What must it be like to think of yourself as simply an evolutionary body - formed by blind chance, with no purpose but to pass on your DNA to the next generation. You would be like the rocks or the sea with no point but to be worn down to dust and detritus.
The materialist
The earth feels no pain
from the wounds of the rain
that in strange constancy
falls emotionlessly;
and the rain does not please
to caress the cold trees.
The stream to the sea
flows ambitionlessly
and there is no disgrace
in the moon’s clouded face,
nor jealousy’s spite
in the stars’ lesser light;
and the wind all day long
does no right and no wrong,
has no sins to rescind.
He is one with the wind.
Thursday, October 07, 2010
German CLL8 part 10
What about complications?
Again click to enlarge. The table relates to grade 3 or 4 adverse events. These are the ones that need to be taken seriously with hospital admission and definitive treatment. The obvious difference between FC and FCR is that adding rituximab causes significantly more neutropenia. As I have previously stated this does not represent bone marrow failure, but increased destruction of neutrophils in the immune complexes cause by antibody reacting with antigen. It need not be viewed as a reason to reduce doses and even as a hazard for future infection. Indeed there were no more infections with FCR than there were with FC, despite the greater incidence of neutropenia.
What about the known rituximab complications? These are primarily to do with the infusion-related cytokine release syndrome. Just one instance in over 400 patients.
Tumor lysis syndrome? Just one instance. Autoimmune hemolytic anemia? Three cases. As I suspected the cyclo and rituximab has cancelled out the fludarabine effect.
Viral and fungal infections? Again penny numbers. It looks to me that in this fit and mostly young population of patients, FCR is well tolerated as a first line therapy. And to be truthful, that is my own experience.
Ten (3%) deaths were related to treatment in the chemotherapy group, and eight (2%) in the chemoimmunotherapy group. Of these, six chemotherapy-treated patients and five chemoimmunotherapy-treated patients died from infections (septicaemia [n=6], pneumonia [n=3], hepatitis B [n=1], and cryptosporidium gastroenteritis [n=1]). In seven patients (three in the chemotherapy group and four in the chemoimmunotherapy group), death occurred before the third treatment course (fatal septicaemia [n=6], sudden cardiac death [n=1]). These early deaths mainly occurred in patients with del 17p, that is unresponsive patients who are in any case highly at risk because of their disease. Virtually all types of treatment damages normal tissue to some extent, but this matters little when the damage to tumor is so much greater that it allows normal tissue to rapidly regrow. It is when both tumor and treatment damage the normal tissue that disaster happens.
In most cases, the underlying cause of death was progressive disease (chemotherapy 48 [56%] of 86, chemoimmunotherapy 33 [51%] of 65). Other fatal events were secondary cancers (chemotherapy 13 [15%], chemoimmunotherapy five [8%]) and causes unrelated to chronic lymphocytic leukaemia, such as myocardial infarction (15 [17%] and 17 [26%], respectively).
There is no mention of patients developing Richter's syndrome or myelodysplastic syndrome. Despite the alarm sounded in some quarters (especially by myself) about the association of these complications with fludarabine usage, I am not surprised that after such short follow up they have not been seen. I would expect them to be late complications and more associated with FCR used as second-line treatment. Indeed we certainly had some concerns about MDS with the REACH trial which used FCR later in the disease.
Again click to enlarge. The table relates to grade 3 or 4 adverse events. These are the ones that need to be taken seriously with hospital admission and definitive treatment. The obvious difference between FC and FCR is that adding rituximab causes significantly more neutropenia. As I have previously stated this does not represent bone marrow failure, but increased destruction of neutrophils in the immune complexes cause by antibody reacting with antigen. It need not be viewed as a reason to reduce doses and even as a hazard for future infection. Indeed there were no more infections with FCR than there were with FC, despite the greater incidence of neutropenia.What about the known rituximab complications? These are primarily to do with the infusion-related cytokine release syndrome. Just one instance in over 400 patients.
Tumor lysis syndrome? Just one instance. Autoimmune hemolytic anemia? Three cases. As I suspected the cyclo and rituximab has cancelled out the fludarabine effect.
Viral and fungal infections? Again penny numbers. It looks to me that in this fit and mostly young population of patients, FCR is well tolerated as a first line therapy. And to be truthful, that is my own experience.
Ten (3%) deaths were related to treatment in the chemotherapy group, and eight (2%) in the chemoimmunotherapy group. Of these, six chemotherapy-treated patients and five chemoimmunotherapy-treated patients died from infections (septicaemia [n=6], pneumonia [n=3], hepatitis B [n=1], and cryptosporidium gastroenteritis [n=1]). In seven patients (three in the chemotherapy group and four in the chemoimmunotherapy group), death occurred before the third treatment course (fatal septicaemia [n=6], sudden cardiac death [n=1]). These early deaths mainly occurred in patients with del 17p, that is unresponsive patients who are in any case highly at risk because of their disease. Virtually all types of treatment damages normal tissue to some extent, but this matters little when the damage to tumor is so much greater that it allows normal tissue to rapidly regrow. It is when both tumor and treatment damage the normal tissue that disaster happens.
In most cases, the underlying cause of death was progressive disease (chemotherapy 48 [56%] of 86, chemoimmunotherapy 33 [51%] of 65). Other fatal events were secondary cancers (chemotherapy 13 [15%], chemoimmunotherapy five [8%]) and causes unrelated to chronic lymphocytic leukaemia, such as myocardial infarction (15 [17%] and 17 [26%], respectively).
There is no mention of patients developing Richter's syndrome or myelodysplastic syndrome. Despite the alarm sounded in some quarters (especially by myself) about the association of these complications with fludarabine usage, I am not surprised that after such short follow up they have not been seen. I would expect them to be late complications and more associated with FCR used as second-line treatment. Indeed we certainly had some concerns about MDS with the REACH trial which used FCR later in the disease.
German CLL8 part 9
So what's left to tell you about this trial? I think we can say something about those who had to have fewer than the recommended number of courses or to have their dose reduced.
The mean number of treatment courses administered was 5·2 (range 0–6) in the chemoimmunotherapy group compared with 4·8 (0–6; p=0·006) in the chemotherapy group. 26% did not receive the planned six courses in the chemoimmunotherapy group compared with 34% in the chemotherapy group. The difference was because there were more non-responders withdrawn from the study in those who did not get rituximab. Patients in Binet stages A and B received more treatment courses (mean 5·28 [range 0–6]) than did those in Binet stage C (4·52 [0–6]; p<0·0001).
For any of the three drugs, the planned dose was reduced by more than 10% in 47% of the patients in the chemoimmunotherapy group and 27% of the patients in the chemotherapy group (p<0·0001). 207 of 800 patients had dose reductions during the first to third courses (chemotherapy 19%; chemoimmunotherapy 33%; p<0·0001), and dose reductions occurred in 216 of 800 patients during the fourth to sixth courses (chemotherapy 20% ; chemoimmunotherapy 34% ; p<0·0001). These dose reductions were mostly because of treatment-related haematological toxicity, particularly neutropenia and leucocytopenia (62% in the chemoimmunotherapy group vs 64% in the chemotherapy group). I think this illustrates that neutrophils get swept up in the immune complexes formed between CD20 and anti-CD20 because they have Fc receptors. The production of neutrophils is not being impaired as it is with chemotherapy-induced neutropenia; they are just being used. I am not sure that it is necessary to dose reduce in this instance, but I admit the matter is moot.
The reason that patients with stage C received less drug that patients with stage B is precisely because these patients start out with hematological impairment.
Although an improvement in PFS with the addition of rituximab was noted in all stages, the improvement for Binet stage C was from only months to 40·7 months which did not reach statistical significance (p=0·081). This may have been a statistical artefact because patients with stage C disease who were given chemoimmunotherapy compared with those who were given chemotherapy showed an accumulation of several unfavourable factors (though none were indivdually statistically different; for all p>0·05): Thus age >65 years 35% vs 26%, unmutated IGHV status 54% vs 48%, elevated ZAP70 42% vs 33%, and β2 microglobulin levels greater than 3·5 mg/L 52% vs 44%.
Dose reductions of more than 10% were more common in patients with Binet stage C disease in the chemoimmunotherapy group 49% vs 28%; p=0·001), mostly because of neutropenia and leucocytopenia. Since dose reductions for prevention of haematological toxicity needed to be maintained for the rest of the treatment according to the protocol recommendations, the authors believe that dose reductions required during early courses of chemoimmunotherapy led to persistently lower doses of all three drugs in patients with Binet stage C disease. Since following the first few courses of treatment the cytopenias might remit, there may not be justification for this continued dose reduction and in clinical practise there exists the possibility of continuing subsequent course at full dose.
The mean number of treatment courses administered was 5·2 (range 0–6) in the chemoimmunotherapy group compared with 4·8 (0–6; p=0·006) in the chemotherapy group. 26% did not receive the planned six courses in the chemoimmunotherapy group compared with 34% in the chemotherapy group. The difference was because there were more non-responders withdrawn from the study in those who did not get rituximab. Patients in Binet stages A and B received more treatment courses (mean 5·28 [range 0–6]) than did those in Binet stage C (4·52 [0–6]; p<0·0001).
For any of the three drugs, the planned dose was reduced by more than 10% in 47% of the patients in the chemoimmunotherapy group and 27% of the patients in the chemotherapy group (p<0·0001). 207 of 800 patients had dose reductions during the first to third courses (chemotherapy 19%; chemoimmunotherapy 33%; p<0·0001), and dose reductions occurred in 216 of 800 patients during the fourth to sixth courses (chemotherapy 20% ; chemoimmunotherapy 34% ; p<0·0001). These dose reductions were mostly because of treatment-related haematological toxicity, particularly neutropenia and leucocytopenia (62% in the chemoimmunotherapy group vs 64% in the chemotherapy group). I think this illustrates that neutrophils get swept up in the immune complexes formed between CD20 and anti-CD20 because they have Fc receptors. The production of neutrophils is not being impaired as it is with chemotherapy-induced neutropenia; they are just being used. I am not sure that it is necessary to dose reduce in this instance, but I admit the matter is moot.
The reason that patients with stage C received less drug that patients with stage B is precisely because these patients start out with hematological impairment.
Although an improvement in PFS with the addition of rituximab was noted in all stages, the improvement for Binet stage C was from only months to 40·7 months which did not reach statistical significance (p=0·081). This may have been a statistical artefact because patients with stage C disease who were given chemoimmunotherapy compared with those who were given chemotherapy showed an accumulation of several unfavourable factors (though none were indivdually statistically different; for all p>0·05): Thus age >65 years 35% vs 26%, unmutated IGHV status 54% vs 48%, elevated ZAP70 42% vs 33%, and β2 microglobulin levels greater than 3·5 mg/L 52% vs 44%.
Dose reductions of more than 10% were more common in patients with Binet stage C disease in the chemoimmunotherapy group 49% vs 28%; p=0·001), mostly because of neutropenia and leucocytopenia. Since dose reductions for prevention of haematological toxicity needed to be maintained for the rest of the treatment according to the protocol recommendations, the authors believe that dose reductions required during early courses of chemoimmunotherapy led to persistently lower doses of all three drugs in patients with Binet stage C disease. Since following the first few courses of treatment the cytopenias might remit, there may not be justification for this continued dose reduction and in clinical practise there exists the possibility of continuing subsequent course at full dose.
German CLL8 - part 8
What about older people? CLL is a disease where the median age at diagnosis is 70, but the median age for this trial was 61. I am on record as publishing an article entitled "FCR: No country for old men." Is this regimen safe for older people?
Although the median age was certainly younger, patients up to the age of 81 were treated in this trial. According to the figures 30% of patients were over 65 and 10% over 70. How did they fare?
Looking at response rates, the CR rate for FCR for under-65s was the same as for over-65s at 45% and 43% respectively, while the overall response rates were 89% and 93% respectively. For 3-year progression-free survival the figures were 64% for under-65s and 68% for over-65s, and for 3-year overall survivals they were 87% for under-65s and 88% for over-65s. But we have to remember that all patients entered into this trial had good performance scores with no significant co-morbidities. As you get older this tends not to apply. All we can say is that a selected group of older people who are physically fit do as well on FCR as younger people.
There is some evidence that older patients have less bone marrow reserve than younger patients which showed itself in the patients over-65 having slightly more hematological toxicity than younger patients. This did not show for any particular type of cytopenia, however bacterial infections were significantly commoner in the over-65s, at 4% rather than 1%. The older patients did not require more dose reductions than the younger ones though.
As the authors say, conclusions from this trial should not be generalised to physically unfit, elderly patients with chronic lymphocytic leukaemia.
Although the median age was certainly younger, patients up to the age of 81 were treated in this trial. According to the figures 30% of patients were over 65 and 10% over 70. How did they fare?
Looking at response rates, the CR rate for FCR for under-65s was the same as for over-65s at 45% and 43% respectively, while the overall response rates were 89% and 93% respectively. For 3-year progression-free survival the figures were 64% for under-65s and 68% for over-65s, and for 3-year overall survivals they were 87% for under-65s and 88% for over-65s. But we have to remember that all patients entered into this trial had good performance scores with no significant co-morbidities. As you get older this tends not to apply. All we can say is that a selected group of older people who are physically fit do as well on FCR as younger people.
There is some evidence that older patients have less bone marrow reserve than younger patients which showed itself in the patients over-65 having slightly more hematological toxicity than younger patients. This did not show for any particular type of cytopenia, however bacterial infections were significantly commoner in the over-65s, at 4% rather than 1%. The older patients did not require more dose reductions than the younger ones though.
As the authors say, conclusions from this trial should not be generalised to physically unfit, elderly patients with chronic lymphocytic leukaemia.
new health bulletin
Health this week has improved. I would say that I am now back where I was before the chemotherapy started. My mucositis is in retreat and the colic is manageable. The diarrhea has abated. The only problem is that I can't sleep more than about 3 hours at night, which is why I am up typing at 1 am. Last night I got up at 4 am having lain awake for an hour without resting. It does mean I can get on with CLL8 and enables me to write poetry. I tell you, Coleridge, opium has nothing on dexamethasone.
Is the chemotherapy working? It is really too soon to tell. unlike CLL, the adenocarcinoma response to chemotherapy is more measured and I shall know whether I am better in about three months. I certainly don't want to stop the steroids until I have some sign that things are improving.
I restart the infusions on Saturday, but I hope that I will be better prepared to jump in with remedies for the side effects this time. I still have my hair.
Is the chemotherapy working? It is really too soon to tell. unlike CLL, the adenocarcinoma response to chemotherapy is more measured and I shall know whether I am better in about three months. I certainly don't want to stop the steroids until I have some sign that things are improving.
I restart the infusions on Saturday, but I hope that I will be better prepared to jump in with remedies for the side effects this time. I still have my hair.
German CLL8 part 7
What I want to talk about today is whether FCR works better for all types of people with CLL or should it be confined to only some groups. The first picture deals with response rates.
Again, click to enlarge. For each category of patients I give the CR rate and the overall response rate. The columns headed chemotherapy refer to FC and those headed immunochemotherapy refer to FCR.
In summary FCR is significantly better at getting CRs than FC for all categories of patients except those with del 17p and those with a normal FISH. It gives a better overall response rate than FC for all patients except patients with Binet stage A (too few to be statistically significant), patients with del 11q or trisomy 12 or a normal FISH, and patients with mutated IGHV genes. Note that the CR rate in this trial was not as high as the MDACC got in their phase II trials. This is probably because MDACC treated patients who were not so severely ill. Anecdotally, it appears that entry to the phase II trials was not so stringent as in this multi-center study.
What is outstandingly different about these results is the CR rate in patients with del 11q. This is thought to be a very bad prognosis group and the CR rate for FC was only 15%. However, the CR rate for FCR was 51%. Similarly for trisomy 12 the CR rate went from 19% to 71%. Both trisomy 12 and del 11q tend to be associated with higher levels of CD20 on the surface, so this is some rationale for using rituximab in such cases.
The response rate for patients with del 17p was dismal. Although FCR pushed up the overall response rate there was only one CR, and the increased ORR was not reflected in an improvement in survival or length of emission. Rituximab may have some non-p53 dependent activity, but not enough to make a difference.
The next slides show overall survival curves according to FISH status
What they demonstrate is that rituximab takes the del 11q survival back into the pack of other karyotypes. It seems to eliminate the bad odour associated with this FISH pattern. Take home message is that if you have del 11q, your first treatment must have rituximab in it.
What is the message being conveyed about the poor outcome of those with normal FISH? We can only speculate, but this will include those with unusual karyotypes like t(14;19) and those who have mutated p53 but intact chromosome 17p.
Again, click to enlarge. For each category of patients I give the CR rate and the overall response rate. The columns headed chemotherapy refer to FC and those headed immunochemotherapy refer to FCR.
In summary FCR is significantly better at getting CRs than FC for all categories of patients except those with del 17p and those with a normal FISH. It gives a better overall response rate than FC for all patients except patients with Binet stage A (too few to be statistically significant), patients with del 11q or trisomy 12 or a normal FISH, and patients with mutated IGHV genes. Note that the CR rate in this trial was not as high as the MDACC got in their phase II trials. This is probably because MDACC treated patients who were not so severely ill. Anecdotally, it appears that entry to the phase II trials was not so stringent as in this multi-center study.
What is outstandingly different about these results is the CR rate in patients with del 11q. This is thought to be a very bad prognosis group and the CR rate for FC was only 15%. However, the CR rate for FCR was 51%. Similarly for trisomy 12 the CR rate went from 19% to 71%. Both trisomy 12 and del 11q tend to be associated with higher levels of CD20 on the surface, so this is some rationale for using rituximab in such cases.
The response rate for patients with del 17p was dismal. Although FCR pushed up the overall response rate there was only one CR, and the increased ORR was not reflected in an improvement in survival or length of emission. Rituximab may have some non-p53 dependent activity, but not enough to make a difference.
The next slides show overall survival curves according to FISH status
What they demonstrate is that rituximab takes the del 11q survival back into the pack of other karyotypes. It seems to eliminate the bad odour associated with this FISH pattern. Take home message is that if you have del 11q, your first treatment must have rituximab in it.
What is the message being conveyed about the poor outcome of those with normal FISH? We can only speculate, but this will include those with unusual karyotypes like t(14;19) and those who have mutated p53 but intact chromosome 17p.
Wednesday, October 06, 2010
Cats
Cats: the world, the flesh and the Devil.
We called her Kitten – just a farm cat loaned
for us to nurse with chloramphenicol
and food; for cats are never really owned
the way that dogs are or a Barbie doll.
She used to bring us gifts: a mouse’s head
or tail, but then she left. No debt was owed.
Her present world attracted her instead,
or else another pet killed on the road.
Beware the tigress, prowling and feeding deep
in the forest, needing her yellow stripes to steal
from her black back the drops of sun that seep
through darkness. Death is her dominion; feel
the blood congeal upon those amber teeth.
The taste of every future meal she knows.
She longs for flesh. Light fails to pierce beneath
the trees, so nothing shows and chaos grows.
The lazy lion roars a lofty yawn;
he lifts his paw and shakes his tawny mane
and contemplates his pride with studied scorn.
In certain ease the lord of air and plain
enjoys his comfort and his prey’s distress,
views his domain, displays his solemn power.
Vain, indolent and proud, he nonetheless
considers whom he might today devour.
My thoughts included 2 Timothy 4:10, Demas, in love with this present world who deserted Paul. Colossians 1:13 and the dominion of darkness, and of course 1 Peter 5:8 the devil like a roaring lion.
We called her Kitten – just a farm cat loaned
for us to nurse with chloramphenicol
and food; for cats are never really owned
the way that dogs are or a Barbie doll.
She used to bring us gifts: a mouse’s head
or tail, but then she left. No debt was owed.
Her present world attracted her instead,
or else another pet killed on the road.
Beware the tigress, prowling and feeding deep
in the forest, needing her yellow stripes to steal
from her black back the drops of sun that seep
through darkness. Death is her dominion; feel
the blood congeal upon those amber teeth.
The taste of every future meal she knows.
She longs for flesh. Light fails to pierce beneath
the trees, so nothing shows and chaos grows.
The lazy lion roars a lofty yawn;
he lifts his paw and shakes his tawny mane
and contemplates his pride with studied scorn.
In certain ease the lord of air and plain
enjoys his comfort and his prey’s distress,
views his domain, displays his solemn power.
Vain, indolent and proud, he nonetheless
considers whom he might today devour.
My thoughts included 2 Timothy 4:10, Demas, in love with this present world who deserted Paul. Colossians 1:13 and the dominion of darkness, and of course 1 Peter 5:8 the devil like a roaring lion.
German CLL8 - part 6
OK. So what about secondary endpoints? The important one for this trial is the difference in overall survival between chemotherapy and immunochemotherapy.
As you can see the curves are separating quite widely so that by 5 years follow-up of those who received FC 62% are still alive, whereas, of those who received FCR 75% are still alive. Unfortunately, there are very few patients who have been followed up for 5 years, so down at the right hand end of the graph the figures are not statistically significant - they could have occurred by chance. We are only going to see how big the difference between the two treatments as the trial matures. Indeed, if we go out even further, the lines actually cross, but the numbers are so small at this level, that the crossing is meaningless. The statisticians are only satisfied to report the position at a median of 3 years follow-up. Overall survival 3 years post randomization: FCR: 87.2% FC: 82.5% n=817, HR 0.664, p=0.012. These are the figures that Chris has been giving in his postings. It is a less than 5% difference, to be sure, but the point is that we are sure that it is a real difference, not one that could have happened by chance. Just by eyeballing the graph, we can be pretty sure that the difference will grow as time passes. But statisticians are creatures of exactitude and they won't allow us to say so until it is mathematically proven.
Let's just emphasize this point. For the first time with CLL a treatment has been shown to improve overall survival. Prior to this trial one could easily say that a treatment might give longer remissions, but if you are happy with less severe treatments given more frequently, then it doesn't matter which treatment you receive first. Three 12 month remissions are as good as two 18 month remissions. Now it is not possible to say that. If you go with FC rather than FCR as first line treatment then on average you waon't live as long.
Of course, patients want to know a great deal more than that. If for example you were absolutely sure that you would live longer with FCR than FC, but only 5 days longer, then I guess there wouldn't be many takers for a more aggressive treatment. So we do need to know some more details.
Here's one: The time to 25% of patients dying with FCR was 62.5 months, but with FC it was only 46.8 months. That is the quarter of patients who actually do worst with either of these regimes get an extra 15 months with FCR - and again that is statistically significant. So despite what Chris has been saying, this trial is holding out hope for improvement for a lot of people.
As you can see the curves are separating quite widely so that by 5 years follow-up of those who received FC 62% are still alive, whereas, of those who received FCR 75% are still alive. Unfortunately, there are very few patients who have been followed up for 5 years, so down at the right hand end of the graph the figures are not statistically significant - they could have occurred by chance. We are only going to see how big the difference between the two treatments as the trial matures. Indeed, if we go out even further, the lines actually cross, but the numbers are so small at this level, that the crossing is meaningless. The statisticians are only satisfied to report the position at a median of 3 years follow-up. Overall survival 3 years post randomization: FCR: 87.2% FC: 82.5% n=817, HR 0.664, p=0.012. These are the figures that Chris has been giving in his postings. It is a less than 5% difference, to be sure, but the point is that we are sure that it is a real difference, not one that could have happened by chance. Just by eyeballing the graph, we can be pretty sure that the difference will grow as time passes. But statisticians are creatures of exactitude and they won't allow us to say so until it is mathematically proven.
Let's just emphasize this point. For the first time with CLL a treatment has been shown to improve overall survival. Prior to this trial one could easily say that a treatment might give longer remissions, but if you are happy with less severe treatments given more frequently, then it doesn't matter which treatment you receive first. Three 12 month remissions are as good as two 18 month remissions. Now it is not possible to say that. If you go with FC rather than FCR as first line treatment then on average you waon't live as long.
Of course, patients want to know a great deal more than that. If for example you were absolutely sure that you would live longer with FCR than FC, but only 5 days longer, then I guess there wouldn't be many takers for a more aggressive treatment. So we do need to know some more details.
Here's one: The time to 25% of patients dying with FCR was 62.5 months, but with FC it was only 46.8 months. That is the quarter of patients who actually do worst with either of these regimes get an extra 15 months with FCR - and again that is statistically significant. So despite what Chris has been saying, this trial is holding out hope for improvement for a lot of people.
Fatherhood
Motherhood is something that fathers never understand. No matter how old your children become, you never cease to be a mother. You rejoice in their successes and grieve for their hardships. Let anyone hurt her fledgelings and mother swan will hiss and spit at them, even when the fledgelings have fledgelings of their own.
Fatherhood is something different. I have been thinking of my own father. He was a serious man, tall and large. He was intimidating, even though he never struck me or even shouted at me. I remember once when I carelessly dirtied the shirt that I would have to wear to school the next day. I was terribly upset and afraid; so much so that I took myself off to bed before he came home from work. When he came home, rather than scold me, he came upstairs and persuaded me that I should come down for supper. He was kindness personified. Somehow, though his relationship was primarily with my mother not with the children. He related to us, through her. Later he was to develop a close relationship to my younger brother and to his grandchildren, but to me he always kept his distance. He was rather austere.
He was a man of the Right with strong political views, though one of his closest friends was a Jamaican. He was frustrated by his lack of an education. He had TB as a teenager and was sent to a residential school for two years at a Sanatorium. I don't think it was much of a teaching emporium. He was apprenticed to a tailor and was a skilled tailor's cutter. He was unfit for military service and spent the war making soldiers uniforms for a man who later became the father of the Speaker of the House of Commons. My parents spent the early part of the war living in a wooden 'Gypsy' caravan at an army camp in the midlands.
Later on he worked for the Royal Army Medical Corps in the Officer's Mess in a pretty menial way. He took on tailoring alterations for the chain stores to supplement his income. He worked every evening long into the night.
He was very keen for me to get a proper education and taught me to read before I was three. He sent me to a private primary school on the proceeds of his tailoring. By the time I left aged 8 I had completed the curriculum for eleven year olds.
He used to play cricket with me. After his spell in the Sanatorium he had a part time job on the Worcestershire Club and Ground, helping to prepare the County pitches. He even turned out occasionally for Worcestershire 2nd XI. He used to tell me of how he once nearly took a hat-trick, putting down a caught and bowled. He said that he was distantly related to certain Test Cricketers. I never knew how much to believe his stories. I think he was a fabulist. He was never very good at sport. He had large hands and could put a fearsome amount of spin on a ball, but whenever I saw him play, either cricket or football, he wasn't very good. I guess he was well into his thirties or even forties then and he may well have been much better when he was younger.
He used to take me fishing with him. He liked being alone by the bank of river or canal. He certainly knew how to fish. There are photographs of him with large pike and tench. My younger brothers have taken up the sport, but I admit I found it boring.
My father was a great organizer. He was obviously a lot more intelligent than the average working man that he associated with. He would become Secretary of this or Treasurer of that, Chairman of the other. He would make things happen. A community Hall got built; away matches were organized; a trip to the seaside arranged; but he was not a sticker. He would inevitably fall out with somebody and take his ball home.
I think, as I grew older and moved in educated circles, I was a bit ashamed of him. He didn't have that cultured edge that I was impressed by. I regret how much I stayed away.
I must be one of the few people in the world who has never smoked a single cigarette. My father died of the weed at 59 years old. He smelled of old tobacco. My mother gave me his old suits to wear, but the smell never left them. He had to paint his living room twice a year to disguise the brown coloration of the walls and ceiling. He used to smoke roll-ups for cheapness, lighting one with the butt-end of another. He would even extract the tobacco from the butts to make a new cigarette.
He never got cancer; at autopsy there wasn't a cancerous cell in his body. He developed a very high hemoglobin so that his blood was like treacle. Of course, I diagnosed the problem - smoker's polycythemia or Gaisbock's syndrome. I persuaded him to stop for a couple of months, but he couldn't hack it. He gradually increased his smoking again, titrating it against his angina. While he could still walk from house to car and from car to office without chest pain, he reckoned he was safe.
I wasn't surprised about the clot in his leg just after Christmas 1978. I arranged for his admission to hospital for anticoagulation. I was thinking more about having become a father for the third time myself and perhaps I should have monitored the physician who was looking after him more closely. New-years day 1979 I had a phone call that he was dead. The stupid physician had refused to anticoagulate him on the grounds that he had microscopic red blood cells in his urine. He should have known that nearly all heavy smokers have that. Of course, he died from a massive blood clot that migrated from his leg to his lungs; a pulmonary embolus.
I am still angry about it. He used to haunt my dreams for months afterwards. He would appear in his fishing clothes, getting scruffier and more unkempt as time passed. He kept asking me why?
I wonder what sort of father I have been. I am very proud of all my children but am I close to them? Or as close as I should be?
When my first daughter was born we had been married for about 15 months. At first, I thought of her as an intrusion into our lives. Because we were both working and a junior doctor's life allowed little time off - no more did a junior librarian's - it seemed that we had little time to be alone together.
I wrote this poem at the time to express what I felt.
Fatherhood
In the luminous blue of a child’s eyes
that shine at the sight of her mother
my breath is caught in sharp surprise
as one is at one with the other.
My breath returns as the sharpness dies,
and with sheer delight I discover,
in the luminous blue of my daughter’s eyes
that I am at one with my lover.
Fatherhood is something different. I have been thinking of my own father. He was a serious man, tall and large. He was intimidating, even though he never struck me or even shouted at me. I remember once when I carelessly dirtied the shirt that I would have to wear to school the next day. I was terribly upset and afraid; so much so that I took myself off to bed before he came home from work. When he came home, rather than scold me, he came upstairs and persuaded me that I should come down for supper. He was kindness personified. Somehow, though his relationship was primarily with my mother not with the children. He related to us, through her. Later he was to develop a close relationship to my younger brother and to his grandchildren, but to me he always kept his distance. He was rather austere.
He was a man of the Right with strong political views, though one of his closest friends was a Jamaican. He was frustrated by his lack of an education. He had TB as a teenager and was sent to a residential school for two years at a Sanatorium. I don't think it was much of a teaching emporium. He was apprenticed to a tailor and was a skilled tailor's cutter. He was unfit for military service and spent the war making soldiers uniforms for a man who later became the father of the Speaker of the House of Commons. My parents spent the early part of the war living in a wooden 'Gypsy' caravan at an army camp in the midlands.
Later on he worked for the Royal Army Medical Corps in the Officer's Mess in a pretty menial way. He took on tailoring alterations for the chain stores to supplement his income. He worked every evening long into the night.
He was very keen for me to get a proper education and taught me to read before I was three. He sent me to a private primary school on the proceeds of his tailoring. By the time I left aged 8 I had completed the curriculum for eleven year olds.
He used to play cricket with me. After his spell in the Sanatorium he had a part time job on the Worcestershire Club and Ground, helping to prepare the County pitches. He even turned out occasionally for Worcestershire 2nd XI. He used to tell me of how he once nearly took a hat-trick, putting down a caught and bowled. He said that he was distantly related to certain Test Cricketers. I never knew how much to believe his stories. I think he was a fabulist. He was never very good at sport. He had large hands and could put a fearsome amount of spin on a ball, but whenever I saw him play, either cricket or football, he wasn't very good. I guess he was well into his thirties or even forties then and he may well have been much better when he was younger.
He used to take me fishing with him. He liked being alone by the bank of river or canal. He certainly knew how to fish. There are photographs of him with large pike and tench. My younger brothers have taken up the sport, but I admit I found it boring.
My father was a great organizer. He was obviously a lot more intelligent than the average working man that he associated with. He would become Secretary of this or Treasurer of that, Chairman of the other. He would make things happen. A community Hall got built; away matches were organized; a trip to the seaside arranged; but he was not a sticker. He would inevitably fall out with somebody and take his ball home.
I think, as I grew older and moved in educated circles, I was a bit ashamed of him. He didn't have that cultured edge that I was impressed by. I regret how much I stayed away.
I must be one of the few people in the world who has never smoked a single cigarette. My father died of the weed at 59 years old. He smelled of old tobacco. My mother gave me his old suits to wear, but the smell never left them. He had to paint his living room twice a year to disguise the brown coloration of the walls and ceiling. He used to smoke roll-ups for cheapness, lighting one with the butt-end of another. He would even extract the tobacco from the butts to make a new cigarette.
He never got cancer; at autopsy there wasn't a cancerous cell in his body. He developed a very high hemoglobin so that his blood was like treacle. Of course, I diagnosed the problem - smoker's polycythemia or Gaisbock's syndrome. I persuaded him to stop for a couple of months, but he couldn't hack it. He gradually increased his smoking again, titrating it against his angina. While he could still walk from house to car and from car to office without chest pain, he reckoned he was safe.
I wasn't surprised about the clot in his leg just after Christmas 1978. I arranged for his admission to hospital for anticoagulation. I was thinking more about having become a father for the third time myself and perhaps I should have monitored the physician who was looking after him more closely. New-years day 1979 I had a phone call that he was dead. The stupid physician had refused to anticoagulate him on the grounds that he had microscopic red blood cells in his urine. He should have known that nearly all heavy smokers have that. Of course, he died from a massive blood clot that migrated from his leg to his lungs; a pulmonary embolus.
I am still angry about it. He used to haunt my dreams for months afterwards. He would appear in his fishing clothes, getting scruffier and more unkempt as time passed. He kept asking me why?
I wonder what sort of father I have been. I am very proud of all my children but am I close to them? Or as close as I should be?
When my first daughter was born we had been married for about 15 months. At first, I thought of her as an intrusion into our lives. Because we were both working and a junior doctor's life allowed little time off - no more did a junior librarian's - it seemed that we had little time to be alone together.
I wrote this poem at the time to express what I felt.
Fatherhood
In the luminous blue of a child’s eyes
that shine at the sight of her mother
my breath is caught in sharp surprise
as one is at one with the other.
My breath returns as the sharpness dies,
and with sheer delight I discover,
in the luminous blue of my daughter’s eyes
that I am at one with my lover.
Tuesday, October 05, 2010
German CLL8 part 5
Here is the progression-free survival curve for the CLL8 trial. 
The median PFS: for FCR: 51.8 months and for FC: 32.8 months (N=790 Hazard ratio 0.563, ranges 0.460-0.689, p<0.001) PFS rate 3 yrs post randomization: FCR: 64.9% FC: 44.7%. The risk of progression was reduced by 44% in the chemoimmunotherapy group compared with the chemotherapy group (HR 0·56 [95% CI 0·46–0·69]).
An improvement in PFS was noted in all stages. Again click to enlarge. I have reprinted the first image to remind you.
Patients with disease in Binet stages B and C showed similar median PFS of 32·5 months (28·4–36·6) and 33·0 months (25·0–41·2), respectively, when treated with chemotherapy. Treatment with chemoimmunotherapy improved the median PFS to 51·8 months (47·8–56·0) in 522 patients with Binet stage B disease (HR 0·50 [95% CI 0·39–0·65]; p<0·0001) and to 40·7 months (0·73 [0·51–1·04]; p=0·081) in 252 patients with Binet stage C disease. The small number of patients (n=40) in Binet stage A did not allow a meaningful analysis of this subgroup, but a non-significant improvement was noted in PFS with chemoimmunotherapy.
The median PFS: for FCR: 51.8 months and for FC: 32.8 months (N=790 Hazard ratio 0.563, ranges 0.460-0.689, p<0.001) PFS rate 3 yrs post randomization: FCR: 64.9% FC: 44.7%. The risk of progression was reduced by 44% in the chemoimmunotherapy group compared with the chemotherapy group (HR 0·56 [95% CI 0·46–0·69]).
An improvement in PFS was noted in all stages. Again click to enlarge. I have reprinted the first image to remind you.
Patients with disease in Binet stages B and C showed similar median PFS of 32·5 months (28·4–36·6) and 33·0 months (25·0–41·2), respectively, when treated with chemotherapy. Treatment with chemoimmunotherapy improved the median PFS to 51·8 months (47·8–56·0) in 522 patients with Binet stage B disease (HR 0·50 [95% CI 0·39–0·65]; p<0·0001) and to 40·7 months (0·73 [0·51–1·04]; p=0·081) in 252 patients with Binet stage C disease. The small number of patients (n=40) in Binet stage A did not allow a meaningful analysis of this subgroup, but a non-significant improvement was noted in PFS with chemoimmunotherapy.
German CLL8 part 4
This is how the trial worked out.
Click on the picture to enlarge.
There were 800 patients who received either chemotherapy or immunochemotherapy. This is therefore a very large trial and it was sufficiently powered to detect a difference in median progression-free survival of 14 months at between 3 and 5 years follow-up, that is when a total of 357 progressions had occurred. An interim analysis was planned for when two thirds this number of events had occurred (ie 238 events) against the possibility that FCR was even better than FC than expected. It would obviously be unethical to continue a trial if one arm was proving to be so much better than the other arm.
The primary end point was chosen to be progression-free survival (pfs) defined as the time between randomization and the date of first documented disease progression or death. The reason for this is that in hematological diseases generally, pfs has been shown to correlate with overall survival and for the benefit of patients we want trials to be as short as possible. I have tended to argue against this decision because in CLL this has not been the case. We have seen trials suggesting that F gives a longer pfs than chlorambucil and that FC gives a better pfs than both. However, patients who fail the lesser regimen can later switch to the better regimen and hitherto in every trial the overall survival has been the same. So the story has grown up that it doesn't matter which treatment you try first, your overall outcome will be the same. Indeed there is a certain logic in trying the milder treatment first, because you may never have to try the more severe one. The other reason for choosing pfs is that the FDA tends to approve a drug combination if they can demonstrate an improvement in pfs.
There were also some secondary endpoints. It is important to name these as part of your intention to examine them, otherwise you can be accused of post-trial data dredging. This is the equivalent of shooting an arrow at a barn door and then drawing a target around where you hit and proclaiming that you have hit the target. The secondary endpoints were: overall survival, event-free survival, disease-free survival, duration of remission, time to new treatment of CLL or death, rates of molecular, complete, and partial remission, response rates and survival times in biological subgroups, rates of treatment related adverse effects, pharmaco-economic effect, and quality of life. Not all these results are reported in this paper.
What today's picture shows is that this was a well conducted trial. There were small numbers of drop-outs and non-compliant patients, but that is usual for such a trial and they did not affect the outcome.
Click on the picture to enlarge.
There were 800 patients who received either chemotherapy or immunochemotherapy. This is therefore a very large trial and it was sufficiently powered to detect a difference in median progression-free survival of 14 months at between 3 and 5 years follow-up, that is when a total of 357 progressions had occurred. An interim analysis was planned for when two thirds this number of events had occurred (ie 238 events) against the possibility that FCR was even better than FC than expected. It would obviously be unethical to continue a trial if one arm was proving to be so much better than the other arm.
The primary end point was chosen to be progression-free survival (pfs) defined as the time between randomization and the date of first documented disease progression or death. The reason for this is that in hematological diseases generally, pfs has been shown to correlate with overall survival and for the benefit of patients we want trials to be as short as possible. I have tended to argue against this decision because in CLL this has not been the case. We have seen trials suggesting that F gives a longer pfs than chlorambucil and that FC gives a better pfs than both. However, patients who fail the lesser regimen can later switch to the better regimen and hitherto in every trial the overall survival has been the same. So the story has grown up that it doesn't matter which treatment you try first, your overall outcome will be the same. Indeed there is a certain logic in trying the milder treatment first, because you may never have to try the more severe one. The other reason for choosing pfs is that the FDA tends to approve a drug combination if they can demonstrate an improvement in pfs.
There were also some secondary endpoints. It is important to name these as part of your intention to examine them, otherwise you can be accused of post-trial data dredging. This is the equivalent of shooting an arrow at a barn door and then drawing a target around where you hit and proclaiming that you have hit the target. The secondary endpoints were: overall survival, event-free survival, disease-free survival, duration of remission, time to new treatment of CLL or death, rates of molecular, complete, and partial remission, response rates and survival times in biological subgroups, rates of treatment related adverse effects, pharmaco-economic effect, and quality of life. Not all these results are reported in this paper.
What today's picture shows is that this was a well conducted trial. There were small numbers of drop-outs and non-compliant patients, but that is usual for such a trial and they did not affect the outcome.
Two books to avoid.
There are so many books to read that I find it welcome when somebody says not to bother. So here are two not worth bothering with.
The first is Diary of a Nobody by George and Weedon Grossmith. This is a classic which introduced us to the Pooters, the clumsy, social climbing misfits. I suppose the adjective to describe it is 'whimsical'. It is the forerunner to the theater of embarrassment as exemptified by Ricky Gervais (whom I can't find funny). I get the joke, of course, but then it is repeated ad infinitum. I couldn't finish the book.
The second is also full of whimsy. It is The Golden Child by Penelope Fitzgerald, who was later to win the Booker Prize. This is a dreadful novel. It ends up as a sort of detective story, but a very poor one. The characters are unreal and uninteresting, and very poorly drawn. The plot is fantastic and unbelievable. The writing is second-rate. I'm sorry that I wasted my time reading it.
In PG Wodehouse I can take whimsy, but I ration my reading of him.
The first is Diary of a Nobody by George and Weedon Grossmith. This is a classic which introduced us to the Pooters, the clumsy, social climbing misfits. I suppose the adjective to describe it is 'whimsical'. It is the forerunner to the theater of embarrassment as exemptified by Ricky Gervais (whom I can't find funny). I get the joke, of course, but then it is repeated ad infinitum. I couldn't finish the book.
The second is also full of whimsy. It is The Golden Child by Penelope Fitzgerald, who was later to win the Booker Prize. This is a dreadful novel. It ends up as a sort of detective story, but a very poor one. The characters are unreal and uninteresting, and very poorly drawn. The plot is fantastic and unbelievable. The writing is second-rate. I'm sorry that I wasted my time reading it.
In PG Wodehouse I can take whimsy, but I ration my reading of him.
Monday, October 04, 2010
German CLL8 Part 3
This is a trial designed to see whether adding the anti-CD20 antibody, rituximab, to the previous gold-standard regimen of fludarabine and cyclophosphamide really makes a difference to patients. Previous phase II studies had shown impressive response rates of 95% with 72% achieving a CR (NB according to the 1996 Guidelines which only require normalization of the blood count, disappearance of palpable lymph nodes and spleen and less than 30% lymphocytes in the bone marrow). These response rates and the apparently longer remissions compared with historical controls had made FCR the treatment of choice in the USA (though it was not approved by the FDA). In Europe, regulatory authorities were not convinced because they could see so many potential biases in the phase II studies and in particular, where the taxpayer was picking up the tab (as in the UK) they were not prepared to pay for the expensive drug, rituximab, on such scanty evidence.
This is how the trial was designed. It was planned to treat patients who had never previously received treatment in whom treatment was indicated according to the 1996 NCI treatment guidelines. There was no age limit on the patients enrolled - in fact they were aged 31-81. There performance status should be ECOG 0 or 1. They should have a low co-morbidity score and have a creatinine clearance of at least 1.17 mL/s. Those with autoimmune disease or a clinically active second disease were excluded. It was necessary for the protocol to be approved by the Institutional Review Board and Ethics Committee of every center taking part in the trial.
The randomization was independent of the investigators. After informed consent was obtained from the patients, investigators faxed the required registration sheets to the central study office in Cologne. At first patients were randomly assigned in a one-to-one ratio in a block size of four, to receive fludarabine and cyclophosphamide (chemotherapy) or fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy). After the fist ammendment in July 27, 2004 they were stratified by centre, and then by country and Binet stage since the first amendment, using a randomisation list that was computer generated at the Institute for Medical Statistics and Epidemiology, Technical University of Munich, Germany. Confirmation of patient randomisation and allocation to treatment group was sent through the Central Study Office in Cologne, Germany, to the investigators. Patients were enrolled by the investigators, and assignment to treatment was done centrally at the Institute for Medical Statistics and Epidemiology, Technical University of Munich.
Treatment consisted of six 28-day courses of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each treatment course, with or without rituximab at a dose of 375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses. These are exactly the same regimens as were developed at MDACC. Prophylaxis with antiviral drugs or granulocyte-colony stimulating factor were not recommended in this study. Prophylaxis of pneumonia caused by Pneumocystis jirovecii was recommended for severe leucocytopenia that lasted for more than 7 days.
An interim response assessment was done after three courses of treatment. Patients who achieved at least a partial response or complete remission continued treatment as planned in the protocol. Patients with stable or progressive disease discontinued study treatment and received a different treatment at the discretion of their treating physician. Patients with stable disease or progressive disease after three cycles were assessed as non-responders and included in the analysis of progression-free survival and overall survival.
Did the randomization work in producing very similar patients in each arm?
Click on the picture to enlarge. As you can see the chemotherapy group and the immunochemotherapy groups were well matched in terms of age, sex, Binet stage, performance status, renal function, beta-2 microglobulin, serum thymidine kinase, IGHV mutations, chromosomal abnormalities, ZAP-70 and CD38 expression. There were slightly more patients with B symptoms in the chemotherapy group. Overall, these were two very well matched groups.
Finally, I should say something on the funding of this trial. This trial was planned and initiated in 2003 as an investigator-initiated trial by the German Chronic Lymphocytic Leukaemia Study Group. Since 2004, F Hoffmann-La Roche assumed the sponsorship for this trial, because it intended to use the trial for the approval of rituximab at regulatory agencies. The sponsor was subsequently involved in the first and second amendments of the study protocol. The sponsor of the study was responsible for data gathering, and shared responsibility for medical review of the data with Michael Hallek. Hallek was responsible for data analysis, data interpretation, writing of the report, had full access to all the data in the study, and had the final responsibility for the decision to submit for publication.
It is important to recognize that although Roche paid for this trial, the design was that of Michael Hallek's group. The subsequent ammendments extended the trial to countries outside Germany and guaranteed independent assesment of the results. Roche also paid for an indpendent data monitoring committee which comprised Peter Hillmen (chairman, Leeds Teaching Hospital NHS Trust, Leeds), Guillaume Dighiero (Institut Pasteur, Paris), Francesc Bosch (Hospital Clínic, Barcelona), Maura Brugiatelli (Azienda Ospedaliera Papardo, Messina, Italy) and Iris Pigeot (Bremen Institute for Prevention Research and Social Medicine Bremen). I can tell you something about what they did because I was the chairman of the data monitoring committee (mainly the same personell except me for Peter Hillmen) for the REACH trial (for second line treatment comparing FC v FCR) that was carried on in parallel to CLL8. The sort of things that we monitored were compliance with the trial, assessment of serious adverse events, and whether any unsuspected side effects were apparent. For example we noted that prolonged neutropenia and late neutropenia were a problem in some patients, and we investigated whether this might be due to a latent MDS caused by the regimen (it wasn't).
This is how the trial was designed. It was planned to treat patients who had never previously received treatment in whom treatment was indicated according to the 1996 NCI treatment guidelines. There was no age limit on the patients enrolled - in fact they were aged 31-81. There performance status should be ECOG 0 or 1. They should have a low co-morbidity score and have a creatinine clearance of at least 1.17 mL/s. Those with autoimmune disease or a clinically active second disease were excluded. It was necessary for the protocol to be approved by the Institutional Review Board and Ethics Committee of every center taking part in the trial.
The randomization was independent of the investigators. After informed consent was obtained from the patients, investigators faxed the required registration sheets to the central study office in Cologne. At first patients were randomly assigned in a one-to-one ratio in a block size of four, to receive fludarabine and cyclophosphamide (chemotherapy) or fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy). After the fist ammendment in July 27, 2004 they were stratified by centre, and then by country and Binet stage since the first amendment, using a randomisation list that was computer generated at the Institute for Medical Statistics and Epidemiology, Technical University of Munich, Germany. Confirmation of patient randomisation and allocation to treatment group was sent through the Central Study Office in Cologne, Germany, to the investigators. Patients were enrolled by the investigators, and assignment to treatment was done centrally at the Institute for Medical Statistics and Epidemiology, Technical University of Munich.
Treatment consisted of six 28-day courses of intravenous fludarabine (25 mg/m2 per day) and cyclophosphamide (250 mg/m2 per day) for the first 3 days of each treatment course, with or without rituximab at a dose of 375 mg/m2 on day 0 of the first course, and 500 mg/m2 on day 1 of the second to sixth courses. These are exactly the same regimens as were developed at MDACC. Prophylaxis with antiviral drugs or granulocyte-colony stimulating factor were not recommended in this study. Prophylaxis of pneumonia caused by Pneumocystis jirovecii was recommended for severe leucocytopenia that lasted for more than 7 days.
An interim response assessment was done after three courses of treatment. Patients who achieved at least a partial response or complete remission continued treatment as planned in the protocol. Patients with stable or progressive disease discontinued study treatment and received a different treatment at the discretion of their treating physician. Patients with stable disease or progressive disease after three cycles were assessed as non-responders and included in the analysis of progression-free survival and overall survival.
Did the randomization work in producing very similar patients in each arm?
Click on the picture to enlarge. As you can see the chemotherapy group and the immunochemotherapy groups were well matched in terms of age, sex, Binet stage, performance status, renal function, beta-2 microglobulin, serum thymidine kinase, IGHV mutations, chromosomal abnormalities, ZAP-70 and CD38 expression. There were slightly more patients with B symptoms in the chemotherapy group. Overall, these were two very well matched groups.
Finally, I should say something on the funding of this trial. This trial was planned and initiated in 2003 as an investigator-initiated trial by the German Chronic Lymphocytic Leukaemia Study Group. Since 2004, F Hoffmann-La Roche assumed the sponsorship for this trial, because it intended to use the trial for the approval of rituximab at regulatory agencies. The sponsor was subsequently involved in the first and second amendments of the study protocol. The sponsor of the study was responsible for data gathering, and shared responsibility for medical review of the data with Michael Hallek. Hallek was responsible for data analysis, data interpretation, writing of the report, had full access to all the data in the study, and had the final responsibility for the decision to submit for publication.
It is important to recognize that although Roche paid for this trial, the design was that of Michael Hallek's group. The subsequent ammendments extended the trial to countries outside Germany and guaranteed independent assesment of the results. Roche also paid for an indpendent data monitoring committee which comprised Peter Hillmen (chairman, Leeds Teaching Hospital NHS Trust, Leeds), Guillaume Dighiero (Institut Pasteur, Paris), Francesc Bosch (Hospital Clínic, Barcelona), Maura Brugiatelli (Azienda Ospedaliera Papardo, Messina, Italy) and Iris Pigeot (Bremen Institute for Prevention Research and Social Medicine Bremen). I can tell you something about what they did because I was the chairman of the data monitoring committee (mainly the same personell except me for Peter Hillmen) for the REACH trial (for second line treatment comparing FC v FCR) that was carried on in parallel to CLL8. The sort of things that we monitored were compliance with the trial, assessment of serious adverse events, and whether any unsuspected side effects were apparent. For example we noted that prolonged neutropenia and late neutropenia were a problem in some patients, and we investigated whether this might be due to a latent MDS caused by the regimen (it wasn't).
Sunday, October 03, 2010
German CLL8 trial 2
What sort of trial is the German CLL8 trial?
It is an open label, randomized phase III trial. First it is 'open label'. This means that both the patients and the doctors knew who was getting which regimen. The alternative would have been to control for this with placebo. Since one arm of the trial was getting rituximab and the other wasn't, it would be pretty hard to disguise this. They could have made up a dummy fluid that looked like rituximab and infused that, but rituximab tends to have side effects and the patients would soon have tumbled to which one they were having, and in any case the doctors would need to know who was having rituximab so that they could apply specific remedies for the side effects.
Second, it was randomized. Randomization is teh great discovery of clinical trials. Ideally patients in either arm of a trial should be very well matched. You can try and select patients that are well-matched, but unfortunately, you don't know in advance all the criteria that they should be matched under. For example, until 10 years ago you would never have known that each arm should have roughly equal numbers of cases with mutated and unmutated IGHV genes. However, if you have large enough numbers, and you allocate patients randomly to either arm, you usually end up with well-matched groups. You should check afterwards to see that this is so.
Third it was a phase III trial. This means that you aren't just looking for whether the disease responds to the particular drug combination, but for whether there is a difference in outcome for the patient. There have been previous phase II trials of FCR, as we know and we also knew that there have been pretty impressive responses, but the only way that we could look at outcome for those patients was to see what had happened in phase II trials of other combinations. Sure enough at MDACC, FCR seemed to out-perform FC or F alone, but over the years other things might have changed. The doctors may have got better, the supportive care might have got better and the type of patient might have changed, with richer, fitter patients following the reputation of the Institute. Randomization sorts out these sorts of biases.
Fourth, it was a multi-center study. Many hospitals in Germany were involved, but also centers in Austria, Belgium, Israel, France, Italy, the Czech Republic, New Zealand and Australia. This means that it covered the generality of cases across a wide area.
It is an open label, randomized phase III trial. First it is 'open label'. This means that both the patients and the doctors knew who was getting which regimen. The alternative would have been to control for this with placebo. Since one arm of the trial was getting rituximab and the other wasn't, it would be pretty hard to disguise this. They could have made up a dummy fluid that looked like rituximab and infused that, but rituximab tends to have side effects and the patients would soon have tumbled to which one they were having, and in any case the doctors would need to know who was having rituximab so that they could apply specific remedies for the side effects.
Second, it was randomized. Randomization is teh great discovery of clinical trials. Ideally patients in either arm of a trial should be very well matched. You can try and select patients that are well-matched, but unfortunately, you don't know in advance all the criteria that they should be matched under. For example, until 10 years ago you would never have known that each arm should have roughly equal numbers of cases with mutated and unmutated IGHV genes. However, if you have large enough numbers, and you allocate patients randomly to either arm, you usually end up with well-matched groups. You should check afterwards to see that this is so.
Third it was a phase III trial. This means that you aren't just looking for whether the disease responds to the particular drug combination, but for whether there is a difference in outcome for the patient. There have been previous phase II trials of FCR, as we know and we also knew that there have been pretty impressive responses, but the only way that we could look at outcome for those patients was to see what had happened in phase II trials of other combinations. Sure enough at MDACC, FCR seemed to out-perform FC or F alone, but over the years other things might have changed. The doctors may have got better, the supportive care might have got better and the type of patient might have changed, with richer, fitter patients following the reputation of the Institute. Randomization sorts out these sorts of biases.
Fourth, it was a multi-center study. Many hospitals in Germany were involved, but also centers in Austria, Belgium, Israel, France, Italy, the Czech Republic, New Zealand and Australia. This means that it covered the generality of cases across a wide area.
Saturday, October 02, 2010
German CLL8 Part 1
The German CLL8 trial by Hallek et al in today's Lancet is the most important CLL paper published for a decade. Why?
Like most chronic lymphoproliferative disorders, CLL will be treated with many, perhaps all, alternative therapies during the course of the disease. There have been many trials of therapy in CLL and many have shown that a new combination of agents produces higher response rates than its comparator. Indeed many have shown that the new combination produces longer remissions than what has gone before, but hitherto there has never been a trial that showed that the new combination made a patient live longer than if he had been treated with the comparator regimen - for the very reason that those relapsing after the lesser regimen could be switched to the greater and not suffer a poorer overall outcome.
Thus until now it has not really mattered which regimen you started with, and there was some merit to selecting one with fewer side effects in the hope that you might never have to proceed to a treatment with greater side effects.
This trial which looks at what happens when you add rituximab to FC clearly demonstrates that you live longer than if you don't. The extra life is both statistically and clinically significant, it is bought without serious side effects and although it is quite expensive, I fully expect that NICE with recommend it for all UK patients who fit into the right category.
This result was unexpected; so much so that overall survival was not the primary endpoint of the trial - progression-free survival was - but overall survival was a secondary endpoint. Rituximab as a single agent has a poor reputation in CLL and even the manufacturers were not that optimistic about the drug.
This is a very large trial with over 400 patients in each arm and it is so important that I am going to go through it slowly on this blog. I will deal with it in bite size chunks so that no-one will feel that it is too complicated to understand.
The Good German
I guess I was almost the last of the generation that was bombed by the Germans. I was two when the war ended and although I lived in Aldershot, the home of the British Army, the nearest bomb fell about 10 miles away. Not so my wife's family who lived in east London. They had their doors and windows blown out by a doodlebug that landed in their street and my wife's mother found an unexploded incendiary in their back garden.
One of the songs of my youth was Bob Dylan's "Masters of War" which contains the lines, "Though they murdered 6 million, in the ovens they fried
The Germans now, too, have God on their side."
Although I look very Aryan, I am one sixteenth Jewish and my wife is three sixteenth Jewish. Had the Nazis invaded we might have been very vulnerable. Our parents were very anti-German and being brought up on British, black and white war films I was subjected to a lot of anti-German propaganda. Actors like Jack Hawkins, Dickie Attenborough, Kenneth More and Michael Caine were regularly defeating square-jawed Nazis with coal-scuttle helmets on our screens.
It is strange that we now complain that the German army is a afraid to get its hands dirty in places like Afghanistan.
I think it is important to remember that the Germans alive today had nothing to do with the war and my experience of them is that they are all very nice chaps. It is time to put to bed wartime propaganda. I learned recently, for example, that the RAF had no air-sea rescue capacity during the Battle of Britain. We lost a lot of pilots who were downed in the channel, but their lives were saved by German air-sea rescue craft. Not something those wartime films told us about.
Today, I want to commend one post-war German who has become a friend. His name is Michael Hallek and he is the lead author of the most important paper to be published on CLL in the last decade. This is the FC v FCR randomized controlled trial CLL8, which I shall be blogging about later. Michael is a fine Christian gentleman, who is very bright, very well organized and I am proud to know him.
One of the songs of my youth was Bob Dylan's "Masters of War" which contains the lines, "Though they murdered 6 million, in the ovens they fried
The Germans now, too, have God on their side."
Although I look very Aryan, I am one sixteenth Jewish and my wife is three sixteenth Jewish. Had the Nazis invaded we might have been very vulnerable. Our parents were very anti-German and being brought up on British, black and white war films I was subjected to a lot of anti-German propaganda. Actors like Jack Hawkins, Dickie Attenborough, Kenneth More and Michael Caine were regularly defeating square-jawed Nazis with coal-scuttle helmets on our screens.
It is strange that we now complain that the German army is a afraid to get its hands dirty in places like Afghanistan.
I think it is important to remember that the Germans alive today had nothing to do with the war and my experience of them is that they are all very nice chaps. It is time to put to bed wartime propaganda. I learned recently, for example, that the RAF had no air-sea rescue capacity during the Battle of Britain. We lost a lot of pilots who were downed in the channel, but their lives were saved by German air-sea rescue craft. Not something those wartime films told us about.
Today, I want to commend one post-war German who has become a friend. His name is Michael Hallek and he is the lead author of the most important paper to be published on CLL in the last decade. This is the FC v FCR randomized controlled trial CLL8, which I shall be blogging about later. Michael is a fine Christian gentleman, who is very bright, very well organized and I am proud to know him.
Update
It is now a week since my last chemo. Days 1 & 2 were spent receiving the stuff. It was less onerous than last time. I felt a little oppressed while it was running in over 48 hours but minus the peripheral neuropathy of the platinum, it was certainly bearable, and when the pump was disconnected on day 3, I felt quite well. Day 4 was OK and I was so well on day 5 that I was able to sand down a door that was sticking after our recent redecoration.
Then at 5-30 pm on day 5 it it me. Severe colicky pain and diarrhea - undoubtedly the effect of the irenotecan. I used hyoscine 10mg and loperamide with some relief, but there were several more attacks during the night. Day 6 was difficult and I began to despair for the schedule I had laid out for myself on day 7 which included 2 visits from church members and a conference call, plus visits from family members on day 8.
So day 6 night I dosed myself with codeine phosphate 30mg and hyoscine 20mg and had a good night's undisturbed sleep. I was able to have my visits and a conference call to America about a Campath clinical trial and then took the same prophylaxis for day 7 night with equally good results.
Today, day 8 morning, my family have all cancelled because they have colds or gastric flu and don't want to infect me, so I have a quiet weekend ahead. We may even be able to get to church tomorrow. The only symptoms I have are mouth ulcers and angular stomatitis - likely to be the 5-FU and some rather mild colic, which I am dealing with.
Then at 5-30 pm on day 5 it it me. Severe colicky pain and diarrhea - undoubtedly the effect of the irenotecan. I used hyoscine 10mg and loperamide with some relief, but there were several more attacks during the night. Day 6 was difficult and I began to despair for the schedule I had laid out for myself on day 7 which included 2 visits from church members and a conference call, plus visits from family members on day 8.
So day 6 night I dosed myself with codeine phosphate 30mg and hyoscine 20mg and had a good night's undisturbed sleep. I was able to have my visits and a conference call to America about a Campath clinical trial and then took the same prophylaxis for day 7 night with equally good results.
Today, day 8 morning, my family have all cancelled because they have colds or gastric flu and don't want to infect me, so I have a quiet weekend ahead. We may even be able to get to church tomorrow. The only symptoms I have are mouth ulcers and angular stomatitis - likely to be the 5-FU and some rather mild colic, which I am dealing with.
Thursday, September 30, 2010
SLVL = SMZL
A major new paper has appeared in Blood about splenic marginal zone lymphoma (aka SLVL). A pan-European group which includes my old unit in Bournemouth have studied chromosomal abnormalities in 330 cases. As we had found before, in our own series, there is a very high incidence of abnormalities (72%) and more than half of which had complex karyotypes. The most common abnormalities were gains of #3 or 3q and 12q, deletions of 7q and 6q, and translocations involving 8q/1q/14q.
SLVL is one of the differential diagnoses for CLL, but it is usually CD5 negative. In this study, however, a quarter of cases were CD5+. Those who were CD5+ were significantly more likely to have trisomy 3/3q, del 6q and trisomy 18 than the CD5-ve cases. However, there was no suggestion that the CD5+ cases were more clinically aggressive. In particular TP53 deletion was not associated with CD5 positivity.
AS has been reported previously some cases of SLVL are mutated and some unmutated. In this series 41% were unmutated and there was an association of these cases with del 7q, but this did not have any impact on overall survival. There was a biased use of IGHV genes. In particular, IGHV1-2 was associated with del7q.
On multivariate analysis the only factors associated with poorer prognosis were age over 65 and hemoglobin less than 12 g/dl - non disease-related factors consistent with the fact that most people die with SLVL, not because of it.
SLVL is one of the differential diagnoses for CLL, but it is usually CD5 negative. In this study, however, a quarter of cases were CD5+. Those who were CD5+ were significantly more likely to have trisomy 3/3q, del 6q and trisomy 18 than the CD5-ve cases. However, there was no suggestion that the CD5+ cases were more clinically aggressive. In particular TP53 deletion was not associated with CD5 positivity.
AS has been reported previously some cases of SLVL are mutated and some unmutated. In this series 41% were unmutated and there was an association of these cases with del 7q, but this did not have any impact on overall survival. There was a biased use of IGHV genes. In particular, IGHV1-2 was associated with del7q.
On multivariate analysis the only factors associated with poorer prognosis were age over 65 and hemoglobin less than 12 g/dl - non disease-related factors consistent with the fact that most people die with SLVL, not because of it.
Wednesday, September 29, 2010
The York Minster Fire
Early in the morning of 9th July 1984 it was discovered that York Minster was on fire. 150 fire fighters from across North Yorkshire took two hours to bring the blaze under control. Apparently, the cathedral was struck by lightning shortly after midnight. Bob Littlewood, Superintendent of works at the time, believes the fire was started when lightning earthed through an electrical panel in the roof void.
Because the exterior of the roof was effectively sealed with lead and the fire was well established at the only entrance to the roof void, it was impossible to tackle the fire effectively. The large quantities of tinder-dry oak in the roof burned hot. A great deal of stonework was seriously damaged, as was the famous Rose Window. It is known the Rose Window itself reached temperatures of around 450 degrees centigrade. The Rose Window, a stained glass masterpiece high in the South Transept of the Minster (though not the best example of such in the UK), was nearly lost after the lightning struck. IT was a very old window. The stonework was completed in the mid 13th century but the stained glass was not added until near the end of the 15th century to commemorate the end of the War of the Roses (1486) and honor the Tudor dynasty.
After fire destroyed the South Transept roof, inspection revealed that the stained glass in the Rose Window was severely cracked. The 73 panels, containing 7,000 pieces of stained glass had crazed into about 40,000 pieces. Miraculously, it was all still in place.
Craftsmen secured the stained glass with adhesive film before removing it, one section at a time. Special adhesives - which would mimic the refractive properties of the glass - had to be researched and were specially developed by the 3M corporation before the window could be restored. Each restored section is sandwiched between layers of clear glass and the whole is further protected by more sheets of glass. The stained glass restoration process, along with the restoration of the roof, took about four years and cost $4 million.
At the time there were speculations on how the disaster might have happened out of a clear sky. It was remembered that York Minster had just been used for the inauguration of David Jenkins as Bishop of Durham. Jenkins was a controversial figure who apparently did not believe in an actual resurrection. He called it "a conjuring trick with bones." Some Christians thought that the lightening bolt was an act of Divine retribution.
My knowledge of the Church of England is sketchy. Although baptised into it as a baby, I never attended C of E services, though I was once on an appointments committee for a C of E Chaplain at my hospital. I worried everybody by asking each candidate whether he believed in Hell. The other members of the interview panel were the hospital chief executive and a Rural Dean and an Archdeacon. They did something that I have only seen women do before. They got up and went to the 'bathroom' together. I followed them out and found that they were having a private meeting about whom they should appoint.
It was this encounter that gave me the character of the Dean in whose voice I have written this poem.
The Dean’s lament after the York Minster fire.
Did you really rain fire down merely for a doubt?
Really flame that antique, Gothic window out?
That is some pique! Because a bishop spoke
out of turn? It was a sort of joke
that ‘conjuring trick with bones’, a bit of wit,
only designed to get a headline hit.
Did you even think about the cost?
All those visitor takings that we lost.
Four mill for the repair and at 3Ms
research on plastics, the price condemns
poor curates to more penury, I fear;
no pay rise now for many another year.
What sort of God do you suppose we want?
An old-style, concentration camp commandant
deriving pleasure from unmaking art,
with us quaking, knees shaking, falling apart?
Some sort of vandal, mannerless and rough,
who then responds to scandal by talking tough?
No, God is love and meekness, kindness: who
shows complete, benevolent blindness to
our foibles. He forgives, forebears; does not
take notice when we sin. A big blind spot
to forty-wink at deviation, short-
falling, or reprobation. That’s the sort
of God. The kind who’d never make a fuss.
Now, more important matters to discuss:
the type of God we’d really like to see
would be more like the archdeacon or me;
I hope, sir, that my pleading words won’t chafe,
we must ensure that Sodom would be safe.
Because the exterior of the roof was effectively sealed with lead and the fire was well established at the only entrance to the roof void, it was impossible to tackle the fire effectively. The large quantities of tinder-dry oak in the roof burned hot. A great deal of stonework was seriously damaged, as was the famous Rose Window. It is known the Rose Window itself reached temperatures of around 450 degrees centigrade. The Rose Window, a stained glass masterpiece high in the South Transept of the Minster (though not the best example of such in the UK), was nearly lost after the lightning struck. IT was a very old window. The stonework was completed in the mid 13th century but the stained glass was not added until near the end of the 15th century to commemorate the end of the War of the Roses (1486) and honor the Tudor dynasty.
After fire destroyed the South Transept roof, inspection revealed that the stained glass in the Rose Window was severely cracked. The 73 panels, containing 7,000 pieces of stained glass had crazed into about 40,000 pieces. Miraculously, it was all still in place.
Craftsmen secured the stained glass with adhesive film before removing it, one section at a time. Special adhesives - which would mimic the refractive properties of the glass - had to be researched and were specially developed by the 3M corporation before the window could be restored. Each restored section is sandwiched between layers of clear glass and the whole is further protected by more sheets of glass. The stained glass restoration process, along with the restoration of the roof, took about four years and cost $4 million.
At the time there were speculations on how the disaster might have happened out of a clear sky. It was remembered that York Minster had just been used for the inauguration of David Jenkins as Bishop of Durham. Jenkins was a controversial figure who apparently did not believe in an actual resurrection. He called it "a conjuring trick with bones." Some Christians thought that the lightening bolt was an act of Divine retribution.
My knowledge of the Church of England is sketchy. Although baptised into it as a baby, I never attended C of E services, though I was once on an appointments committee for a C of E Chaplain at my hospital. I worried everybody by asking each candidate whether he believed in Hell. The other members of the interview panel were the hospital chief executive and a Rural Dean and an Archdeacon. They did something that I have only seen women do before. They got up and went to the 'bathroom' together. I followed them out and found that they were having a private meeting about whom they should appoint.
It was this encounter that gave me the character of the Dean in whose voice I have written this poem.
The Dean’s lament after the York Minster fire.
Did you really rain fire down merely for a doubt?
Really flame that antique, Gothic window out?
That is some pique! Because a bishop spoke
out of turn? It was a sort of joke
that ‘conjuring trick with bones’, a bit of wit,
only designed to get a headline hit.
Did you even think about the cost?
All those visitor takings that we lost.
Four mill for the repair and at 3Ms
research on plastics, the price condemns
poor curates to more penury, I fear;
no pay rise now for many another year.
What sort of God do you suppose we want?
An old-style, concentration camp commandant
deriving pleasure from unmaking art,
with us quaking, knees shaking, falling apart?
Some sort of vandal, mannerless and rough,
who then responds to scandal by talking tough?
No, God is love and meekness, kindness: who
shows complete, benevolent blindness to
our foibles. He forgives, forebears; does not
take notice when we sin. A big blind spot
to forty-wink at deviation, short-
falling, or reprobation. That’s the sort
of God. The kind who’d never make a fuss.
Now, more important matters to discuss:
the type of God we’d really like to see
would be more like the archdeacon or me;
I hope, sir, that my pleading words won’t chafe,
we must ensure that Sodom would be safe.
The end point of treatment in CLL
There has been an interesting exchange of letters in the correspondence columns of Blood (Blood 2010; 116:1187-8) between Ken Foon and Michael Hallek concerning the end-point of treatment. Confusion arises because what was published in the Guidelines in Blood in June 2008 was not agreed by all the authors and it had to be revised in the electronic records in December 2008.
The problem arose because the 1996 Guidelines were widely used for both clinical practice and for clinical trials, and these suggested that a complete response should mean that there were fewer than 30% lymphocytes in a bone marrow trephine following treatment. If the trephine showed lymphoid nodules then the type of remission should be categorized nodular PR. Since 1996 there has been evidence that a deeper remission than just <30% lymphoid cells in the bone marrow, might be more advantageous to the patient, and also that it is possible to distinguish whether a nodular PR comprises tumor tissue of just reactive lymphocytes.
In order to retain a comparison with older trials, the new Guidelines now suggest that the old (1996) criteria are retained, but that in trials aimed at maximizing CR rate, assessment should be made of minimal residual disease by 4-color flow and that lymphoid nodules should be assessed by immmunohistochemistry. Why should this not be done for all patients? I guess it is because the experts are not sufficiently convinced that attempts to wipe out all trace of discernible CLL is beneficial to the patient - witness the recent CALGB trial of post-treatment Campath.
The second point concerns the use of CT scans. The Guidelines suggest that CT scans are not required for either the initial valuation of follow-up in clinical practice. However, they recommended that they be used in clinical trials - one at the start of therapy and the other at first restaging after therapy if it had been previously abnormal. A second CT is not necessary if residual disease can be detected some other way - such as blood tests or clinical examination.
I think this is now clear.
The problem arose because the 1996 Guidelines were widely used for both clinical practice and for clinical trials, and these suggested that a complete response should mean that there were fewer than 30% lymphocytes in a bone marrow trephine following treatment. If the trephine showed lymphoid nodules then the type of remission should be categorized nodular PR. Since 1996 there has been evidence that a deeper remission than just <30% lymphoid cells in the bone marrow, might be more advantageous to the patient, and also that it is possible to distinguish whether a nodular PR comprises tumor tissue of just reactive lymphocytes.
In order to retain a comparison with older trials, the new Guidelines now suggest that the old (1996) criteria are retained, but that in trials aimed at maximizing CR rate, assessment should be made of minimal residual disease by 4-color flow and that lymphoid nodules should be assessed by immmunohistochemistry. Why should this not be done for all patients? I guess it is because the experts are not sufficiently convinced that attempts to wipe out all trace of discernible CLL is beneficial to the patient - witness the recent CALGB trial of post-treatment Campath.
The second point concerns the use of CT scans. The Guidelines suggest that CT scans are not required for either the initial valuation of follow-up in clinical practice. However, they recommended that they be used in clinical trials - one at the start of therapy and the other at first restaging after therapy if it had been previously abnormal. A second CT is not necessary if residual disease can be detected some other way - such as blood tests or clinical examination.
I think this is now clear.
Subscribe to:
Posts (Atom)