Figure 25.1 Chronic lymphocytic leukemia. Survival of a large series of 0.0

patients from the Hospital Clfnic, Barcelona, according to Binet's clinical stages


The mutational status of IgVH genes separates CLL into two forms with distinct presenting features and outcome. Thus, as compared to those with IgVH mutations, patients with unmutated IgVH genes have a more malignant disease, including evidence of advanced, progressive disease, atypical cell morphology, adverse cytogenetic features, and resistance to therapy.24-26 The prognostic significance of IgVH mutations is independent from that of clinical stages and cytogenetic abnormalities. Unfortunately, studying IgVH mutations is not yet possible on a routine basis, hence the interest in finding a surrogate for IgVH mutations easily applicable in clinical practice. CD38 expression on leukemic lymphocytes correlates, although not absolutely, with IgVH mutations; moreover, CD38 expression may vary over time.27 Recently, it has been demonstrated that ZAP-70 expression on leukemic cells, as evaluated by cytofluorometry or PCR, strongly correlates with IgVH mutations and has important prognostic significance by itself. The expression of ZAP-70 in more than 20% of neoplastic lymphocytes correlates with unmutated IgVH genes and conveys a poor prognosis.28-31 It has also been shown that high expression of activation-induced cytidine deaminase mRNA is associated with unmutated IgVH gene status and unfavorable cytogenetic aberrations in CLL32; however, the clinical applicability of this test has not yet been established.

Besides findings at diagnosis, evolutive features are also important in prognosis. In about 3-10% of patients, the disease undergoes transformation into a more aggressive type, most commonly large-cell lymphoma (Richter syndrome), which is usually revealed by fever, weight loss, night sweats, enlarged lym-phadenopathy, and increased LDH serum levels.33-35 The prognosis of such an event is poor, with a median survival of less than 6 months.

Patients with CLL may also experience transformation into prolymphocytoid leukemia (PL), in which larger lymphocytes (prolymphocytes) coexist with small, typical CLL cells; the prognosis of the so-called CLL/PL is poorer than that of the typical CLL.36

In addition, the outcome of patients with CLL can be blurred by the appearance of second malignancies to which patients with CLL are prone.3738 Risk assessment, however, is not easy because of the variability in the criteria used to evaluate it. In a study based on data from population-based cancer registries, the observed/ expected ratio was 1.20, with an increased risk for Kaposi sarcoma, malignant melanoma, larynx cancers, lung cancer, and also bladder and gastric cancer in men. No relationship was found between the characteristics of the disease and its treatment with the incidence of second cancers.37 Recently, cases of myelodys-plasia/acute leukemia have been reported in patients treated with chlorambucil and fludarabine39; because of the increasing use of purine analogs in combination with other agents in CLL therapy, physicians should be alert to this possible complication.

Hypogammaglobulinemia may be observed in up to 60% of the patients with advanced disease, and contributes to the increased risk for infections, occasionally opportunistic, that patients with CLL may present and that are the most important cause of death.40'41

Patients with CLL may also develop AIHA, which can be triggered by treatment; although it usually responds to corticosteroids, some fatal cases of AIHA have been reported.42

As previously discussed, response to therapy is an important prognostic parameter in itself,7-943-45 the higher the degree of response the better the outcome. Thus, the patients who achieve MRD-negative status have a better prognosis than those with inferior response to therapy, including those in CR by classical criteria but with persistence of MRD.9 In addition, the detection of MRD predicts clinical relapse with the exception of patients submitted to allogeneic transplantation, thus reflecting the importance of a graft-versus-leukemia effect in such a context.4647

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