It has long been recognized that chronic lymphocytic leukemia (CLL) may on the one hand adopt a benign aspect, scarcely troubling the patient over many years, or, on the other hand, may fiercely attack the patient, killing him (or, less commonly, her) within 2 years (1). The two clinical staging systems introduced a generation ago (2,3) have been important prognostically. We know there is no advantage in the early treatment of Binet stage A or Rai stage 0 disease. Nevertheless, about half of such patients will eventually progress and require treatment. Despite the recognition of numerous prognostic factors, it has not, hitherto, been possible to predict reliably at diagnosis which patients will progress and which will not.

An attempt was made 25 years ago (4) to separate CLL into two different tumors, one arising from a cell early in maturation (and thus expressing surface IgD) and being more malignant, and one arising later in maturation (and thus lacking IgD) and being more benign. Unfortunately, this distinction fell foul of the poor reagents available at that time. The anti-IgD that was used was of low avidity and therefore only reacted with cells that had plentiful surface immunoglobulin. Such cells are seldom found in CLL, and in retrospect all that was being asserted was that the leukemic phase of mantle cell lymphoma is more malignant than is CLL.

Recently, a reliable method of distinguishing subtypes of CLL by sequencing the immunoglo-bulin variable region genes and searching for somatic mutations has revealed two forms of the disease with very different prognoses (5,6). Again, the apparent difference between them is that one arises early in B-cell maturation and the other one later.

Both the Binet (3) and Rai (2) staging systems are of immense value, and for a whole generation they have been the cornerstones of treatment decisions. It is disappointing that they make no distinction between genders over what constitutes anemia and do not insist that cytopenias should be caused by bone marrow suppression before assigning them a malign influence. Nevertheless, without these systems we would not be certain that early CLL does not benefit from early treatment with chlorambucil (7).

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