Saturday, March 28, 2009

Well enough to work

Today I felt well enough to do some work so I wrote a book review for the New England Journal of Medicine. Here it is.

Chronic Lymphocytic Leukemia. Edited by Susan O’Brien and John G Gribben 301 pp. New York, Informa Healthcare.2008. ISBN-13: 978-1-4200-6895-5

Chronic lymphocytic leukemia (CLL) is a fast changing field. There can be few hematologists who still see it as the boring condition that I was brought up on. A new understanding of the nature of the disease, better delineation of its limits and more effective treatments that have supplanted chlorambucil, the fifty-year old stand-by, have all attracted the interest of serious scientists and high-flying physicians. This volume, largely written by the generation that came after me, presents an effective summary of the state of play in 2008, but, make no mistake, other books on this topic will surely follow since there are many questions as unanswered now as when I first took an interest in the disease some forty years ago.

The normal-cell equivalent that the leukemia derives from is still unknown. Analogies with the mouse have often been misleading and any particular candidate-cell has no more justification for its status than any other, save for the enthusiasm of those who espouse it. The recent understanding that a quarter of patients with CLL have B-cell receptors shaped according to a small number of stereotypes, suggests a common antigenic stimulus, but raises further questions as to how an immune response can be transformed into malignant growth.

If we think back to 1975, when Kanti Rai introduced his staging system, to diagnose CLL you needed a lymphocyte count of 15,000 /microlitre. As immunophenotyping became secure, the threshold reduced to 5000 /microlitre, but this resulted in many people being diagnosed with the condition whose clinical features and outcome were most un-leukemia-like. The latest guidelines from the International Workshop on CLL require in excess of 5000 /microlitre of monoclonal B lymphocytes for the diagnosis – if there are fewer then the diagnosis of monoclonal B lymphocytosis (MBL) is made. Although this largely restores the position of 1975, the figure of 5000 is quite arbitrary and the exact relationship between CLL and MBL is a matter of ongoing research. Furthermore, much of the current understanding of CLL reflects experience with a threshold of 5000 lymphocytes; this will have to be reviewed with the new threshold.

Other unsolved puzzles include why immunity against infectious agents diminishes while immune attacks against self increase and why the disease transforms to an aggressive form sometimes derived from tumor cells but sometimes from apparently uninvolved normal B cells.

In January last year we were informed by a commercial website that the German CLL Study Group CLL8 trial had fulfilled its primary endpoint at the first interim analysis. Although the results of this trial have still to be published in a peer-reviewed journal, it was immediately clear to the cognoscenti that adding rituximab to the combination of fludarabine and cyclophosphamide improved significantly progression-free survival. This result is a vindication for doctors at the MD Anderson Cancer Center in Houston, Texas who have eschewed randomized clinical trials in this area and instead have pursued a series of Phase II studies relying on historical comparisons. It should raise questions for regulators who have insisted on Simon-pure studies before approving new drugs. Most patients and many US physicians have been convinced of the value of the fludarabine, cyclophosphamide and rituximab combination even though until now there has been no formal proof of its superiority. Even now there is no evidence that this combination improves overall survival, but surely this will come as the German study matures.

John Byrd’s remarkable chapter lists 107 agents in early stage trials for the treatment of CLL. Simple arithmetic tells us that patients do not have enough time for conventional trial progression to deliver the best of these to the clinic.


Burke said...

Dr. Hamblin,

In the past, I've gotten the impression that you regard the practice of relying on Phase II trials as reckless and profit-driven.

Have you changed your outlook?

Anonymous said...

Dr. H,

Glad to hear that you feel better.

What to do you mean by "aggressive disease developing from apparently normal B cells"?

Take care,


Brian Koffman said...


I am always hesitant to buy a textbook on such a fast moving topic as CLL. You do make it sound worthwhile.

Be well


Anonymous said...

Dr. Hamblin

Do you still recommend chlrambucil as fisrst line treatment instead of FCR because of the toxicity associated with FCR?

Anonymous said...

Dr Hamblin

What is your opinion today of using chlorambucil as first line treatment?

Terry Hamblin said...

Being on the receieving end of treatment certainly changes one's perspective. Clearly, the best way of finding an answer is to do proper comparisons with well designed randomized controlled trials, and I certainly still blame the companies for doing the wrong trials at the wrong times in such a way that it favors their share price.

The drug that many CLL sufferers around the world have missed out on is not fludarabine, but rituximab. FCR is the best current approach if elimination of disease is the treatment strategy, but it seems that some patients live a normal lifespan without symptoms on lesser aims than that. What is the point of trying to cure an 85 year old of a disease that will take 20 years to kill them, especially if the 'curative' treatment has a risk of killing them in the first year? Obviously the age of teh patient, the comorbidities and the reate of progression of the leukemia must all be taken into account when deciding on treatment. However, it seems that adding rituximab to any sort of treatment is probably going to be beneficial.

Chlorambucil still has a place for some people, and I am not so convinced that fludarabine is a better option given the side effects of the latter.

Given that 107 new agents are currently in early stage trials, I don't think we have time to find out enough about them all by Phase III trials, let alone their combinations. We need to devise a better way of bringing these drugs to market quickly. I gave FCR for the first time 7 years ago, but was prevented from giving it to most of my NHS patients because there had been no randomized controlled trial.

"aggressive disease developing from apparently normal B cells" refers to Richter's syndrome. Between a quarter and a half of all cases arise in normal lymphocytes as a totally separate malignancy to the CLL. My own suspicioin is that these are consequent on the immunodeficiency, and more likely to occur in patients who have had fludarabine or Campath.

Anonymous said...

Take good care Terry. You have tremendous support from so many people. And please believe one who knows.....chemo is not quite as bad as what you are imagining it to be. Sending you positive TEXAS YeHaws!

Jenny Lou Park