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.