than 1 per cent. Indians have squirrelled away more money in Swiss bank accounts (a total of £900 billion since independence from Britain in 1947) than the rest of the world combined. And when they were invited recently by the Indian Government to exchange for paper money the gold bars and jewellery stashed in their homes (so pumping cash into the national economy), a horde of £160 billion was offered up. Such is the economic power of India that it now gives out more foreign aid than it receives, and has handed over £3.5 billion to cement relations with impoverished Africa.
Meanwhile, it invests huge sums in ambitious projects: £2 billion will put the first Indian astronauts into space by 2016, and the annual defence budget tops £22 billion, with a third aircraft carrier now under construction in an Indian shipyard. Perhaps the perfect example of the garish spending of India’s newly-rich is the £2 billion, 27-storey skyscraper in Mumbai built by a local industrialist as a home for his wife and three children. It is the most expensive house anywhere in the world.
But if this is a nation with enormous reserves of wealth, it is also blighted by widespread and endemic corruption at every level of society. An official report has revealed that 90 per cent of government officials have accepted a bribe for favours, from ripping up a speeding fine to rubber-stamping a building deal. Corruption, as the Indian prime minister confessed the other day, is as much a national sport as cricket. No wonder that in broke Britain questions are at last being asked about why we are handing billions to India in aid. A new report from an independent watchdog says that the rapid expansion of the UK’s aid programme has left taxpayers’ money at risk from corruption and fraud overseas.
The Independent Commission for Aid Impact (ICAI) last week criticised the work of the British government department that doles out the money as ‘fragmented’ and in need of ‘significant improvement’ to stop millions being squandered. It also demanded anti-corruption measures to protect funds sent to countries — such as India — where there is a high risk of fraud. They are concerning findings, given that David Cameron has decided to give India £1.4 billion between now and 2015. The sum is almost 1 per cent of Britain’s own £159 billion debts. So do we need to re-think our aid profligacy, especially in light of the shockingly grim economic forecast announced by Chancellor George Osborne this week? Despite the fact that Osborne has extended his austerity programme in Britain — which includes cuts to welfare payments and housing benefits — beyond the next election, David Cameron doesn’t seem to think so.
The Government is trimming just £1.164 billion off the aid budget over the next three years, meaning we are still committed to spending more than £29 billion on overseas aid between next April and April 2015. Earlier this week the Government announced that £330 million of taxpayers cash will be poured into Africa to help them with climate change, funding solar panels and investment in low-carbon transport. A few months ago, he made a speech during a trade visit to Africa admitting that foreign aid has been ‘wasted’, but that it was still imperative for us to shell out more.
But does India really need our funds, and, perhaps more pertinently, what’s happening to it when it gets there? During my inquiries in India, I discovered that much of our money is frittered away or stolen. India’s assassinated former prime minister Rajiv Gandhi once estimated that only 15 per cent of funds given to the country’s welfare schemes, whether financed by foreign or Indian aid, reach the poor people they are meant to help. His views were endorsed by Barun Mitra, director of a Delhi-based think-tank, the Liberty Institute, who told me: ‘I am surprised that Department For International Development [DFID] officials work so hard to continue their presence in India. Is it really to help some of the poorest Indians, or is it to justify their own existence? Apart from wastage, which is hardly a surprise in India, there seems to be little effort to assess how the money is spent.’
A growing group of ‘aid-sceptics’ go much further. One leading economist and expert on the Third World, Zambian-born Dambisa Moyo, says that aid has made the poor poorer. ‘Aid has been, and continues to be, an unmitigated political, economic and humanitarian disaster for most parts of the developing world,’ she warns. So are we helping at all? I spoke to politicians, officials, teachers, doctors and parents in four regions of India where the British government’s DFID runs education and health programmes.
The very first primary school I went to — opened this summer in Bhopal, the capital of Madhya Pradesh state in central India — was half empty of pupils. It had not one desk or chair because they had never been delivered and are presumed stolen from the factory where they were made or from the lorries taking them to school. The children sat on the concrete floor, which was riddled with holes because the builders had put too much sand into the concrete mix so they could, I was told, sell off the spare concrete. Officials admit that £70 million of the £388 million given by Britain towards a national flagship education programme called Sarva Shiksha Abbiyan (‘education for all’), which promises free classes for every child from the age of six to 14, has been squandered though widespread corruption and theft.
Standards of writing, reading and arithmetic are down since the education programme began. Half of ten-year-olds cannot read a sentence, and only a third can perform a simple sum. Meanwhile, teachers in a quarter of primary schools are routinely absent because they take part-time jobs outside school to compensate for low pay. In another scandal, India’s auditor-general discovered £14 million of DFID aid had simply been snaffled by Indian officials and never reached schools. Education chiefs used the money to buy themselves cars. An estimated 8,000 colour TVs bought for schools never arrived. In any case, many would never have worked because few of the classrooms have electricity. What’s more, tens of thousands of pounds were ‘allocated’ to schools that don’t even exist. As a result, even poor parents scrimp to send their children to private schools to escape the government-run ones which receive British aid. A recent report by Indian vice-president Shri Hamid Ansari revealed that British taxpayers’ money spent on education has been wasted. ‘Close scrutiny reveals a sobering truth, that this large investment has been spent poorly,’ he said bluntly. Certainly, many Indians I met scoffed at DFID’s boast that: ‘Because a third of the world’s poor people live in India, this has been our largest programme for more than a decade. It is our bold ambition to give every mother the healthcare she needs to give birth in safety and raise a healthy child who has a chance to learn.’ In a country with such deep-rooted poverty (despite the inexorable rise of the rich) that is a mountain to climb. Indian cities are riddled with slums and there are 500 in Bhopal alone. Thousands of families — even those from the middle classes — live in squalor. Sewage runs down the muddy streets lined with shacks made of corrugated iron with no front doors. It was in one such slum — Rahul Nagar — that I found the new primary school with no furniture. On the walls were posters of the English alphabet and nursery rhymes. On a Tuesday morning, only 170 of the children on the roll of 350 turned up. In the class for eight and nine-year-olds there were 21 children instead of the expected 70. The headmistress Ratnaprabha Verma says she is not surprised because the pupils have nowhere to sit, apart from the floor, and their parents object to this. ‘At five or six, the children enrol in a big rush. The parents know we give out free uniforms, books and pencils. But within days they begin to drop out, one by one. Some simply come for the free midday meal and leave before classes start again. There are no toilets here. Even with the aid money, no one thought to build them.’
All this begs the question: why does DFID insist that our money gives millions of Indian children free schooling and their families a better life? As youth worker Sen Vijay, 27, said with a concerned look as we travelled to the Bhopal school: ‘We think your government is playing a game with statistics. It means they can boast they are helping India. But it is a lie.’ His words are echoed by one of India’s most respected academics, Delhi University’s former dean of education. Professor Anil Sadgopal told me: ‘I don’t know what the British mean when they say their free school project is ‘proving very effective and making remarkable progress. ‘I think the British people should be asking their Government why it is funding such bad-value projects out of your public exchequer.’
His question is equally pertinent when it comes to Indian maternity services, which have received £60 million in British aid. At the first maternity clinic I visited, an operating theatre with thousands of pounds of equipment was gathering dust because a surgeon, anaesthetist and theatre nurse cannot be hired as there is no money to pay them. A rare oversight? Not at all, Sudhir Pattnaik, an editor and political commentator in the impoverished north-eastern state of Orissa, has revealed: ‘In the health sector, the British Government provides infrastructure which is unused. So what is the point of putting the money in? When somebody comes with a big money bag and says: “I will support this,” the state government here will say yes. But there is no practical plan.’ He added: ‘At one city hospital, the medical officer took me to an intensive care unit. Inside, there were six beds and life support units but no patients. The equipment was bought with your aid money, but there was no manpower to operate the machines. This is happening in all other areas, too.’
Back in the Madhya Pradesh region, thousands have been spent on giving pregnant women cash incentives to persuade them to travel, often miles, to a clinic to give birth. But what do they find when they get there? The region’s health officer, Raj Gopal Nair, told me that women often give birth by candlelight because there is no electricity. Many of the clinics’ doctors have quit because of poor pay. I visited a small maternity clinic in busy Bhopal. It has five beds, although it caters for 250,000 people. The operating theatre on the first floor has a new anaesthesia machine which is still in its plastic cover, the instructions in an unopened manual. The theatre bed is unused. Not one child has been delivered here since it was opened a few years ago. ‘We do not have the money to pay for medical staff to perform an operation, such as an emergency Caesarean, in the operating theatre. We can only deal with the uncomplicated births at our clinic,’ says Dr Rajasree Bajaj, the medical director, bluntly. ‘The expensive equipment bought with your aid money has been wasted.’ Then she adds, with sadness: ‘None of your Government people has been to see what is happening here. You are the only British person to come and ask where your country’s money has gone.’
At the Rolls-Royce showroom, behind imposing iron gates off dusty Ashoka Road, the chief salesman is pleased with his latest sale of a £600,000 Phantom to a billionaire Delhi businessman. Thirty-five Phantoms, the biggest and most expensive Rolls-Royce, have been bought in India already in 2011. By the end of the year, another 35 will be sold to Indian tycoons and Bollywood film stars. ‘There’s always someone here with enough cash to buy a Rolls-Royce, even though the import tax doubles the price,’ the sharp-suited salesman says with pride.
Ferrari, Aston Martin and Land Rover have each opened up showrooms here. On sale too is the king of supercars, the Bugatti Veyron, with an eye-watering price tag of almost £1.5 million. The country is racing up the league of rich nations. Indeed, its soaring economy will outstrip the UK’s by 2022. According to financial advisers Merrill Lynch, India has 153,000 dollar-millionaires — a 20 per cent rise in a year, compared with Britain’s own paltry increase of less than 1 per cent. Indians have squirrelled away more money in Swiss bank accounts (a total of £900 billion since independence from Britain in 1947) than the rest of the world combined. And when they were invited recently by the Indian Government to exchange for paper money the gold bars and jewellery stashed in their homes (so pumping cash into the national economy), a horde of £160 billion was offered up. Such is the economic power of India that it now gives out more foreign aid than it receives, and has handed over £3.5 billion to cement relations with impoverished Africa.
Meanwhile, it invests huge sums in ambitious projects: £2 billion will put the first Indian astronauts into space by 2016, and the annual defence budget tops £22 billion, with a third aircraft carrier now under construction in an Indian shipyard. Perhaps the perfect example of the garish spending of India’s newly-rich is the £2 billion, 27-storey skyscraper in Mumbai built by a local industrialist as a home for his wife and three children. It is the most expensive house anywhere in the world.
But if this is a nation with enormous reserves of wealth, it is also blighted by widespread and endemic corruption at every level of society. An official report has revealed that 90 per cent of government officials have accepted a bribe for favours, from ripping up a speeding fine to rubber-stamping a building deal. Corruption, as the Indian prime minister confessed the other day, is as much a national sport as cricket. No wonder that in broke Britain questions are at last being asked about why we are handing billions to India in aid. A new report from an independent watchdog says that the rapid expansion of the UK’s aid programme has left taxpayers’ money at risk from corruption and fraud overseas.
The Independent Commission for Aid Impact (ICAI) last week criticised the work of the British government department that doles out the money as ‘fragmented’ and in need of ‘significant improvement’ to stop millions being squandered. It also demanded anti-corruption measures to protect funds sent to countries — such as India — where there is a high risk of fraud. They are concerning findings, given that David Cameron has decided to give India £1.4 billion between now and 2015. The sum is almost 1 per cent of Britain’s own £159 billion debts. So do we need to re-think our aid profligacy, especially in light of the shockingly grim economic forecast announced by Chancellor George Osborne this week? Despite the fact that Osborne has extended his austerity programme in Britain — which includes cuts to welfare payments and housing benefits — beyond the next election, David Cameron doesn’t seem to think so.
The Government is trimming just £1.164 billion off the aid budget over the next three years, meaning we are still committed to spending more than £29 billion on overseas aid between next April and April 2015. Earlier this week the Government announced that £330 million of taxpayers cash will be poured into Africa to help them with climate change, funding solar panels and investment in low-carbon transport. A few months ago, he made a speech during a trade visit to Africa admitting that foreign aid has been ‘wasted’, but that it was still imperative for us to shell out more.
But does India really need our funds, and, perhaps more pertinently, what’s happening to it when it gets there? During my inquiries in India, I discovered that much of our money is frittered away or stolen. India’s assassinated former prime minister Rajiv Gandhi once estimated that only 15 per cent of funds given to the country’s welfare schemes, whether financed by foreign or Indian aid, reach the poor people they are meant to help. His views were endorsed by Barun Mitra, director of a Delhi-based think-tank, the Liberty Institute, who told me: ‘I am surprised that Department For International Development [DFID] officials work so hard to continue their presence in India. Is it really to help some of the poorest Indians, or is it to justify their own existence? Apart from wastage, which is hardly a surprise in India, there seems to be little effort to assess how the money is spent.’
A growing group of ‘aid-sceptics’ go much further. One leading economist and expert on the Third World, Zambian-born Dambisa Moyo, says that aid has made the poor poorer. ‘Aid has been, and continues to be, an unmitigated political, economic and humanitarian disaster for most parts of the developing world,’ she warns. So are we helping at all? I spoke to politicians, officials, teachers, doctors and parents in four regions of India where the British government’s DFID runs education and health programmes.
The very first primary school I went to — opened this summer in Bhopal, the capital of Madhya Pradesh state in central India — was half empty of pupils. It had not one desk or chair because they had never been delivered and are presumed stolen from the factory where they were made or from the lorries taking them to school. The children sat on the concrete floor, which was riddled with holes because the builders had put too much sand into the concrete mix so they could, I was told, sell off the spare concrete. Officials admit that £70 million of the £388 million given by Britain towards a national flagship education programme called Sarva Shiksha Abbiyan (‘education for all’), which promises free classes for every child from the age of six to 14, has been squandered though widespread corruption and theft.
Standards of writing, reading and arithmetic are down since the education programme began. Half of ten-year-olds cannot read a sentence, and only a third can perform a simple sum. Meanwhile, teachers in a quarter of primary schools are routinely absent because they take part-time jobs outside school to compensate for low pay. In another scandal, India’s auditor-general discovered £14 million of DFID aid had simply been snaffled by Indian officials and never reached schools. Education chiefs used the money to buy themselves cars. An estimated 8,000 colour TVs bought for schools never arrived. In any case, many would never have worked because few of the classrooms have electricity. What’s more, tens of thousands of pounds were ‘allocated’ to schools that don’t even exist. As a result, even poor parents scrimp to send their children to private schools to escape the government-run ones which receive British aid. A recent report by Indian vice-president Shri Hamid Ansari revealed that British taxpayers’ money spent on education has been wasted. ‘Close scrutiny reveals a sobering truth, that this large investment has been spent poorly,’ he said bluntly. Certainly, many Indians I met scoffed at DFID’s boast that: ‘Because a third of the world’s poor people live in India, this has been our largest programme for more than a decade. It is our bold ambition to give every mother the healthcare she needs to give birth in safety and raise a healthy child who has a chance to learn.’ In a country with such deep-rooted poverty (despite the inexorable rise of the rich) that is a mountain to climb. Indian cities are riddled with slums and there are 500 in Bhopal alone. Thousands of families — even those from the middle classes — live in squalor. Sewage runs down the muddy streets lined with shacks made of corrugated iron with no front doors. It was in one such slum — Rahul Nagar — that I found the new primary school with no furniture. On the walls were posters of the English alphabet and nursery rhymes. On a Tuesday morning, only 170 of the children on the roll of 350 turned up. In the class for eight and nine-year-olds there were 21 children instead of the expected 70. The headmistress Ratnaprabha Verma says she is not surprised because the pupils have nowhere to sit, apart from the floor, and their parents object to this. ‘At five or six, the children enrol in a big rush. The parents know we give out free uniforms, books and pencils. But within days they begin to drop out, one by one. Some simply come for the free midday meal and leave before classes start again. There are no toilets here. Even with the aid money, no one thought to build them.’
All this begs the question: why does DFID insist that our money gives millions of Indian children free schooling and their families a better life? As youth worker Sen Vijay, 27, said with a concerned look as we travelled to the Bhopal school: ‘We think your government is playing a game with statistics. It means they can boast they are helping India. But it is a lie.’ His words are echoed by one of India’s most respected academics, Delhi University’s former dean of education. Professor Anil Sadgopal told me: ‘I don’t know what the British mean when they say their free school project is ‘proving very effective and making remarkable progress. ‘I think the British people should be asking their Government why it is funding such bad-value projects out of your public exchequer.’
His question is equally pertinent when it comes to Indian maternity services, which have received £60 million in British aid. At the first maternity clinic I visited, an operating theatre with thousands of pounds of equipment was gathering dust because a surgeon, anaesthetist and theatre nurse cannot be hired as there is no money to pay them. A rare oversight? Not at all, Sudhir Pattnaik, an editor and political commentator in the impoverished north-eastern state of Orissa, has revealed: ‘In the health sector, the British Government provides infrastructure which is unused. So what is the point of putting the money in? When somebody comes with a big money bag and says: “I will support this,” the state government here will say yes. But there is no practical plan.’ He added: ‘At one city hospital, the medical officer took me to an intensive care unit. Inside, there were six beds and life support units but no patients. The equipment was bought with your aid money, but there was no manpower to operate the machines. This is happening in all other areas, too.’
Back in the Madhya Pradesh region, thousands have been spent on giving pregnant women cash incentives to persuade them to travel, often miles, to a clinic to give birth. But what do they find when they get there? The region’s health officer, Raj Gopal Nair, told me that women often give birth by candlelight because there is no electricity. Many of the clinics’ doctors have quit because of poor pay. I visited a small maternity clinic in busy Bhopal. It has five beds, although it caters for 250,000 people. The operating theatre on the first floor has a new anaesthesia machine which is still in its plastic cover, the instructions in an unopened manual. The theatre bed is unused. Not one child has been delivered here since it was opened a few years ago. ‘We do not have the money to pay for medical staff to perform an operation, such as an emergency Caesarean, in the operating theatre. We can only deal with the uncomplicated births at our clinic,’ says Dr Rajasree Bajaj, the medical director, bluntly. ‘The expensive equipment bought with your aid money has been wasted.’ Then she adds, with sadness: ‘None of your Government people has been to see what is happening here. You are the only British person to come and ask where your country’s money has gone.’
Thursday, December 01, 2011
CLL8 the same bad news is bad news.
977 Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG) Anna Fink, Raymonde Busch, Natali Pflug, Sebastian Boettcher, Dirk Winkler, Andreas Buehler, Matthias Ritgen, Kirsten Fischer, Barbara Eichhorst, Clemens-Martin Wendtner, Myriam Mendila, Michael K. Wenger, Hartmut Doehner, Michael Kneba, Stephan Stilgenbauer and Michael Hallek.
Introduction:
For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ³ 24 months. 15 % of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis.
Methods:
In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10-4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors.
Results:
This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-ß2m. A combination of MRD levels of less than 10e2 or of MRD levels of less than 10e4 to less than 10e2 plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970-10.347; p=0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799-11.844, p=0.0001)
Conclusion:
The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation.
A predictable picture is emerging. The same old prognostic factors - IGVH mutations and TP53 abnormalities determine the pace of the disease. It confirms my opinion that all CLL patients ought to get them done.
Introduction:
For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ³ 24 months. 15 % of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis.
Methods:
In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10-4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors.
Results:
This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-ß2m. A combination of MRD levels of less than 10e2 or of MRD levels of less than 10e4 to less than 10e2 plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970-10.347; p=0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799-11.844, p=0.0001)
Conclusion:
The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation.
A predictable picture is emerging. The same old prognostic factors - IGVH mutations and TP53 abnormalities determine the pace of the disease. It confirms my opinion that all CLL patients ought to get them done.
ASCT buys a later second treatment for 4 months of impaired quality of life.
There is still some lingering thought that autologous stem cell transplant is an advantageous way of treating some cases of CLL, despite papers suggesting that the risk of secondary MDS/AML is higher than with conventional therapy. This abstract from ASH this year seems to gainsay that.
1989 High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation (ASCT) Has a Significant but Transient Impact on Quality of Life: Lessons From the Chronic Lymphocytic Leukemia (CLL) ASCT Study by the CLL Subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Liesbeth C. de Wreede, Maggie Watson, Donald Milligan, Mauricette Michallet, Peter Dreger, Marleen van Os, Claire E. Dearden, Catherine Cordonnier, Michel Leporrier, Vladimir Koza, Janis Homewood, Bernadette Corront, Gabriela M. Baerlocher, Wolfgang Herr, Dietger Niederwieser, Laurent Sutton, Theo M. de Witte, and Johannes Schetelig,
Objective:
High-dose therapy (HDT) and ASCT is the standard of care in a variety of hematologic malignancies. Whereas for some indications a survival advantage for HDT and ASCT has been demonstrated, a benefit only in terms of better progression-free survival has been shown for CLL. Because of this the quality of life (QoL) deserves particular attention. QoL assessment was a major focus of a randomized controlled EBMT-Intergroup trial on the value of HDT compared to observation in first or second remission of CLL.
Methods:
222 patients were enrolled into the study and allocated to either ASCT or observation. In the transplant arm, 72% received HDT and ASCT (for those median time from randomization to transplant was 3.01 months); in the observation arm 9% received ASCT. QoL was assessed with the EORTC QLQ C30 version 3.0, a questionnaire that has to be filled in by the patients. The answers to the questions yielded 15 scores, each on a scale from 0 to 100. The scores represent 15 domains: global health status/QoL, 5 functional scales (100 representing perfect health) and 9 symptom scales (0 representing no complaints). QoL forms had to be completed at randomization and at months 4, 8, 12, and 24. Data on 56%, 53%, 54%, 61%, and 50% of the baseline patients are available for the respective periods. Missing forms were not systematically related to baseline variables or relapse. The numbers of drop outs due to death at 2 years were 5 patients in the HDT arm and 4 patients in the control arm.
All QoL outcomes were analyzed with mixed models according to the intent to treat principle. Time (as factor), age, gender, treatment arm and the interaction of time and treatment arm were modelled as fixed effects, whereas individual random effects were added for the intercept.
Results:
Global health status/QoL at 4 months (estimated effect from the multivariate model -7.15, p=0.034) was significantly inferior in the transplant cohort compared to the control group. At 8 months the estimated effect of HDT on global health status/QoL was -3.06 (p=0.36). This difference further diminished over the first year (estimate at 1 year -0.53, p=0.87). QoL did not decrease independently from the treatment during the first 2 years. The same global pattern of change over time was observed for physical functioning, role functioning and social functioning; however, the treatment impact was still significant at 8 months for physical functioning (-6.58; p=0.025) and social functioning (-11.18; p=0.014). No significant covariate effects could be delineated for either of these scales apart from age having a beneficial effect on social functioning.
Conclusions:
Quality of life is affected multi-dimensionally in the first year after high-dose therapy and autologous stem cell support. The negative impact of HDT on QoL has disappeared after two years. Patients should be informed that HDT followed by ASCT impairs quality of life in the first year after transplantation.
The plain facts are that you cannot get improved survival from ASCT, but you do delay your next treatment at the cost of a worse quality of life for 4 months.
1989 High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation (ASCT) Has a Significant but Transient Impact on Quality of Life: Lessons From the Chronic Lymphocytic Leukemia (CLL) ASCT Study by the CLL Subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Liesbeth C. de Wreede, Maggie Watson, Donald Milligan, Mauricette Michallet, Peter Dreger, Marleen van Os, Claire E. Dearden, Catherine Cordonnier, Michel Leporrier, Vladimir Koza, Janis Homewood, Bernadette Corront, Gabriela M. Baerlocher, Wolfgang Herr, Dietger Niederwieser, Laurent Sutton, Theo M. de Witte, and Johannes Schetelig,
Objective:
High-dose therapy (HDT) and ASCT is the standard of care in a variety of hematologic malignancies. Whereas for some indications a survival advantage for HDT and ASCT has been demonstrated, a benefit only in terms of better progression-free survival has been shown for CLL. Because of this the quality of life (QoL) deserves particular attention. QoL assessment was a major focus of a randomized controlled EBMT-Intergroup trial on the value of HDT compared to observation in first or second remission of CLL.
Methods:
222 patients were enrolled into the study and allocated to either ASCT or observation. In the transplant arm, 72% received HDT and ASCT (for those median time from randomization to transplant was 3.01 months); in the observation arm 9% received ASCT. QoL was assessed with the EORTC QLQ C30 version 3.0, a questionnaire that has to be filled in by the patients. The answers to the questions yielded 15 scores, each on a scale from 0 to 100. The scores represent 15 domains: global health status/QoL, 5 functional scales (100 representing perfect health) and 9 symptom scales (0 representing no complaints). QoL forms had to be completed at randomization and at months 4, 8, 12, and 24. Data on 56%, 53%, 54%, 61%, and 50% of the baseline patients are available for the respective periods. Missing forms were not systematically related to baseline variables or relapse. The numbers of drop outs due to death at 2 years were 5 patients in the HDT arm and 4 patients in the control arm.
All QoL outcomes were analyzed with mixed models according to the intent to treat principle. Time (as factor), age, gender, treatment arm and the interaction of time and treatment arm were modelled as fixed effects, whereas individual random effects were added for the intercept.
Results:
Global health status/QoL at 4 months (estimated effect from the multivariate model -7.15, p=0.034) was significantly inferior in the transplant cohort compared to the control group. At 8 months the estimated effect of HDT on global health status/QoL was -3.06 (p=0.36). This difference further diminished over the first year (estimate at 1 year -0.53, p=0.87). QoL did not decrease independently from the treatment during the first 2 years. The same global pattern of change over time was observed for physical functioning, role functioning and social functioning; however, the treatment impact was still significant at 8 months for physical functioning (-6.58; p=0.025) and social functioning (-11.18; p=0.014). No significant covariate effects could be delineated for either of these scales apart from age having a beneficial effect on social functioning.
Conclusions:
Quality of life is affected multi-dimensionally in the first year after high-dose therapy and autologous stem cell support. The negative impact of HDT on QoL has disappeared after two years. Patients should be informed that HDT followed by ASCT impairs quality of life in the first year after transplantation.
The plain facts are that you cannot get improved survival from ASCT, but you do delay your next treatment at the cost of a worse quality of life for 4 months.
Persecution in Kashmir
An Indian pastor who baptised converts from Islam was arrested and his church raided following a sharia court hearing.
Rev. Chander Mani Khanna was called by the Grand Mufti of Kashmir to a sharia court on 8 November to explain alleged forced conversions of young Muslims, after a video appeared on YouTube that shows the pastor baptising seven adult converts from Islam. He was accused of converting Muslims in exchange for money. Muslims responded angrily to the footage, threatening to burn Mr Khanna to death, kill all Christian missionaries and burn their buildings, schools and churches.
Amid concerns for the pastor’s safety following the sharia court hearing, the police initially asked him not to move from his home in Srinagar, saying that they were protecting him. But they then raided his church and arrested him on charges of fomenting communal strife. He was released on bail after spending ten days in police custody. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him.
Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him. Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media: There will be serious consequences of this. We will implement our part and the government should implement its.
Following Mr Khanna’s arrest, Indian Christian leaders have questioned why the authorities are siding with the sharia court in a country with a secular constitution, which guarantees all citizens the “right freely to profess, practice and propagate [their] religion”. Sajan K George, president of the Global Council of Indian Christians (GCIC), said: Allowing a Sharia Court to enforce its laws on Christians represents an end to the rule of law and equality of Indian citizens.
While a number of Indian states have introduced “anti-conversion laws”, Jammu and Kashmir is not one of them. Mr Khanna was instead arrested under Articles 153A (Promoting enmity between different groups on ground of religion, race, place of birth, residence, language, etc., and doing acts prejudicial to maintenance of harmony) and 295A (Deliberate and malicious acts intended to outrage religious feelings of any class by insulting its religion or religious beliefs) of the Indian Penal Code.
Rev. Chander Mani Khanna was called by the Grand Mufti of Kashmir to a sharia court on 8 November to explain alleged forced conversions of young Muslims, after a video appeared on YouTube that shows the pastor baptising seven adult converts from Islam. He was accused of converting Muslims in exchange for money. Muslims responded angrily to the footage, threatening to burn Mr Khanna to death, kill all Christian missionaries and burn their buildings, schools and churches.
Amid concerns for the pastor’s safety following the sharia court hearing, the police initially asked him not to move from his home in Srinagar, saying that they were protecting him. But they then raided his church and arrested him on charges of fomenting communal strife. He was released on bail after spending ten days in police custody. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him.
Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him. Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media: There will be serious consequences of this. We will implement our part and the government should implement its.
Following Mr Khanna’s arrest, Indian Christian leaders have questioned why the authorities are siding with the sharia court in a country with a secular constitution, which guarantees all citizens the “right freely to profess, practice and propagate [their] religion”. Sajan K George, president of the Global Council of Indian Christians (GCIC), said: Allowing a Sharia Court to enforce its laws on Christians represents an end to the rule of law and equality of Indian citizens.
While a number of Indian states have introduced “anti-conversion laws”, Jammu and Kashmir is not one of them. Mr Khanna was instead arrested under Articles 153A (Promoting enmity between different groups on ground of religion, race, place of birth, residence, language, etc., and doing acts prejudicial to maintenance of harmony) and 295A (Deliberate and malicious acts intended to outrage religious feelings of any class by insulting its religion or religious beliefs) of the Indian Penal Code.
Religious freedom in Kazakhstan
Religious freedom is not something that most countries in the world subscribe to. In the UK religious freedom is subsidiary to supporting gay rights.
But things are far worse in the former Russian Republics.
A teenager was knocked unconscious by a policeman in a raid on a church meeting in Kazakhstan as the authorities continue their crackdown on religious freedom under strict new laws.
The 17-year-old girl was hit by the officer in a raid on a worship service by an officially registered Protestant church in Atyrau. The congregation was targeted because it was meeting away from its legal address, which is not allowed under the new Religion Law. They had been forced to gather at a hotel because the authorities had blocked them from using their regular venue. Since the new legislation came into force on 11 October, Baptist churches, which refuse to register with the authorities on principle, have reported increased harassment and pressure from officials, who interrupt their services and issue threats. Children who attend Baptist churches are being taunted by their classmates, who say that their churches will be closed down and their parents sent to prison, having apparently heard this on television and from some teachers.
In other developments, churches and mosques in the Almaty’s Turksib District have been instructed to report “on a daily basis” what measures they are taking to counter extremism, while regulations are being drawn up regarding the state censorship of almost all imported religious literature and objects. Only registered religious organisations may import “informational materials of religious content”, apart from small quantities for personal use, with prior approval from the Agency of Religious Affairs (ARA), which will conduct an “expert analysis” of each title. It will be an offence to import, produce or distribute any literature rejected by the ARA, punishable by fines and, if done by a registered organisation, a suspension of the organisation’s activity for three months.
Observers have highlighted the fact that such censorship directly violates Kazakhstan’s international human rights commitments. The new Religion Law also requires compulsory state registration of both foreigners and Kazakh citizens engaged in “missionary activity” and “spreading a faith”. ARA chairman Kairat Lama Sharif said that this was to prevent and counter “the destructive influence of several non-traditional religious organisations on the process of the spiritual/moral development of Kazakh society”.
The new legislation favours the country’s “traditional religions”, notably the Hanafi school of Islam and Russian Orthodox Christianity, leaving smaller Christian denominations and other religious minority groups concerned that their activities will be targeted and curtailed. The New Life Protestant Church in Almaty has already fallen victim to this. Five foreign guest speakers could not attend a conference the church organised following a ruling from the ARA just four days before the event. Officials have insisted that they did not ban the speakers, but the ARA wrote to the church recommending “refraining from inviting” them, leaving the church with no real alternative in the current climate.
The Kazakh authorities are speedily implementing the new laws; regulations are now being prepared that will govern other elements including the re-registration process, how and where places of worship can be built, and where religious books and materials are allowed to be sold.
But things are far worse in the former Russian Republics.
A teenager was knocked unconscious by a policeman in a raid on a church meeting in Kazakhstan as the authorities continue their crackdown on religious freedom under strict new laws.
The 17-year-old girl was hit by the officer in a raid on a worship service by an officially registered Protestant church in Atyrau. The congregation was targeted because it was meeting away from its legal address, which is not allowed under the new Religion Law. They had been forced to gather at a hotel because the authorities had blocked them from using their regular venue. Since the new legislation came into force on 11 October, Baptist churches, which refuse to register with the authorities on principle, have reported increased harassment and pressure from officials, who interrupt their services and issue threats. Children who attend Baptist churches are being taunted by their classmates, who say that their churches will be closed down and their parents sent to prison, having apparently heard this on television and from some teachers.
In other developments, churches and mosques in the Almaty’s Turksib District have been instructed to report “on a daily basis” what measures they are taking to counter extremism, while regulations are being drawn up regarding the state censorship of almost all imported religious literature and objects. Only registered religious organisations may import “informational materials of religious content”, apart from small quantities for personal use, with prior approval from the Agency of Religious Affairs (ARA), which will conduct an “expert analysis” of each title. It will be an offence to import, produce or distribute any literature rejected by the ARA, punishable by fines and, if done by a registered organisation, a suspension of the organisation’s activity for three months.
Observers have highlighted the fact that such censorship directly violates Kazakhstan’s international human rights commitments. The new Religion Law also requires compulsory state registration of both foreigners and Kazakh citizens engaged in “missionary activity” and “spreading a faith”. ARA chairman Kairat Lama Sharif said that this was to prevent and counter “the destructive influence of several non-traditional religious organisations on the process of the spiritual/moral development of Kazakh society”.
The new legislation favours the country’s “traditional religions”, notably the Hanafi school of Islam and Russian Orthodox Christianity, leaving smaller Christian denominations and other religious minority groups concerned that their activities will be targeted and curtailed. The New Life Protestant Church in Almaty has already fallen victim to this. Five foreign guest speakers could not attend a conference the church organised following a ruling from the ARA just four days before the event. Officials have insisted that they did not ban the speakers, but the ARA wrote to the church recommending “refraining from inviting” them, leaving the church with no real alternative in the current climate.
The Kazakh authorities are speedily implementing the new laws; regulations are now being prepared that will govern other elements including the re-registration process, how and where places of worship can be built, and where religious books and materials are allowed to be sold.
Hindu threats to Christians in Nepal
My home town of Aldershot has had a massive influx of Nepalese Ghurkas, which has embarrassed the town council in their ability to provide housing, education and medical services. In grateful recognition of this hospitality the Nepalese government has turned against Christians in Nepal.
An extremist Hindu group behind a bomb blast outside a Christian mission building in Nepal has demanded that the country become a Hindu state and all churches in the capital be closed within 50 days. An explosive device was detonated beside the offices of the United Mission to Nepal, an association of Christian and government organisations devoted to social justice and poverty alleviation, in Kathmandu on Tuesday 22 November. The building is situated in a residential area, but there were no casualties and minimal property damage. Another bomb found nearby was defused by a bomb disposal squad. Five days later, a bomb was discovered outside a Protestant church in central Kathmandu by the janitor; it was defused by security forces.
The Nepal Defence Army (NDA), an extremist Hindu group that wants to reinstate the country’s Hindu monarchy, claimed responsibility for the blast outside the United Mission. Pamphlets signed by the group reportedly demanding that Nepal should be a Hindu state, that all churches in Kathmandu should be closed within 50 days and that all missionary organisations should leave Nepal, were found by the police.
The NDA bombed a church in Lalitpur, south of Kathmandu, in May 2009. Three people were killed and more than a dozen injured in that attack, which happened on the eve of national elections for a new prime minister. The group has also been behind the murder of a church pastor and other attacks against Christians, who are feeling increasingly under threat in Nepal. They are concerned about proposed new legislation that would outlaw converting from one religion to another or inciting someone else to do so. Offenders could face up to five years in prison.
Christian leaders fear that the witness of the Church in Nepal will be seriously threatened if the government proceeds with the legislation. It would be a retrograde step for religious freedom in Nepal, overturning the provisions of the 2007 interim constitution, which guarantees freedom of religion and expression to all groups. In a worrying indication of the growing climate of hostility over religious conversions, especially to Christianity, two people were beaten and forcibly evicted from their village in Sindupalcowk on 22 November because they had become Christians.
An extremist Hindu group behind a bomb blast outside a Christian mission building in Nepal has demanded that the country become a Hindu state and all churches in the capital be closed within 50 days. An explosive device was detonated beside the offices of the United Mission to Nepal, an association of Christian and government organisations devoted to social justice and poverty alleviation, in Kathmandu on Tuesday 22 November. The building is situated in a residential area, but there were no casualties and minimal property damage. Another bomb found nearby was defused by a bomb disposal squad. Five days later, a bomb was discovered outside a Protestant church in central Kathmandu by the janitor; it was defused by security forces.
The Nepal Defence Army (NDA), an extremist Hindu group that wants to reinstate the country’s Hindu monarchy, claimed responsibility for the blast outside the United Mission. Pamphlets signed by the group reportedly demanding that Nepal should be a Hindu state, that all churches in Kathmandu should be closed within 50 days and that all missionary organisations should leave Nepal, were found by the police.
The NDA bombed a church in Lalitpur, south of Kathmandu, in May 2009. Three people were killed and more than a dozen injured in that attack, which happened on the eve of national elections for a new prime minister. The group has also been behind the murder of a church pastor and other attacks against Christians, who are feeling increasingly under threat in Nepal. They are concerned about proposed new legislation that would outlaw converting from one religion to another or inciting someone else to do so. Offenders could face up to five years in prison.
Christian leaders fear that the witness of the Church in Nepal will be seriously threatened if the government proceeds with the legislation. It would be a retrograde step for religious freedom in Nepal, overturning the provisions of the 2007 interim constitution, which guarantees freedom of religion and expression to all groups. In a worrying indication of the growing climate of hostility over religious conversions, especially to Christianity, two people were beaten and forcibly evicted from their village in Sindupalcowk on 22 November because they had become Christians.
How exactly do American doctors treat CLL?
Back to the ASH abstracts. This is one that tries to work out what is actually hapenning in America with the treament of CLL.
2864 Patterns of Care for Patients with Chronic Lymphocytic Leukemia (CLL): The Connect® CLL Disease Registry Jeff Sharman, Christopher R Flowers, Mark Weiss, David Grinblatt, Charles Farber, Neil Kay, Thomas Kipps, Nicole Lamanna, Chris Pashos, Ian W Flinn, Mark Kozloff, Susan Lerner, Arlene Swern, Kristen A Sullivan, Thomas K. Street, and Michael Keating.
Introduction:
Clinical trials have illuminated a number of unique treatment strategies for patients with CLL. The impact of these strategies on routine practice remains unknown as trial participants may not reflect the same population encountered outside of a clinical trial setting. Many questions remain regarding the sequencing of therapies based on age and performance status. By characterizing current patterns of care; patients, treating physicians, and regulatory agencies will be able to understand the current landscape of CLL treatment. The Connect® CLL registry was designed to report the natural history and real world management of patients receiving therapy for CLL. In this first report, we characterize the therapeutic approaches used for the treatment of patients with CLL of different age groups (i.e. < 65 years, 65–75 years, and ≥ 75 years) and with an ECOG PS status score of 0 compared to 1 or greater.
Methods:
Connect® CLL is a prospective, longitudinal, observational, multi-center registry conducted in community and academic research centers in the United States. At present, 237 sites are actively participating with a projected study enrollment of 1500 patients. Eligible patients are to be enrolled within 2 months of being initiated on any line of therapy; whether initial therapy or salvage therapy. Each patient will be followed for up to 60 months. Clinical data, physician choices, patient-reported health-related quality of life, response and survival are to be collected approximately every 3 months during participation.
Results:
A total of 607 patients have been enrolled (4% from academic sites) with a median age of 70 years. 198 were < 65 years old (age group 1), 187 were between 65–75 years old (age group 2), and 222 were ≥ 75 years old (age group 3). ECOG status varied across the three age groups, with an ECOG status score of ≥ 1 for 39%, 52%, and 70% of patients respectively. Treatment patterns varied across the age groups and by ECOG status in the 496 patients reporting therapies. The most commonly recorded first-line regimens independent of age included fludarabine (F) cyclophosphamide (C) and rituximab (R) (33%), bendamustine (B) +/- R (19%), F +/- R (15%), or investigational therapy (15%). For second-line regimens and beyond, the most frequently recorded regimen was B +/- R (30%), FCR (23%), other F-based regimens (13%), or investigational therapy (8%).
Note that nearly three quarters of patients over-75 had a poor ECOG score. This is why you can't translate clinical trials results to how to treat most cases of CLL. The average age of diagnosis in CLL is at least 70 and the age thay theu need treatment for the first time is even older.
The use of FCR for first-line treatment decreased significantly with increasing age group, (45%, 32%, 20%, for age group 1, 2, 3 respectively, p=0.04, spearman correlation) while use of F +/- R remained level across the age groups (14%, 15%, 15%, respectively). Compared to age group 1, first-line therapy with B +/- R in age groups 2 and 3 (15%, 22%, 21%, respectively) was higher but did not achieve statistical significance. B +/- R represented the most common treatment for all age groups (37%, 26%, 29%, respectively) as second line therapy but did not vary by age (P=0.35). The use of chlorambucil was infrequent in all age groups, but was more common in age group 3 patients compared to the others (P=0.01), in both first-line (2%, 4%, 12%, respectively) and subsequent lines of therapy (0%, 1%, 8%, respectively).
Note: only 35% of the over-75s even had fludarabine, let alone FCR. Mind you this would have included many mutated patients who would never need any treatment.
Treatment assignments did not vary by ECOG PS score for patients in age group 1. First-line therapy for patients with an ECOG PS score of 0 in age groups 2 and 3 consisted of FCR (32% and 15%, respectively), F +/- R (19% and 15%, respectively), B +/- R (16% and 15%, respectively), and alkylating agents (3% and 23%, respectively). Patients in age groups 2 and 3 with ECOG PS score ≥ 1 received B +/- R regimen (33% and 22%, respectively), FCR (23% and 21%, respectively), F +/- R (14% and 10%, respectively) and alkylating agents (7% and 9%, respectively) as first-line therapy. Further description and clarification on the various treatment regimens based on the three age groups and by ECOG PS score will be presented at the meeting.
Note: B +/- R does not have any validation by clinical trials in this situation. It is toxic, but I am willing to believe that there is another mechanism by which it has an advantage second line.
Conclusion:
The Connect® CLL Registry is the largest prospective, multicenter registry in the United States evaluating management for patients with CLL. With the currently available data, we characterize the extent to which age and performance status are associated with treatment selection in both first-line and subsequent lines of therapy in routine practice. As enrollment increases and additional follow-up is completed, the data will provide more extensive and real world overview of the current treatment strategies used in CLL patients.
This study is obviously funded by Celgene. I wonder what their ulterior motive is in doing so.
2864 Patterns of Care for Patients with Chronic Lymphocytic Leukemia (CLL): The Connect® CLL Disease Registry Jeff Sharman, Christopher R Flowers, Mark Weiss, David Grinblatt, Charles Farber, Neil Kay, Thomas Kipps, Nicole Lamanna, Chris Pashos, Ian W Flinn, Mark Kozloff, Susan Lerner, Arlene Swern, Kristen A Sullivan, Thomas K. Street, and Michael Keating.
Introduction:
Clinical trials have illuminated a number of unique treatment strategies for patients with CLL. The impact of these strategies on routine practice remains unknown as trial participants may not reflect the same population encountered outside of a clinical trial setting. Many questions remain regarding the sequencing of therapies based on age and performance status. By characterizing current patterns of care; patients, treating physicians, and regulatory agencies will be able to understand the current landscape of CLL treatment. The Connect® CLL registry was designed to report the natural history and real world management of patients receiving therapy for CLL. In this first report, we characterize the therapeutic approaches used for the treatment of patients with CLL of different age groups (i.e. < 65 years, 65–75 years, and ≥ 75 years) and with an ECOG PS status score of 0 compared to 1 or greater.
Methods:
Connect® CLL is a prospective, longitudinal, observational, multi-center registry conducted in community and academic research centers in the United States. At present, 237 sites are actively participating with a projected study enrollment of 1500 patients. Eligible patients are to be enrolled within 2 months of being initiated on any line of therapy; whether initial therapy or salvage therapy. Each patient will be followed for up to 60 months. Clinical data, physician choices, patient-reported health-related quality of life, response and survival are to be collected approximately every 3 months during participation.
Results:
A total of 607 patients have been enrolled (4% from academic sites) with a median age of 70 years. 198 were < 65 years old (age group 1), 187 were between 65–75 years old (age group 2), and 222 were ≥ 75 years old (age group 3). ECOG status varied across the three age groups, with an ECOG status score of ≥ 1 for 39%, 52%, and 70% of patients respectively. Treatment patterns varied across the age groups and by ECOG status in the 496 patients reporting therapies. The most commonly recorded first-line regimens independent of age included fludarabine (F) cyclophosphamide (C) and rituximab (R) (33%), bendamustine (B) +/- R (19%), F +/- R (15%), or investigational therapy (15%). For second-line regimens and beyond, the most frequently recorded regimen was B +/- R (30%), FCR (23%), other F-based regimens (13%), or investigational therapy (8%).
Note that nearly three quarters of patients over-75 had a poor ECOG score. This is why you can't translate clinical trials results to how to treat most cases of CLL. The average age of diagnosis in CLL is at least 70 and the age thay theu need treatment for the first time is even older.
The use of FCR for first-line treatment decreased significantly with increasing age group, (45%, 32%, 20%, for age group 1, 2, 3 respectively, p=0.04, spearman correlation) while use of F +/- R remained level across the age groups (14%, 15%, 15%, respectively). Compared to age group 1, first-line therapy with B +/- R in age groups 2 and 3 (15%, 22%, 21%, respectively) was higher but did not achieve statistical significance. B +/- R represented the most common treatment for all age groups (37%, 26%, 29%, respectively) as second line therapy but did not vary by age (P=0.35). The use of chlorambucil was infrequent in all age groups, but was more common in age group 3 patients compared to the others (P=0.01), in both first-line (2%, 4%, 12%, respectively) and subsequent lines of therapy (0%, 1%, 8%, respectively).
Note: only 35% of the over-75s even had fludarabine, let alone FCR. Mind you this would have included many mutated patients who would never need any treatment.
Treatment assignments did not vary by ECOG PS score for patients in age group 1. First-line therapy for patients with an ECOG PS score of 0 in age groups 2 and 3 consisted of FCR (32% and 15%, respectively), F +/- R (19% and 15%, respectively), B +/- R (16% and 15%, respectively), and alkylating agents (3% and 23%, respectively). Patients in age groups 2 and 3 with ECOG PS score ≥ 1 received B +/- R regimen (33% and 22%, respectively), FCR (23% and 21%, respectively), F +/- R (14% and 10%, respectively) and alkylating agents (7% and 9%, respectively) as first-line therapy. Further description and clarification on the various treatment regimens based on the three age groups and by ECOG PS score will be presented at the meeting.
Note: B +/- R does not have any validation by clinical trials in this situation. It is toxic, but I am willing to believe that there is another mechanism by which it has an advantage second line.
Conclusion:
The Connect® CLL Registry is the largest prospective, multicenter registry in the United States evaluating management for patients with CLL. With the currently available data, we characterize the extent to which age and performance status are associated with treatment selection in both first-line and subsequent lines of therapy in routine practice. As enrollment increases and additional follow-up is completed, the data will provide more extensive and real world overview of the current treatment strategies used in CLL patients.
This study is obviously funded by Celgene. I wonder what their ulterior motive is in doing so.
Yesterday's strikes
Withe the Help of David Aaronovitch of the Times:
Yesterday’s strikes were, in historical terms, a pinprick. The co-ordinated day of action was a huge organisational feat by Britain’s relatively weak trades unions and is not easily repeated. Yet, although a pain to many parents and a worry to patients and relatives, it will be largely forgotten by next week. Then will come the issue of what to do next. Does any public sector union imagine that it can successfully get its membership out on proper strike action — you know, where you go on strike indefinitely until your demands are met or moved towards? David Cameron called them a "damp squib" as part of the propaganda war. True 58% of schools were closed and a further 13% had teachers off, and 7-8000 elective procedures in hospitals were postponed, but the expected chaos at ferry and airports did not materialise and many said that ingress and egress was easier than normal.
A group of pickets stood outside the North London comprehensive that educated both the Miliband brothers. Arranging their placards in the bright, cold breakfast-time air, the strikers were young, clean and happy. The impression they gave was of having fun and of being sure that what they were doing was right. The strikers were the optimists yesterday. People don’t usually take this kind of action out of despair, but out of a belief that somehow things can be made better (at least for them) and that their activities will help things along. Perhaps many of those on the picket lines had lodged somewhere in their psyches a personal version of a Plan B, in which a government started making a different series of decisions and, bingo, good replaced bad.
The image was comforting. You knew where you were with it. In the same way that yesterday’s Prime Minister’s Questions suddenly reverted to the archetypical PMQs of the 1980s and MPs settled down into ancient trenches, dug and furnished by previous more certain generations. Ed Miliband had become a creature of the unions, “irresponsible, left-wing and weak”, according to the PM to hear-hears so loud and contented it seemed they had been pent up for years.
Ed then released the atavistic instincts of his own side with accusations that the Etonians were “demonising the dinner lady, the cleaner and the nurse”. Some of whom, he said, earned in a week what the Chancellor spent on a ski-ing holiday. I doubt they do earn that much, but here was a Labour leader, a Labour leader, who would never do anything so bourgeois as ski.
Why were things so grim? Labour’s fault for spending too much? The coalition’s for not spending enough? The unions? The bankers? Nothing so easily dealt with. The deficit reduction plan, which had banked on private sector growth, was stalled because of oil prices, food prices and the crisis in the eurozone and America. This left us facing the fact that, as I heard the Chancellor say yesterday, “Britain is poorer than it used to be”. And worse than this, even these gloomy assumptions were based on Angela Merkel — who does not rely on many votes in Britain — taking action that she seems disinclined to take.
This means that, whatever is said in Parliament and by union leaders, in general we must expect to be less well off for a while. This notwithstanding the galling spectacle of a very small number of business people who have insulated themselves very effectively against any pain-sharing. An irony here is that this reduction in expectation is just what the Greens have been advocating for years, yet you could find their one MP yesterday supporting action to protect the value of public sector workers’ pensions and pay. Well, a predictable irony.
Aaronovitch reports: "Then, by a series of accidents in early adulthood I found myself more struck against than striking. When staff at the National Union of Students went on strike, all of us Commie and left Labourite reps were to be discovered crossing a picket line and being called scabs by people earning several times as much as we did. There — and later at the BBC — I quickly became aware of some of the cynical theatricality of these occasions. Unions can be ruthless with the truth if it suits them. And employers can be bastards.
Some strikers may fantasise about it after the cheerfulness and colour of yesterday’s actions, but I cannot see it. You don’t put your livelihood and that of your family on the line unless you have a plan you can believe in — and it becomes ever more apparent that there just isn’t one. Which is one reason why the Occupy movement is a relative success in publicity and longevity — exactly because its remedies are so nebulous that you don’t have to imagine them being implemented. Whereas the TUC is extremely unlikely to adopt the slogan “A union is its own demand”. You don’t pay your weekly dues for optimism as airy as that. So if you ask me how bad things are, my reply is that they are so bad that there won’t be many more strikes, but there may be lots of tents."
Yesterday’s strikes were, in historical terms, a pinprick. The co-ordinated day of action was a huge organisational feat by Britain’s relatively weak trades unions and is not easily repeated. Yet, although a pain to many parents and a worry to patients and relatives, it will be largely forgotten by next week. Then will come the issue of what to do next. Does any public sector union imagine that it can successfully get its membership out on proper strike action — you know, where you go on strike indefinitely until your demands are met or moved towards? David Cameron called them a "damp squib" as part of the propaganda war. True 58% of schools were closed and a further 13% had teachers off, and 7-8000 elective procedures in hospitals were postponed, but the expected chaos at ferry and airports did not materialise and many said that ingress and egress was easier than normal.
A group of pickets stood outside the North London comprehensive that educated both the Miliband brothers. Arranging their placards in the bright, cold breakfast-time air, the strikers were young, clean and happy. The impression they gave was of having fun and of being sure that what they were doing was right. The strikers were the optimists yesterday. People don’t usually take this kind of action out of despair, but out of a belief that somehow things can be made better (at least for them) and that their activities will help things along. Perhaps many of those on the picket lines had lodged somewhere in their psyches a personal version of a Plan B, in which a government started making a different series of decisions and, bingo, good replaced bad.
The image was comforting. You knew where you were with it. In the same way that yesterday’s Prime Minister’s Questions suddenly reverted to the archetypical PMQs of the 1980s and MPs settled down into ancient trenches, dug and furnished by previous more certain generations. Ed Miliband had become a creature of the unions, “irresponsible, left-wing and weak”, according to the PM to hear-hears so loud and contented it seemed they had been pent up for years.
Ed then released the atavistic instincts of his own side with accusations that the Etonians were “demonising the dinner lady, the cleaner and the nurse”. Some of whom, he said, earned in a week what the Chancellor spent on a ski-ing holiday. I doubt they do earn that much, but here was a Labour leader, a Labour leader, who would never do anything so bourgeois as ski.
Why were things so grim? Labour’s fault for spending too much? The coalition’s for not spending enough? The unions? The bankers? Nothing so easily dealt with. The deficit reduction plan, which had banked on private sector growth, was stalled because of oil prices, food prices and the crisis in the eurozone and America. This left us facing the fact that, as I heard the Chancellor say yesterday, “Britain is poorer than it used to be”. And worse than this, even these gloomy assumptions were based on Angela Merkel — who does not rely on many votes in Britain — taking action that she seems disinclined to take.
This means that, whatever is said in Parliament and by union leaders, in general we must expect to be less well off for a while. This notwithstanding the galling spectacle of a very small number of business people who have insulated themselves very effectively against any pain-sharing. An irony here is that this reduction in expectation is just what the Greens have been advocating for years, yet you could find their one MP yesterday supporting action to protect the value of public sector workers’ pensions and pay. Well, a predictable irony.
Aaronovitch reports: "Then, by a series of accidents in early adulthood I found myself more struck against than striking. When staff at the National Union of Students went on strike, all of us Commie and left Labourite reps were to be discovered crossing a picket line and being called scabs by people earning several times as much as we did. There — and later at the BBC — I quickly became aware of some of the cynical theatricality of these occasions. Unions can be ruthless with the truth if it suits them. And employers can be bastards.
Some strikers may fantasise about it after the cheerfulness and colour of yesterday’s actions, but I cannot see it. You don’t put your livelihood and that of your family on the line unless you have a plan you can believe in — and it becomes ever more apparent that there just isn’t one. Which is one reason why the Occupy movement is a relative success in publicity and longevity — exactly because its remedies are so nebulous that you don’t have to imagine them being implemented. Whereas the TUC is extremely unlikely to adopt the slogan “A union is its own demand”. You don’t pay your weekly dues for optimism as airy as that. So if you ask me how bad things are, my reply is that they are so bad that there won’t be many more strikes, but there may be lots of tents."
More troubles
I had another fall this morning. I slipped while coming downstairs and twisted the knee I injured 50 years ago. I have a longstanding anterior cruciate tear that was never repaired (there was no operation then) that has left my left knee unstable. For a while I was in great pain, but my wife came and laid hands on my knee and after a bit of massage all the pain was gone. I didn't realise she had that skill. Or perhaps it was a miracle.
We were let down by Currys who delivered the new dishwasher but the fitter was unable to fit it. "More than my jobsworth" he said. I suppose he could have plugged an electric plug into a socket, but the dishwasher was hard-wired into the wall. They were evening threatening to take the old one away. Happily, our friend Bob was visiting us and he was able to disconnect the old machine and allow them to remove it. A private fitter will call in to connect it this evening.
Still waiting for the monoclonal antibody; I am now expecting a positive result by lunchtime.
We were let down by Currys who delivered the new dishwasher but the fitter was unable to fit it. "More than my jobsworth" he said. I suppose he could have plugged an electric plug into a socket, but the dishwasher was hard-wired into the wall. They were evening threatening to take the old one away. Happily, our friend Bob was visiting us and he was able to disconnect the old machine and allow them to remove it. A private fitter will call in to connect it this evening.
Still waiting for the monoclonal antibody; I am now expecting a positive result by lunchtime.
John 8:23-24. Only believe
But he continued, “You are from below; I am from above. You are of this world; I am not of this world. I told you that you would die in your sins; if you do not believe that I am he, you will indeed die in your sins.”
Three more "I AMs" The demand that God makes on us is not a Herculean cleansing of the stables, but to believe. Unbelief is the unforgivable sin.
Three more "I AMs" The demand that God makes on us is not a Herculean cleansing of the stables, but to believe. Unbelief is the unforgivable sin.
Another benefits cheat
A drummer in a marching band who claimed he could walk no more than 15 yards and couldn’t even tie his own shoelaces has been exposed as a benefits cheat, after investigators secretly filmed him marching through the streets. Alexander Clarkson was caught marching through Great Harwood in Lancashire in full Scottish pipe band regalia and kilt. At the same time, the 63-year-old was receiving thousands of pounds every year by claiming he could walk only short distances and was always falling over because of his disabilities.
Clarkson, from Blackpool Lancs, admitted cheating the Department of Work and Pensions (DWP) out of £17,329 over a six-year period by failing to tell them his disabilities had improved. District judge Jeff Brailsford at Blackpool Magistrates’ Court handed Clarkson a 56-day jail term, suspended for a year. He was told the former soldier turned bricklayer had not worked for 33 years.
Prosecutor Michael Woosnam told how Clarkson lived a double life. On one hand he said he needed crutches to get about and could not travel anywhere alone. As well as a disabled living allowance Clarkson also claimed carer's allowance because he needed help cooking meals. But at the same time he was a dedicated member of the City of Preston Scottish Pipe and Drum band and a member of the Blackpool Male Voice Choir. The court heard that the DWP were tipped off about Clarksons's cheating and sent a surveillance team to follow him. They filmed him at a Remembrance Day ceremony in the Lancashire town of Great Harwood where he was lead drummer marching the streets for 30 minutes. When he was confronted about his actions Clarkson said that he had been mistaken for someone else who had borrowed his car for the day.
The following day he was followed walking to a funeral and then attending the wake that followed. Mr Woosnam said: ‘In interview Clarkson said he had continued to claim benefits because he quite simply did not want to lose the money. He also said he had applied to have the carer's element of his claim upgraded.’
Peter Manning, defending, said that Clarkson did have arthritic knees, asthma and diabetes and had recently had an operation on his groin. ‘My client accepts he should have informed the department about his improved mobility.’ Sentencing Clarkson, the judge said: ‘It is clear from the film I have seen, you got pleasure from being in the band. You clearly marched and bent down to pick up your drum. There seemed to be no hindrance to your mobility. ‘And when you were questioned about it you denied it was you. ‘You have been living a comfortable lifestyle as a result of your benefits allowing you to pay £100 a month TV subscriptions and £80 a month on drink and £120 a month on travel.’
Clarkson, from Blackpool Lancs, admitted cheating the Department of Work and Pensions (DWP) out of £17,329 over a six-year period by failing to tell them his disabilities had improved. District judge Jeff Brailsford at Blackpool Magistrates’ Court handed Clarkson a 56-day jail term, suspended for a year. He was told the former soldier turned bricklayer had not worked for 33 years.
Prosecutor Michael Woosnam told how Clarkson lived a double life. On one hand he said he needed crutches to get about and could not travel anywhere alone. As well as a disabled living allowance Clarkson also claimed carer's allowance because he needed help cooking meals. But at the same time he was a dedicated member of the City of Preston Scottish Pipe and Drum band and a member of the Blackpool Male Voice Choir. The court heard that the DWP were tipped off about Clarksons's cheating and sent a surveillance team to follow him. They filmed him at a Remembrance Day ceremony in the Lancashire town of Great Harwood where he was lead drummer marching the streets for 30 minutes. When he was confronted about his actions Clarkson said that he had been mistaken for someone else who had borrowed his car for the day.
The following day he was followed walking to a funeral and then attending the wake that followed. Mr Woosnam said: ‘In interview Clarkson said he had continued to claim benefits because he quite simply did not want to lose the money. He also said he had applied to have the carer's element of his claim upgraded.’
Peter Manning, defending, said that Clarkson did have arthritic knees, asthma and diabetes and had recently had an operation on his groin. ‘My client accepts he should have informed the department about his improved mobility.’ Sentencing Clarkson, the judge said: ‘It is clear from the film I have seen, you got pleasure from being in the band. You clearly marched and bent down to pick up your drum. There seemed to be no hindrance to your mobility. ‘And when you were questioned about it you denied it was you. ‘You have been living a comfortable lifestyle as a result of your benefits allowing you to pay £100 a month TV subscriptions and £80 a month on drink and £120 a month on travel.’
Benefits culture
What benefits frauds do with their ill-gotten gains:
For the past decade, the Whitney family have been spoken of in hushed tones on the backstreets of Anfield, just a stone’s throw from Liverpool Football Club. Drug addicts turned to them when they needed their next hit of heroin or crack cocaine. Those unfortunate enough to live in the same street as the family’s semi may have whispered about the carrier bags of cash exchanging hands on the Whitneys’ doorstep, but they turned a blind eye for fear of reprisals.Seven members of the clan were jailed last week at Liverpool Crown Court, making them one of Britain’s most shameless — and dangerous — families.
The Whitneys made hundreds of thousands of pounds from what police have described as a ‘24-hour drugs cash and carry service’. They were caught after one of Merseyside police’s largest surveillance operations. During the 18 months officers followed the family, they saw an accomplice throw 2kg of heroin, with a street value of £120,000, from the window of a speeding Mercedes in a bid to avoid being caught with it.
The Whitneys’ arrogant police mugshots make a gruesome mockery of the traditional family photograph. At the head of the clan is Leslie Whitney, a 57-year-old former factory worker known as the Godfather. His estranged wife Carol, 54, was nicknamed the Banker by police officers, who discovered thousands of pounds in cash hidden at her home, as well as cocaine and 12 kg of uncut heroin. The couple’s three children, Paul, 33, Lisa, 31, and Anthony, 30, were found guilty of conspiracy to supply Class A drugs, along with Lisa’s boyfriend Wayne Hincks and Leslie’s girlfriend, Emma Mackenzie, 29. Emma’s mother Mary McCabe was also part of the gang. When police searched her car, they found a stolen SA80 assault rifle, stolen from an Army base, and 1,200 rounds of ammunition.
But for the Whitneys’ innocent relatives, many of whom live in Liverpool, the past week has been filled with shame and humiliation. They are struggling to come to terms with how this once typically hard-working family deteriorated into a feared drugs gang. ‘They’ve brought shame on the family,’ says one relative, who asked not to be named.
For the past decade, the Whitney family have been spoken of in hushed tones on the backstreets of Anfield, just a stone’s throw from Liverpool Football Club. Drug addicts turned to them when they needed their next hit of heroin or crack cocaine. Those unfortunate enough to live in the same street as the family’s semi may have whispered about the carrier bags of cash exchanging hands on the Whitneys’ doorstep, but they turned a blind eye for fear of reprisals.Seven members of the clan were jailed last week at Liverpool Crown Court, making them one of Britain’s most shameless — and dangerous — families.
The Whitneys made hundreds of thousands of pounds from what police have described as a ‘24-hour drugs cash and carry service’. They were caught after one of Merseyside police’s largest surveillance operations. During the 18 months officers followed the family, they saw an accomplice throw 2kg of heroin, with a street value of £120,000, from the window of a speeding Mercedes in a bid to avoid being caught with it.
The Whitneys’ arrogant police mugshots make a gruesome mockery of the traditional family photograph. At the head of the clan is Leslie Whitney, a 57-year-old former factory worker known as the Godfather. His estranged wife Carol, 54, was nicknamed the Banker by police officers, who discovered thousands of pounds in cash hidden at her home, as well as cocaine and 12 kg of uncut heroin. The couple’s three children, Paul, 33, Lisa, 31, and Anthony, 30, were found guilty of conspiracy to supply Class A drugs, along with Lisa’s boyfriend Wayne Hincks and Leslie’s girlfriend, Emma Mackenzie, 29. Emma’s mother Mary McCabe was also part of the gang. When police searched her car, they found a stolen SA80 assault rifle, stolen from an Army base, and 1,200 rounds of ammunition.
But for the Whitneys’ innocent relatives, many of whom live in Liverpool, the past week has been filled with shame and humiliation. They are struggling to come to terms with how this once typically hard-working family deteriorated into a feared drugs gang. ‘They’ve brought shame on the family,’ says one relative, who asked not to be named.