Monday, October 29, 2007

Late treatment in CLL

I have been looking at a group of patients with who manage to go a long time before requiring treatment, and comparing them with patients who go a long time and never require treatment. These are preliminary findings.

The database contains 424 patients in whom we have done the prognostic markers. Of these 168 have required treatment (some of them have not yet been followed for long and may yet need treatment). 19/168 survived for longer than 8 years before treatment was necessary.

The first thing to notice is that their average age at diagnosis was very low at 47 (range 36-73). There were 15 men and only 4 women. 7/19 had unmutated IgVH genes and 6 out of these 7 were also ZAP-70 positive, and 6/7 were also CD38 positive.

None of the patients had del 17p, but two had del 11q and of these one was unmutated (ZAP-70+, CD38 negative) and the other was mutated (ZAP-70 negative, CD38+).

Of the 12 with mutated IgVH genes, none were ZAP-70+ and 3 were CD38+.

Two of the mutated group were first treated because they developed autoimmune hemolytic anemia and one because he developed CLL-related nephrotic syndrome. Another patient was not treated until she developed an unrelated acute myeloblastic leukemia.

Six of the patients are still alive with post treatment survivals of 11, 20, 32, 37. 41 and 70 months. Only one patient has survived longer than 10 years post first treatment, and she was the one who was youngest when diagnosed.

There were 99 patients who remained untreated at 8 years or longer after diagnosis. This group was older with a mean age at presentation of 67 (range 38-91). There were 55 women and 44 men. 92 had mutated IgVH genes and 7 unmutated IgVH genes. Of those who were unmutated, 3 were also ZAP-70+ and 2 CD38+. Of those with mutated IgVH genes 2 were ZAP-70 positive and 12 CD38+. There were 5 cases of autoimmune hemolytic anemia that had resolved with steroids and not required any treatment of the CLL.

For completeness there are another 101 patients diagnosed long enough ago to have potentially survived more than 8 years. Their average age at presentation was 64 (24-93). There were 66 men and 35 women. 68 had unmutated IgVH genes and 33 mutated. 26/101 are still alive, 11 with mutated IgVH genes, 9 female, 9 CD38 negative and 18 ZAP-70 negative. Only one had del 17p and one del 11q. 26 (not the same 26) survived for more than 8 years after their first treatment, and 5 of these had had a transplant, and 7 had had CHOP.

Is it possible to draw any conclusions from these data? They confirm that it is better to have good prognostic markers even if you do require treatment, and it is better to be female. It seems to me that those with poor prognostic markers who live a long time without treatment are simply diagnosed earlier than those who seem to live shorter periods. It also seems that those who have the longest survival post treatment have either received a transplant or an anthracycline.

In the meantime this should be regarded as a work in progress as I think there are some missing data that I should be able to obtain.

Sunday, October 28, 2007

The anointing of Jesus

Just who is the woman who anoints Jesus with perfume in Mark Chapter 14? In John Ch 12 she is identified as Mary, the sister of Lazarus and Martha. Who was Simon the Leper of Bethany, in whose house the anointing took place? Google Simon of Bethany and you find the interesting suggestion that Simon the Leper and Lazarus are one and the same. We have the English meaning of Lasar house - a hospital for lepers - taken form the story of Lazarus and Dives. We then have the interesting possibility that the Lazarus of that parable really did refer to Simon Lazarus of Bethany. Perhaps that parable rather than being just a made up story, was pointedly referring to certain well known characters. Dives just means a rich man so it could have referred to any rich man in Jerusalem. But there was one rich man at whom it might be pointed - Caiaphas. Like Dives, Caiaphas had five brothers.

I found these ideas on a Christadelphian website and I certainly don't endorse them. It is just this speculation about genealogies that detracts us from the message of the passage by arguing about its provenance.

This is well known story, which Jesus prophesied would be told whenever the Gospel is preached.

The message is first that we should do what we can.

Mary couldn't preach like Peter or write like Paul. She didn't even have the domestic skills of her sister Martha. What she had was a pint of pure nard. This exotic perfume was expensive and was also used for anointing dead bodies. At the feast in Bethany she gave it to Jesus.

Jesus doesn't expect us to be what we are not. Gladys Aylward was very short, unprepossessing, and had short, straight black hair. (Not at all like Ingrid Bergman in Inn of the Sixth Happiness). God had called her to China. No Missionary Society endorsed he call, so she saved her wages as a servant and found the cheapest way to get there - third class on the Trans Siberian Express. When she arrived she found that the women of China were just like her; short, unprepossessing, and with short, straight black hair. She gave what she had to Jesus and made a difference.

We don't need to envy the skills of others; God has given us certain gifts and it is these that we bring to Him.

If we do that He will regard it as a beautiful thing.

Saturday, October 27, 2007

Global warming

Despite the Nobel Prize, the global warming debate continues. David Bellamy, who was always on TV until he was outed as a global warming heretic had an impassioned piece in the Times last week.

Scientists are supposed to understand these things, but the truth is that unless you actually work in the field you are no better than an enthusiastic amateur. However, meteorologists do get somethings right. On Thursday night the weather forecasters produced a map for Friday which showed rain spreading in from North-West Scotland and the rest of Britain covered in cloud. Then about 12 o'clock a small triangle of sunshine breaking out over the area between the Purbeck hills and the Solent. Taking them at their word, Diane and I transported ourselves to Bournemouth beach where at ten-past twelve the sun came out and we spent a happy hour strolling in the sunshine on a deserted beach.

Wednesday, October 24, 2007


I have been meaning to say something about James Watson's comments about black people and his subsequent banishment by both the London Science Museum and the Cold Spring Harbor Laboratory.

In a Sunday Times interview, Dr Watson was quoted as saying he was "inherently gloomy about the prospect of Africa" because "all our social policies are based on the fact that their intelligence is the same as ours - whereas all the testing says not really". He was further quoted as saying that his hope was that everyone was equal but that "people who have to deal with black employees find this is not true".

In comments published in The Independent newspaper Dr Watson tried to clarify his position. "We do not yet adequately understand the way in which the different environments in the world have selected over time the genes which determine our capacity to do different things," he is quoted as saying. "The overwhelming desire of society today is to assume that equal powers of reason are a universal heritage of humanity. It may well be. But simply wanting this to be the case is not enough. This is not science. To question this is not to give in to racism. This is not a discussion about superiority or inferiority, it is about seeking to understand differences, about why some of us are great musicians and others."

As a general point, I am against restrictions on free speech. It is far better that all views should be open to debate and contradiction, rather than that they develop covertly and secretly among small cohorts who may then react violently and unacceptably. For example extreme Islamist views are being secretly preached in British prisons in a language that few English speakers understand. Again there has to be some restriction on how these views are expressed. Incitement to violence cannot be admitted. However, even though Dr Watson won't be heard in London, the hare has been raised and needs chasing.

There are several things that need saying. One was neatly articulated by Craig Venter, "Skin colour as a surrogate for race is a social concept not a scientific one. There is no basis in scientific fact or in the human genetic code for the notion that skin colour will be predictive of intelligence."

Nevertheless, putting aside stereotyping the question of the relative intelligence of different racial groups remains a question to be debated. The problem with the answers provided by IQ tests is that the tests themselves may be culturally biased. Attempts have been made to make them less so, but I am insufficiently expert to know how successful these have been.

For readers who want to explore this topic further I suggest reading these two reviews of Richard J. Herrnstein and Charles Murray's The Bell Curve: Intelligence and Class Structure in American Life. Readers will find that people have very polarized views on the subject which tend to correlate with whether they are on the left or right of the political spectrum. I am almost certain that both are wrong (and right).

There is some good evidence that intelligence (as measured by IQ tests) contains a large inherited component, though attempts to prove it so by separated twin studies by British psychologist Cyril Burt were later generally thought to have been fraudulent. There is also good evidence that intelligence (as measured by IQ tests) correlates well with 'success' in Western society (larger salaries, greater longevity, nicer places to live, better schools for their children). However, this is not always the case.

I went to a very academic school. I was close to the top of the class, but never top. There were two boys who always surpassed me and I was interested to discover what became of them. One of them turned out to be the inventor of an important anti-cancer drug and has pursued a stellar career in academia. He currently holds an important Chair at an Ivy League University. But he usually came second; the guy who came first every term bar one is working as the editor of an obscure magazine for wireless anoraks. He lives alone on $30K a year. He is probably happy, but not what the world would call a success.

On the other hand there are many actors, sports stars, TV celebrities, dancers and rock stars who are about as bright as a forty-watt light bulb and many successful entrepreneurs couldn't hack it academically.

Another characteristic of very clever people is that they are often supremely silly.

One example of extreme silliness was the attempt by Robert Klark Graham to set up a "genius sperm bank", from which nearly 230 children were conceived. he tried to recruit Nobel Prize winners as donors. William Shockley and James Watson were believed to be donors and Watson's DNA colleague Francis Crick is also believed to have contributed. Other Laureates including Crick and Watson's co-winner for the structure of DNA, Maurice Wilkins tore up their invitation letters in disgust.

The 'science' of Eugenics (it means good genes) was invented by Darwin's cousin, Sir Francis Galton, though the basic idea goes back to Plato. After Hitler, most people downplayed their interest in eugenics. However, it should be remembered that the opposite view - that if you change the environment you change the child - can have equally disastrous consequences. Stalin was very much of the opinion that environment is everything.

I tend to take my ideas on sociology from the Bible, which says, "Do not think of yourself more highly than you ought, but rather think of yourself with sober judgment, in accordance with the measure of faith God has given you. Just as each of us has one body with many members, and these members do not all have the same function, so in Christ we who are many form one body, and each member belongs to all the others. We have different gifts, according to the grace given us. If a man's gift is prophesying, let him use it in proportion to his faith. If it is serving, let him serve; if it is teaching, let him teach; if it is encouraging, let him encourage; if it is contributing to the needs of others, let him give generously; if it is leadership, let him govern diligently; if it is showing mercy, let him do it cheerfully."

When we say that are men are born equal, we are not talking about their abilities or their position in society, we are talking about their worth before God. So the death or suffering of a child in Africa or Iraq should concern us as much as the death or suffering of a child in America or Britain. That it does not is a measure of how much we fall short.

Even on a strictly utilitarian basis, the idea that intelligence is everything is a busted flush. If you don't believe me, try getting an intellectual to fix your toilet.

Sunday, October 21, 2007

Overview of Mark's Gospel

Mark's Gospel is a reMarkable book. People who are looking for discrepancies between the Gospels miss the point that each was written according to a particular plan, and none more so than Mark. He loved to organize his material so that it appeared to balance. The book is in five sections. Beginning in Chapter 1 and ending in Chapter 6 versus 29, he tells us that Jesus is Lord. He like to use bookends for each section and the bookends here are the stories of John the Baptist. His message was "Prepare the way for the Lord." Jesus is demonstrated to be Lord over disease, over Sin, over the Mosaic Law, over the Sabbath, over Satan, over Nature, over evil spirits and over death. In this section also are the kingdom parables, demon stating the nature of his kingship.. This section ends with the beheading of John.

The bookends for the second section are the feeding stories - first the 5000 then the 4000. These two stories are similar but different. The symbolism of the first is distinctly Jewish, but of the second Gentile. Here is the message that Jesus is not just the King of the Jews but King of the whole world. The story of the Syro-Phoenician woman exemplifies it.

The third section is bookended by two healings of the blind; the man at Bethsaida who could see people who looked like trees walking and the later healing of Bartimaeus. Cleverly, this is the passage of enlightenment, where Jesus reveals what was hidden, where he explains what his purposes are and opens the eyes of the disciples.

The fourth section is encapsulated within stories of the Temple. First he clears the Temple and in the end he predicts its destruction. He was the culmination of Temple worship. No longer would God be worshiped in Jerusalem but in the person of Jesus.

The final section is marked by two stories of anointing. First the pint of pure nard at Bethany and finally the women going to anoint his body but finding no body there. The stories include the crucifixion and resurrection and proclaim Jesus as Messiah or Christ. Both words mean 'anointed one'.


At Exbury Gardens there is a Domesday Yew. Although very old, going back to the fourteenth Century, it certainly does not go back to the Domesday book in 1086. Also in the gardens is a tree that was felled in the storms of the 1990s on which the tree rings demonstrate that it was a foot in diameter at the time of the American Revolution. The greatest set of tree ring data comes from the Bristlecone Pines in the White Mountains of North America. History back to 7000 BC van be traced there.

What I want to know is whether it works at the equator where there is no winter.

Friday, October 19, 2007

Early stage treatment

What follows is an early draft of a paper I am writing that makes the case for new trials of whether early treatment might benefit some patients with CLL. I would welcome comments.


For most patients with neoplastic disease it is almost axiomatic that early diagnosis leads to earlier treatment and better outcomes. For chronic lymphocytic leukemia (CLL) there is no evidence to support this. Indeed a meta-analysis of six trials involving more than 2000 patients that compared early treatment with treatment deferred until the disease became progressive or symptomatic showed no significant difference in overall survival [1]. However, in these trials nearly half the patients in both arms were still alive after 10 years follow-up and therefore the trials must have included patients who would never under require treatment current guidelines [2]. Moreover, the patients were treated with chlorambucil, with or without prednisolone. Many authorities believe that there are now more effective treatments than that. Although there as yet no randomized clinical trials that show longer overall survivals for any first-line treatment than chlorambucil [3], the use of purine analogues alone or in combination with cyclophosphamide with or without rituximab and with or without mitoxantrone all give a higher rate of complete remission and complete remissions without minimal residual disease, as well as longer progression-free survivals [4-8].

In recent years several prognostic markers have been described that are able to predict which patients will eventually require treatment. In particular, unmutated IGVH genes [9, 10], the use of the IGVH3.21 gene [11], increased CD38 expression [9, 12], increased ZAP-70 expression [13-15] and the detection of deletions of portions of the long arm of chromosome 11 (del 11q23) or the short arm of chromosome 17 (del 17p13) by fluorescent in-situ hybridization (FISH) [16] all usefully predict poor outcome in early stage disease. Patients with del 17p13 are a group with very poor survival with disease that is resistant to most active agents [17] and because of this we have excluded them from this analysis.

In this study we have looked at the feasibility of re-examining the question of early versus deferred treatment in a new randomized controlled trial.

In this retrospective study we have examined 297 patients with Binet stage A CLL who presented at the Royal Bournemouth Hospital and have had prognostic markers performed. The following prognostic markers were studied: IGVH mutational status, use of IGVH 3.21 heavy chain gene, CD38 expression, ZAP-70 expression and the presence of deletions at 11q23 or 17p13. Those with del 17p13 were excluded from the analysis. Patients were treated according to NCI guidelines [2]. Times from presentation to first treatment were calculated and treatment-free survival times calculated for patients with nought, one, or two or more adverse factors. Overall survival curves were also calculated for the same three groups.

IGVH gene analysis
Prior to October 2004 IGVH genes were sequenced as previously described [10]. The preferred source material was RNA. cDNA was synthesized and amplified by polymerase chain reaction (PCR) using a mixture of oligonucleotide 5’ primers specific for each leader sequence of the VH1 to VH6 families or a consensus 5’ FW1 region primer, together with either a consensus 3’ primer complementary to the germ line JH regions or a 3’ primer complimentary to the constant region. From 2004 onwards gDNA was extracted from whole blood using the QIAmp®DNA mini kits (Qiagen, Crawley, West Sussex, UK) according to the manufacturers instructions. gDNA was amplified in a single multiplexed PCR reaction consisting of 6VH framework 1 primers combined with one JH consensus primer (standardises BIOMED-2 primers). Clonal sequences were determined by sequencing amplicons from at least 2 independent PCR reactions. The majority of samples were sequenced directly using an automated DNA sequencer. Nucleotide sequences were aligned to EMBL/GenBank and current databases (V-BASE sequence directory IMGT/V-QUEST, using MacVector 4.0 sequence analysis software; International Biotecnologies, New Haven, CT, and Lasegene; DNASTAR, Madison, WI.). Percentage homology was calculated by counting the number of mutations between the 5’ end of FR1 and the 3’ end of FR3. Homology with the germline sequence of 98% or more was regarded as unmutated.
CD38 expression on fresh or cryopreserved cells was determined by flow cytometry as previously described [12] using FITC labeled anti-CD5 (clone DK23; DAKO, Glostrup, Denmark), PE labeled anti-CD38 (clone HB7; Becton Dickinson, San Jose, CA) and RPE-Cy5 labeled anti-CD19 (clone HD37, DAKO). We chose a cut-off point for CD38 that give the highest possible Youden index. Cut-off points of 20% and 30% gave the highest, but similar, Youden values—58% and 60%, respectively, and in this instance we chose 20%.
ZAP-70 expression on fresh or cryopreserved cells was measured by flow cytometry as previously described [14], using an indirect assay that makes use of an unlabelled anti-ZAP-70 (clone 2F3•2, Upstate Biotechnology, Milton Keynes, UK) followed by secondary antibody (Sheep-anti-mouse FITC-conjugate, Novocastra, Newcastle Upon Tyne, UK). An isotype control (mouse IgG2a, DAKO) was used to define negative staining and T and NK cells were identified using and anti-CD2-PE conjugate (DAKO). A cut-off level of 10% positivity was chosen as previously described.
Separate hybridizations were carried out for loci on chromosomes 11 and 17 as previously described [18]. LSIp53, together with CEP17 alpha satellite DNA probe labeled with Spectrum Orange and Spectrum Green (Vysis UK, London, United Kingdom), respectively, were used to evaluate chromosome deletion at 17p13.1. For chromosome 11, CEPH yacs 755b11 and 801b11 were labeled by nick translation with Spectrum Orange dUTP and Spectrum Green dUTP (Vysis), respectively, according to the manufacturer’s protocol. Hybridization was to peripheral blood lymphocytes or to cells from our archive of fixed TPA stimulated lymphocyte cultures.
Statistical methods
Data were analyzed using GraphPad Prism 4. Survival functions comparing patients have been estimated using the product limit method of Kaplan Meier.


Of the 297 stage A patients there were 148 patients who had none of these adverse factors, 78 who had one of them and 71 (23.9%) who had two. Actuarial treatment-free survival curves were constructed for these three groups and are shown in the figure. Median treatment-free survival for those with no adverse prognostic factors has not been reached; for those with one adverse prognostic factor the median treatment-free survival was 123 months and for those with two it was 37 months (p<0.0001).

The median overall survival for patients with at least two adverse prognostic factors was 102 months.


Nearly a quarter of all stage A patients presenting to a district general hospital had at least two adverse prognostic markers. Half of these required treatment according to NCI guidelines within three years of diagnosis. Given the number of patients presenting annually in the United Kingdom there should be no difficulty in accruing sufficient patients for a randomized clinical trial of early treatment versus ‘watch and wait’.

On the other hand the use of only a single adverse prognostic factor (such as unmutated IgVH genes) would mean that it would take more than ten years for half the patients to require treatment and some patients would normally remain treatment-free for more than 20 years. In view of the unproven nature of early treatment, such a trial would be ethically suspect.

Of greater difficulty is deciding which treatment should be offered. Although drug combinations that include purine analogues yield the highest complete response rates, the possibility of selecting for p53 mutant subclones has been raised [19] and risk that early intervention might generate drug-resistant disease is apparent. Furthermore, the prolonged depletion of CD4 positive T cells might be responsible for the reported higher incidence of Richter’s syndrome after fludarabine therapy [20]. To avoid the potential dangers of early chemotherapy, treatment with monoclonal antibodies might be assessed. Although single agent rituximab does produce objective responses in 51% of patients when used first line in CLL [21], complete responses are very rare.

On the other hand alemtuzumab is capable of producing complete remissions in 72% of patients without lymphadenopathy and complete remissions with the absence of minimal residual disease in 39% [22]. Although its toxicity is seen as an important drawback in multiply treated patients, when used as a first line agent its only serious toxicity is CMV viremia and this is regarded as manageable [23]. Although profound depletion of CD4 positive T cells occurs following alemtuzumab treatment, recovery is probably quicker than after treatment with fludarabine [24].

The most meaningful end-point for a trial of early treatment versus deferred treatment is overall survival. Trialists have been reluctant to use this as an endpoint for clinical trials in CLL, preferring progression-free survival as a surrogate, since patients may be expected to be long-lived and receive several rounds of subsequent therapy. However, this particular group has a median overall survival of only eight and a half years so that any difference in overall survival is likely to be apparent well before the ten year follow up of the meta-analysis quoted above.

1. CLL Trialists’ Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukaemia: a meta-analysis of the randomised trials. J Natl Cancer Inst 1999;91:861-8.
2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990-7.
3. Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R; Cochrane Haematologic Malignancies Group. Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. Cancer Treat Rev. 2006;32:377-89.
4. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-1757.
5. O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:1414-20.
6. Bosch F, Ferrer A, López-Guillermo A, Giné E, Bellosillo B, Villamor N, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976-84.
7. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia J Clin Oncol 2005;23:4079-88.
8. Wierda W, O’Brien S, Faderl S, Ferrajoli A, Wang X, Do K-A et al. A Retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 2006;106:337–45.
9. Damle RN, Wasil T, Fais F Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840-7.
10. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848-54.
11. Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M. Somatically mutated Ig VH3-21 genes characterize a new subset of chronic lymphocytic leukemia Blood. 2002;99:2262-4.
12. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002, 99: 1023-1029.
13. Crespo M, Bosch F, Villamor N Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775
14. Orchard JA, Ibbotson RE, Davis Z Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression by flow cytometry is a good prognostic marker in CLL and a potential surrogate for immunoglobulin VH gene mutations. Lancet 2004 363:105-111.
15. Rassenti LZ, Huynh L, Toy TL Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004 351:893-901.
16. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-6.
17. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJS, Bezares RF et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370:230–9
18. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors Blood.2002;100:1177-84
19. Rosenwald A, Chuang EY, Davis RE, Wiestner A, Alizadeh AA, Arthur DC et al. Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood. 2004;104:1428-34.
20. Thornton PD, Bellas C, Santon A, Shah G, Pocock C, Wotherspoon AC et al. Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis.
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21. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network . J Clin Oncol 21:1746-51.
22. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99:3554-61.
23. Hillmen P, Skotnicki A, Robak T, Jaksic B, Sirard C, Mayer J. Alemtuzumab (CAMPATH ®, MABCAMPATH®) has superior progression free survival (PFS) vs chlorambucil as front line therapy for patients with progressive B-cell chronic lymphocytic leukemia. Blood 2006;108:93a (abstract 301)
24. Lundin J, Porwit-MacDonald A, Rossmann ED, Karlsson C, Edman P, Rezvany MR et al. Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia. Leukemia 2004;18: 484–90.

Wednesday, October 17, 2007

Marriage a la mode.

I don't normally pick these things up, but there is a piece in the Independent that caught my eye. When Elizabeth Hurley got married recently at her local parish church, the vicar waived the usual £1000 fee in the expectation that a larger donation would be forthcoming. None was.

Maybe we were naive and should have stuck with our normal charges," the church treasurer added ruefully. "We'll know next time she gets married."

Quite apart from the fact £1000 seems a bit extortionate the whole point of a church marriage seems to be lost. No wonder young people choose to live together instead.

Saturday, October 13, 2007

Leukemic Stem Cells

The question is often asked as to whether there are leukemic stem cells for CLL. The theory goes like this. Most of the cells in a cancer are committed cells without self-renewal capacity. In any tumor there are small numbers of stem cells carrying the basic neoplastic defect that are capable of self-renewal and differentiation. The great bulk of the cells are differentiated cells that have committed themselves to maturation and eventual death. If you transplanted only those, they would eventually die out because they do not have the capacity for self-renewal. It is suggested that such cells are the ones that are killed by conventional therapy, while the true stem cells are resistant to treatment. This explains the phenomenon of remission and relapse. The great bulk of cells of the tumor are not stem cells so that when they respond to treatment the patient appears to be in complete remission. However, lurking somewhere in the body are the stem cells that are resistant to the treatment, and when the coast is clear they will start dividing and replenish all the cells that have been killed so that the disease relapses.

This scenario certainly appears to be the case for many solid tumors like colon cancer and pancreatic cancer, and is also the case for myeloid leukemias, both acute and chronic. Is it also the case for lymphoid tumors, and especially for CLL?

I submit that it cannot be so. The stem cells of lymphocytes are pluripotent blasts found in the bone marrow, that can commit to either myeloid or lymphoid tumors. That is why in chronic myeloid leukemia, transformation can be to either acute myeloid leukemia or acute lymphoid leukemia. However, lymphoid tumors mostly arise from lymphocytes that have already committed themselves by rearranging their immunoglobulin genes (in the case of B cells tumors) or their T cell receptor genes (in the case of T cell tumors). This is a step that can't be gone back on. You can certainly conceive of a stem cell origin for a lymphoid tumor, but there is no reason that all the cells in such a tumor would have the same Ig rearrangement in every cell as happens in CLL, myeloma and mantle cell lymphoma, and while where there is some variation in follicular lymphoma, it is usually possible to construct a 'family tree' of the variations demonstrating an origin in a single cell.

If relapse in CLL was fed by a self-renewing stem cell from a lineage arising before Ig rearrangement the relapsing tumor would have a different rearrangement.

In fact lymphocytes have a circular lifestyle. The apparently small mature lymphocytes of CLL can turn back into blasts capable of division before resuming their 'mature' appearance again. there is no need for a stem cell to answer the relapse/remission conundrum. There may certainly be cells that lack Cd20 and are thus immune to rituximab, but they are not stem cells in the conventional way.

Thursday, October 11, 2007

Making Money

The new Terry Pratchett has arrived. The star of the book is again Moist von Lipwig whom we last saw in Going Postal. In this one Vetinari, the despot who runs Ankh-Morpork, decides to put Moist in charge of the central bank. The Bank has run on the gold standard for years and Moist decides that the whole thing would run better on paper money. After all gold is a pretty useless commodity that you can't do anything with; it's not worth as much as potatoes. If you were shipwrecked on a desert island, which would you rather have, a bag of gold or a bag of potatoes? It would be far better to base the currency on the strength of the City, its entrepreneurship, energy and hard work.

Those who start here should know that Moist is in reality Albert Spangler, the notorious con-man whom Vetinari (clearly a pun upon Medici) smuggled out of the hangman's grasp to put his talents to work for the city. Von Lipwig is the man in the golden suit, the man who could sell sand to the Arabs and ice to the Eskimos. To sell the sausage, he says, you must be able to sell the sizzle. Moist can sell the sizzle without necessarily being able to produce the sausage.

The story is full of characters who are not quite what they seem. Another, rather dimmer, con-man appears to be as sort of priest of an obscure religion, a Chief Cashier at the bank is actually a clown, an Igor (a race of Frankenstein's monsters with a penchant for recycling bits or corpses) reveals that his lisp (or lithp) is not real but put on for show, a golem (large clay men with nothing in the trousers department)thinks it is a modest young lady and the chairman of the bank is a dog. But Cosmo Lavish, one of the Bank's shareholders, takes the cake. He imagines he is Vetinari, the ruling tyrant.

To know a man, walk a mile in his shoes. He takes things rather literally and gets his servant, Heretofore, to steal a pair of Vetinari's old boots (they are too small, but it's a good pain). He grows a goatee beard like Vetinari's, though it looks ridiculous on his heavy jowls. He has a ring made of stygium (a very strange metal - or alloy - that heats up when exposed to the light. It is engraved with a 'V' and it too is too small. His finger becomes a stranger and stranger color as the book progresses. Try as he might he cannot pull off his Vetinari impression (or the ring, for that matter). He is too slow, too fat, not fast enough on his feet, too maladroit. He ends up in a madhouse in a ward for megalomaniacs. Vetinari triumphs and Moist von Lipwig is clearly destined for bigger things. What task for the man that everybody loves to love? It looks like he is set to run the tax office. That will test his bonhomie.

Of course, Pratchett is funny because he comments on our existing society. Who is Moist von Lipwig? Why, who but Tony Blair? The man that everyone loves to love. The crook who could sell you your own hands and feet. We know he's a rogue but we enjoy being taken to the cleaners.

And who is Cosmo Lsvish? Who do we know who tries to be leader, but is too fat, too ponderous, can't think on his feet and used to run a financial institution?

David Cameron took him to pieces at the Dispatch Box this week at PMQs.

Wednesday, October 10, 2007

Pan's Labyrinth

Last night I watched the DVD of Pan's Labyrinth, which some have called the only great film of the 21st Century. This is Mexican director, Guillermo del Toro's masterpiece. Set in 1944 in Spain, it tells the story of a Falangist Captain Vidal whose mission is to wipe out the remaining Republican irregulars (he would call them terrorists) holed up in the mountains. He summons his very pregnant wife to the military camp together with his 10 year old step daughter, Ofelia.

The film explores the parallel worlds of Ofelia and Mercedes, the Captain's peasant housekeeper. Ofelia is drawn into a world of fantasy where she a lost princess is set three tasks that she must accomplish to return to her father and his kingdom. Mercedes is a spy in the camp, aiding the rebels with succor and information.

The Spanish Civil War was the war that the baddies won. Hitler's ally Franco defeated the Republicans who were a mixture of liberals, intellectuals and soviet-style communists. It was a very dirty war in which the fascists were not the only villains. Nevertheless in this story Vidal (played by comic actor Sergi Lopez)is a vicious tyrant, shooting prisoners and torturing the wounded. He sees himself as one of a ruling elite and the notion that all men are equal as laughable.

The underlying themes are those of obedience and choice. In her fantasy world Ofelia triumphs by choosing to shed her own blood rather than that of an innocent. In the real world Franco triumphed and the rebels were scattered. In the long run Spain has become a democracy and Franco is a hated figure. Perhaps in the long run Ofelia's fantasy (or something like it) is the real world.

Tuesday, October 09, 2007

Private Practice in the UK

The great debate on health service financing has produced an array of mutually exclusive solutions. The one that is most laughable is the suggestion that private health care as currently practised in the UK might expand to fill the gap. It is perfectly possible to argue that some form of compulsory insurance, perhaps related to employment, might generate money more acceptably than direct taxation, but to suggest that the shortfalls in care for the elderly, hip replacements, accident and emergency departments, kidney transplants and anti-cancer drugs can be made good by the stately pleasure domes of BUPA hospitals is to betray a crass misunderstanding of why such palaces make their money and what the health service really needs.

In Britain, the private sector thrives on exclusivity. This is the Virgin Upper Class of health care. You have a room to yourself, a telephone, china cups and Sky TV. You don't have to strap hang with hoi polloi. Who would want to go private if everybody did it?

Private practice is a form of alternative medicine and is successful for the same reason. Make the patient feel special. Your disease is not something that any doctor can deal with. It requires my personal attention.

Guidelines for Clinical Trials

The CLL Guidelines also lay out special recommendations for clinical trials.

1 For patients who enter clinical trials it is recommended that a full range of prognostic marker tests is performed. This includes FISH for del 13q14, del 11q23. del 6q, del 17p13 and trisomy 12; IgVH mutations; CD38 and ZAP-70 by an agreed and valdated method, and serum tests for beta-2 microglobulin, CD23 and thymidine kinase. There are other prognostic markers under study, and these could with profit be evaluated at teh same time.

2 CT scanning of chest, abdomen and pelvis is encouraged especialy in trials where complete response is the aim. (Note however that these will not change the Rai of Binet stage).

3 Definitions of different types of response have been clarified. Complete remission (CR) requires all of the following for at least three months: absence of clonal lymphocytes in the blood; absence of lymph nodes > 1.5 cm in diameter by both physical examination and CT scan; no splenomegaly or hepatomegaly by both clinical examination and CT scan; absence of constitutional symptoms; neutrophils >1.5/microliter, platelets >100,000/microliter, Hb >11.0 g/dL (untransfused).

4 Bone marrow aspirate and trephine performed at least three months after last treatment should be free of clonal CLL B cells (by conventional imunophenotyping). In some bone marrow trephines lymphoid nodules could be detected; the term nodular PR was used. This term is now discarded; immunohistochemistry should be used to distinguish whether these are T cells, normal B cells or tumor B cells. If teh marrow is hypocellular it should be repeated after 4-6 weeks. The timing of a marrow might have to be delayed until the other criteria of a CR are fulfilled, but it should not be delayed after 6 months.

5. For patients who fulfill all teh other features of a CR, but fail to recover their blood counts, the term CR with incomplete bone marrow recovery (CRi) shopuld be used.

6 Partial remission requires the following: a decrease of blood lymphocytes by at least 50%; reduction of lymph node size (by CT scan) of at least 50% in the sum of the products of up to 6 lymph nodes or in the diameter of one lymph node if only one lymph node was present before treatment AND no new abnormal nodes and no increase in size of any nodes; a decrease in the size of liver and/or spleen by 50% or more; and at least one of teh following:- neutrophils at 1,500/microliter of a 50% improvement over baseline without G-CSF support, playelets at 100,000 or a 50% improvement over baseline, or Hb >11.0 g/dL or a 50% improvement without transfusion or Epo support.

7. Progressive disease (PD) is defined by the appearance of any new lesion such as a lymph node >1.5 cm in diameter, clinical splenomegaly, hepatomegaly or infiltration of any other organ; by the increase of >50% in the greatest diameter of any previously documented disease; an increase in spleen or liver size by 50%; an increase of lymphocyte count by at least 50%; transformation to Richter's syndrome (confirmed by lymph node biopsy); occurrence of any cytopenia attributed to CLL (as opposed to the treatment).

8. Stable disease refers to those who do not achieve CR or PR yet do not have PD.

9 Duration of response is measured from the date of the end of last treatment until evidence of PD. Progression-free survival is defined as the interval between the first day of treatment and the first sign of disease progression. event-free survival is defined as the time from the first day of treatment to the first sign of progression or treatment for relapse, or death. Overall survival is the interval from the first day of treatment until death.

10. Relapse is defined as evidence of disease progression after a period of 6 or more months after a CR or PR. Refractory is defined as failure to achieve a CR or PR within 6 months of the last anti-leukemic therapy.

11. The elimination of Minimal Residual Disease (MRD) may be a desirable treatment endpoint, though prospective clinical trials are needed to demonstrate that this has clinical benefit. he techniques for assessing MRD have been standardized. Either four-color flow cytometry or allele specific oligonucleotide PCR are reliably sensitive down to a level of one cell in 10,000 leukocytes. It is satisfactory to use blood for this estimate except within three months of treatment with monoclonal antibodies, in which case marrow must be used.

Jab and Dab

Readers will know all about the problem of infection in CLL. Although there are many treatments that make the lymph nodes go away and the white count come down, although both hemoglobin and platelet counts can be restored to normal, although the marrow can be cleared of CLL cells, nothing makes the immune system normal.

Everybody agrees that it is worth being vaccinated against common infections including influenza, but tests show that responses to vaccines are poor. For this reason and inspired by an idea of Chaya's we are recruiting to a trial which attempts to enhance the response to flu vaccine.

The Jab and Dab trial is being sponsored by CLL Topics and details are laid out on Chaya's website. Briefly it involves the use of imiquimod, a cream used to treat rather indolent skin cancers, to be rubbed on the skin after the flue jab. Imiquimod activates one of the Toll-like receptors, TR7, which stimulates the immune response. The trial will be run by Dr Helen McCarthy in Bournemouth. The trial protocol and patient information sheet are available on line.

Dr McCarthy is one of the hematologists who replaced me when I retired from Bournemouth. She has a long standing interest in CLL and spent a year working with Dr Keating and Dr Wierda at MD Anderson. While there she discovered that high levels of AID could be detected in patients with unmutated IgVH genes.

Monday, October 08, 2007

Del 11q23

I am responding to one of my correspondents up front because not everybody reads the 'comments' on this blog. 'Anonymous' has misinterpreted the situation with del 11q23, which means I have made myself insufficiently clear, and I apologise.

Up to 20% of patients with CLL have del 11q23 at diagnosis, and more acquire it as the disease progresses. On the piece of chromosome that is deleted is the gene that codes for the the protein that is missing in a strange congenital disease called ataxia telangectasia. The gene is known as ATM (which stands for 'mutated in Ataxia Telangectasia). We know the gene is involved in the same apoptosis-inducing pathway as p53, but it seems that whereas a defect in only one of the two p53 genes is necessary to cripple this pathway, both ATM genes have to be damaged or missing to achieve the same effect. You can read in more detail about it here.

The importance of this pathway is that most of the drugs that kill CLL cells do so by making use of it. This is true for fludarabine, chlorambucil and rituximab. The only exceptions we are sure of are Campath (alemtuzumab) and high dose steroids. Flavopiridol also by-passes this pathway, but a safe and effective way of giving it is still being developed. Revlimid (lenalidamide) might also be useful in this situation, but comprehensive results are not in. HuMax is another antibody not fully tested in this situation.

Clinical trials have shown that most patients that are primarily resistant to fludarabine combinations have a defect of p53. On the other hand patients with del 11q tend to respond well, but they also tend to relapse earlier than other patients. This may be because there is an increased tendency for these patients to acquire an ATM defect on the other chromosome 11. The problem then becomes how should such patients be retreated. Another round of FCR or perhaps PCR will put most patients back in remission, but being exposed to these drugs a second time raises risk of immunodeficiency and marrow failure. Perhaps these patients should be the ones in whom clinical trials of newer agents should take place. Drugs like HuMax, Revlimid and flavopiridol might be tried. Newer drugs that inhibit the enzyme PARP1 look promising in the laboratory, and I hope they will shortly make an appearance in the clinic.

Some would argue that such patients should be treated with Campath and high dose steroids. This regimen would likely work as well as it does for p53 deleted patients, though it cannot at the moment be justified for use as first line treatment in those who have never been treated. The problem with Campath and steroids is that responses are likely to last less than 18 months, and this regimen is best used in preparation for a later low intensity allograft.

I have been criticised as being unduly pessimistic about stem cell transplants. I might respond that that is because transplanters are unduly optimistic. To a man with a hammer, everything looks like a nail. But I want to reflect the truth, not opinion. It is true that a stem cell allograft is probably the only treatment that offers a cure in CLL, even in those with bad-risk cytogenetics. There is a sufficient graft-versus-leukemia effect to be confident that when it works patients can enjoy a long and healthy life. However, it is risky. Transplant-related-deaths used to account for 40% of patients when full intensity conditioning was used. It was higher in CLL then in other conditions because the patients tended to be older, they were already immunodeficient and it was usually done as a last resort when all sorts of other body poisons had been administered. It had been hoped that the introduction of reduced intensity conditioning would reduce the treatment-related mortality.

What has happened is that the age at which transplants are attempted has increased. It is quite commonplace for patients up to the age of 70 to be offered a transplant, whereas 50 used to be the absolute upper age limit and most were unhappy about anyone over 40. The reason for increasing the age is that patients would no longer have to withstand total body irradiation or high dose cyclophosphamide and busulphan. Instead they might simply receive immunosuppressive treatment such as fludarabine and Campath. That being said there is not just one type of reduced intensity conditioning, and no-one has worked out what is best for CLL. At Seattle the use low-dose total body irradiation; at Kings College, London they use fludarabine, busulphan and Campath. At University College, London they have been doing a trial to see how little Campath they can manage with. Others use anti-lymphocyte globulin. There are many possibilities. So when you sign up for a reduced intensity allograft - also known as a mini-allograft - you are taking part in experimental therapy.

The problem that transplanters are grappling with is graft-versus-host disease. This first shows itself as a rash, typically involving the palms of the hands and soles of the feet, and if that is all it is it can usually be managed - indeed those who have grade I GVH have the best outcome. But it also involves the gut (causing diarrhea), the liver and other organs. Acute GVH can be avoided by removing the T cells (Campath does a very good job), but abolishing GVH gets rid of the graft versus leukemia effect and without that, relapse is inevitable. So you need some T cells, and indeed, if the disease shows signs of relapsing the transplanters add some back as a donor lymphocyte infusion. Keeping the balance between too many and too few T cells is the transplanters' art. Too many and the graft versus host disease becomes uncontrollable, too few and not only is relapse likely, but viral infection - especially from CMV becomes a danger. Even if acute GVH is avoided, chronic GVH can be very difficult to live with.

In my reading about stem cell transplants, I have found it difficult to find much comment about chronic GVH. One text book (Handin, Lux and Stossel) says "It is the most insidious of transplantation complications and, in some respects, the most difficult to handle." Characteristically it involves the skin which develops a condition akin to scleroderma, with thinning, scarring, and ulcer formation. Hair loss is a feature as well as photosensitivity and depigmentation. There is an absence of saliva and tears. Muscle and joint pains, inflamed tendons, joint contractures, strictures of the gullet, sore mouth, liver damage and cirrhosis, and failure of the immune system are all problems that occur. Of course, it is not severe in everyone, but it is quite common. In a study from Nashville two thirds of patients had some degree of chronic GVH and in a third of these it was classified as severe.

This is what Peter Dreger, the leader of the German stem cell transplant program, said at the IWCLL meeting in London, "Allo-SCT from matched-related or matched unrelated donors can be highly effective in patients with otherwise resistant CLL. With modern strategies, non-relapse mortality can be kept to ~20% or lower, but the morbidity asociated with graft-versus-host disease remains a significant problem. Due to the absence of controlled trials in defined disease settings, however, it is unclear what the real impact of allo-SCT in the treatment of CLL might be, and whether it can change the natural history of poor-risk CLL. A randomized phase III trial addressing these issues, as well as the optimum time of transplantation is currently being prepared by the German CLL study Group."

The difficulties of reduced intensity stem cell allografts in CLL are reflected in the outcome data. No-one has huge experience, but there are a number of reports of 30-70 patients treated at single centers or groups of centers. Treatment-related-mortality varies from 18% to 39% and two year survival from 51% to 80%. There is no way of selecting out who does it best, because none of the studies is really a clinical trial, there are no standard entry criteria and some of the studies (including one of the largest with the best results) used several kinds of conditioning regimes over the period of the study.

So I am not against stem cell transplants any more than I am against marriage. And you know what the Book of Common Prayer says about marriage, " is not by any to be enterprised, nor taken in hand, unadvisedly, lightly or wantonly ... but discreetly, advisedly, soberly and in the fear of God."

Sunday, October 07, 2007

A Day at Exbury

Fawley must be one of the ugliest places on earth.

The Exxon refinery is the largest in the UK. With its intricate pipework knitting, ugly containers and distressed buildings it might have been the model for the sets in Blade Runner. It is plastered onto the end of Southampton Water, opposite the Isle of Wight and my vision of Hell on Earth.

Yet only a couple of miles away is the Heaven on Earth of Exbury Gardens.

On Friday the weather forecast said it would be a cloudless day and we took the opportunity to take the day off and go out for the day. We hadn't visited Exbury for about 15 years, and when we last went Diane developed such severe hay fever that we had to curtail our visit. That was in May, so October should have been alright. Late April to May is the optimal time to visit Exbury, because the attraction is the world famous collection of Azaleas and Rhododendrons. The gardens are those of a stately home owned by the de Rothschild family. They comprise 280 acres with 26 miles of pathways. October sees the rhododendrons and azaleas in leaf but not in flower, but the attraction is the other trees turning red, yellow and gold. We had thoughts of New England in the Fall, but here, not thirty miles from our front door was its rival.

We arrived at 11 am and just sauntered through the gardens. We were there for almost 5 hours, just meandering along pathways. There were perhaps a hundred other people there, so plenty of solitude. At the furthest edge of the estate were delightful views over the Beauleu River and the Solent, on Friday, electric blue in color. In the sundial garden, walled in by Yew hedges, sun-trapped Cannas bloomed and strange sub-tropical plants flowered in bright blues and oranges with alien-shaped blooms.

Each member of the family seemed to have a hobby, for one it was rhodedendrons, for another it was steam trains. In the past five years they have laid a narrow gauge (12.5 inches) track and two steam trains pull passengers through part of the gardens only accessible that way. I have had fun helping to build my grandson's model railway, but this is the way that a really rich man does it.

Another family member has a passion for Nerines. These are sometimes known as the Spider Lily, Jersey Lily or Guernsey lily. originally native to South Africa, they can thrive only in the balmiest parts of England such as this. The temperature on Friday was in the low seventies. The collection on view was bred by a retired civil servant, now at 93, living in Switzerland, and his collection housed with the de Rothschilds for safe keeping.

Friday, October 05, 2007

Conradin Kreutzer

An almost forgotten German composer, Kreutzer was born in 1780 and like Beethoven, studied under Albrechtsberger in Vienna. He is believed to have been the last pupil of Joseph Haydn. He died in Riga in 1848.

I have been listening to two of his pieces all week. Opus 62 is a septet and opus 43 a piano trio. The CD I have features the Mithras Octet (of the Broadcasting Corporation of Saarland) with Paul Rivinius on piano.

The music is delightful. If you can get hold of the disc I recommend it.

CLL Guidelines

Guidelines for the management of CLL were issued in 1988 and 1996 and these are about to be replaced by a new set of guidelines produced by a group from the IWCLL led by Michael Hallek. There are several changes. Here are the most important.

1 The new WHO classification makes it clear that we no longer have to talk about B-CLL. What used to be called T-CLL is now recognized as T-PLL, so all true CLL is B-CLL and just needs to be called CLL. CLL is only distinguishable from SLL by appearing in the blood. Thus SLL with a lymphocyte count of at least 5000 per microliter is called CLL. CLL with less than 5000 lymphocytes per microliter is called SLL if there enlargement of lymph nodes, spleen or liver (either by physical examination or an imaging technique or if there is a cytopenia caused by marrow infiltration; if there is not it is called monoclonal B-lymphocytosis (MBL), which may or may not progress to CLL.

2. The diagnosis of CLL, as well as having a lymphocytosis of at least 5000 per microliter, must have lymphocytes that are small and mature with a narrow border of cytoplasm and a dense nucleus lacking discernable nucleoli and having partially aggregated chromatin. There may be an admixture of atypical cells, cleaved cells or prolymphocytes. The matter may under extremes circumstances comprise up to 55% of cells. If there are more then the condition is B-PLL. Smudge cells (also known as Gumprecht shadows) are often a feature of CLL.

3. For diagnosis of CLL it is essential to do an immunophenotype. CLL cells co-express CD5, CD19, CD20 and CD23. The levels of surface immunoglobulin, CD20 and CD79b are characteristically lower than what is seen on normal B cells. There is restricted expression of either kappa or lambda chains of immunoglobulin. There is no such thing as 'polyclonal' CLL, but there is a 'polyclonal lymphocytosis' characterized by binucleate lymphocytes, which characteristically occurs in female smokers. It is a benign condition, but sometimes confused with CLL.

4. No other tests are necessary for diagnosis and only one other test currently influences treatment decisions. A FISH test showing deletion of the short arm of chromosome 17 (del 17p13) signifies that the disease is unlikely to respond to conventional agents and that alemtuzumab (Campath), either alone or in combination, will be required.

5. Five other markers: Unmutated IgVH genes, use of VH3.21, increased expression of CD38 or ZAP-70, and del 11q23 are all associated with poor outcome. It is uncertain from clinical trials whether any of these, alone or together, influence response to treatment or overall survival once treatment is required. Trials are ongoing to establish this point. On the other hand the mutational status of IgVH genes in particular, and probably the other tests are useful for predicting the clinical course in individual cases, and may be recommended for patients who want a better prediction of the rate at which their disease might progress.

6 Several studies have found that the serum markers CD23, thymidine kinase and beta-2-microglobulin may predict survival or progression-free survival. Standardized assays for these and those in section 5 should be incorporated into all future clinical trials, but are not essential in general practice.

7. Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. They may be useful to evaluate the factors that might contribute to cytopenias, and therefore they are recommended immediately prior to starting treatment.

8. Clinical staging is unchanged. It is emphasized that both Rai and Binet staging rely on physical examination and imaging techniques should not be used.

9. Evaluation before treatment is different for patients treated in general practice and those entered into clinical trials. The following are regarded as essential for all patients: CBC (including retics), immunophenotyping (if not already performed), history, physical examination, performance status, serum chemistry (creatinine, bilirubin, LDH, transaminases, alkaline phosphatase), serum immunoglobulins, Coombs test (DAT), chest X-ray, infectious disease status (HIV, Hep B and C, CMV). A marrow aspirate and biopsy is desirable. FISH for del 17p should always be performed. In general practice imaging tests are unnecessary unless the aim of treatment is CR, in which case the investigation of choice in CT scan, and not MRI or PET scan. US scan for abdominal nodes is used in some countries, but suffers from observer variability.

10. PET scans are only indicated where there is suspicion of Richter's disease and they are not 100% reliable for this.

11. Lymph node biopsy is not required except for the diagnosis of SLL or if Richter's transformation is suspected.

12. The indications for treatment are unchanged, but some of the details have been clarified. Lymphocyte doubling time can be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of 2-3 months; patients with lymphocyte counts of less than 30,000 per microliter may require longer periods of observation. Other factors contributing to lymphocytosis such as infection or steroid ingestion must be excluded. Fatigue must be ECOG performance score 2 or worse (unable to work or carry out normal activities).

13. Neither a high white count nor low serum immunoglobulins are indications in themselves for starting treatment.

The rest of the new guidelines relate to clinical trials and I shall summarize these in a separate posting.

Tuesday, October 02, 2007

What is man? Psalm 8

What is Man? I remember fifty years ago as a young man being asked to lead a Bible Study on Psalm 8 and regaling my audience with a description of evolution cribbed from my Grove and Newell Biology textbook. In those days I saw mankind involved in a sort of brilliant progress from ape-man to superman. Everyday, in every way, things are getting better and better. It was a terrific time to be alive. On every front there was progress. Average life expectancy was increasing as the great infectious scourges of the past were defeated. Penicillin had only lately become available and the difference it had made was miraculous. Even more important, TB, ‘the captain of the men of death’, was being driven back by streptomycin. Infantile paralysis was being abolished by the Salk vaccine. Nuclear power, had not only ended a long and bitter war, but would now keep the peace and what’s more provide a cheap, safe and endless supply of electricity. Francis Crick and James Watson had unlocked the secret of DNA, and this would be the clue we needed to destroy the terror of cancer. Jet airplanes had made their appearance. The Comet made successful flights across the Atlantic and to Australia, holding out the promise of cheap travel. Science was the solution to all our fears and woes. There would be a better tomorrow. Poverty would be wiped out. Hunger would be no more. Insecticides like DDT were killing the mosquitoes that transmitted malaria, so that even in Africa people would be able to live healthy productive lives.

This was the hubristic view that I had of the world and Man’s place in it. Nemesis was to follow.

Antibiotic resistant bacteria appeared so that infectious diseases like MRSA and clostridium difficile run rampant through our hospitals. AIDS has killed millions, especially in Africa where malaria is unabated. TB, far from being defeated has returned in a yet more virulent form. While smallpox (vaccine available since 1796) has been wiped from the planet, polio remains; vaccinators frustrated by imams in Nigeria who teach their followers that vaccines are the work of the Devil. Nuclear power is no longer the savior of mankind, but another spawn of Satan (Chernobyl means wormwood). The Comet crashed because of metal fatigue and though Jet planes do circle the world they are now damned as CO2 polluters. And nobody dares use DDT. As for cancer, it (and DNA) appear much more complex than we ever contemplated. Our biggest success has come from epidemiologists who proved James the first right in hating tobacco smoke.

To think of evolution as a progressive force would be to be laughed out of court, nowadays. There is no progress, just ecological niches filled by chance and the survival of the fittest.

In 1916 James Leuba asked the question of scientists, “Do you believe in a God who actively communicates with humanity, to whom one may pray and expect an answer?”
40% of scientists said they did, 20% said they weren’t sure and 40% said they did not (a mixture of deists and atheists). Leuba predicted that over time as education improved, the proportion of scientists not believing in God would increase significantly.

The survey was repeated in 1997. The results then were 40% believed, 15% were agnostic and 45% were atheists or deists.

In 2006 Richard Dawkins published The God Delusion a polemical attack on religion that is largely a reworking of 19th Century atheistic arguments culled from the internet which also betrays the author’s ignorance of the subject of his attack. In the same year Owen Gingerich, a noted Harvard astronomer, published God’s Universe, declaring that ‘the universe has been created with intention and purpose, and this belief does not interfere with the scientific enterprise’. Francis Collins, Director of the National Center for Human Genome Research, and one of those who helped to sequence the human genome, published The Language of God: A Scientist Presents Evidence for Belief. Collins, an atheist when young was converted to Christianity after observing the faith of his critically ill patients and reading Mere Christianity by C. S. Lewis. A few months later, Cosmologist and former atheist, Paul Davies published The Goldilocks Enigma in which he argues that the existence of ‘fine-tuning’ in the universe that militates against it being a chance event.

None of these three would necessarily describe themselves as the sort of Christian that I am, but it does tend to blow holes in the Dawkins theory that science is a superhighway to atheism.

Psalm 8 is not about the hubris of mankind, nor about Man’s progress towards Superman. Still less is about the futility of life – it does not inform us that we are creatures of chance and necessity. In Psalm 8 we are told that God made us a little lower than the angels and that he put the world under our feet. We are to be custodians of the Earth.

What went wrong? Rousseau said, “Man was born free but everywhere he is in chains.” It is difficult to argue with him. Marx blames capitalism. Humanists blame lack of education. Existentialists say that Man cannot come to terms with the fact that life is pointless. But the Bible has a different explanation. In the parable of the wheat and the tares (Matthew ch 13) Jesus says, “An enemy has done this.” In the beginning of Genesis we learn that Eve and Adam were tempted by Satan, and believed him rather than God. This rebellion against God had disastrous consequences. There is something corrupt in the heart of man – Jesus, in Mark ch 7, says “For from within, out of men’s hearts, come evil thoughts, sexual immorality, theft, murder, adultery, greed, malice, deceit, lewdness, envy, slander, arrogance and folly. All these evils come from inside and make a man ‘unclean’.

If that is the diagnosis is there any remedy? In Hebrews Ch 2 there are echoes of Psalm 8. We read of Jesus, “He was made a little lower than the angels,” in other words he was made man, subject to the same pain and temptations that we are, and like us, mortal, so that ‘by his death he might destroy him who holds the power of death – that is the devil – and free those who all their lives were held in slavery by the fear of death. For this reason … he might make atonement for the sins of the people.’ v 18.

What can we learn? First, you are not a fool for believing in God, despite what Richard Dawkins and other media darlings say. Very learned men, with exactly the same access to the evidence as Dawkins, conclude that there is a God, and moreover one who interacts with humanity and answers prayer. Second, my fifty-year old ideas of mankind on an upward path are clearly wrong; the facts fit better with the Bible’s idea that we have gone in the opposite direction – we were created perfect but have fallen into corruption. Third, God has not left us there. God so loved the world that he gave his one and only son, so that all who believe in him should not perish but have everlasting life.

Monday, October 01, 2007


For many years now, the most popular poet in America has been a 13th-century mystical Muslim scholar.

Translations of Mawlana Jalaluddin Rumi's - better known as Rumi - verse are hugely popular and have been used by Western pop stars such as Madonna.

Well, that's news to me and I suspect to most Americans.

I would guess that the most popular poet in America (if he can be called such) is Bob Dylan, but as far as proper poets are concerned William Shakespeare is unlikely to have been knocked off his perch. If we are talking about poets who lived in America then Robert Frost would be my choice, though others would vote for Walt Whitman or Emily Dickinson but remember Longfellow and Poe and countless other famous names. Of American born poets, TS Eliot is something special. Trust Al-Beeb to chose some obscure Muslim.

Visit the Rumi entry on Wikipedia and you will find that all the poems and sayings that are critical of Islam have been labelled as 'not by Rumi' but by an imitator and falsley attributed to him!