Change from stage A disease to stage B or C, or from stage B to C

At least one of the following: > 50% increase in the size of at least two lymph nodes or new palpable lymph nodes; > 50% increase of splenomegaly or hepatomegaly or appearance if there was no transformation to a more aggressive histology, Richter or prolymphocyte leukemia;> 50% increase in the absolute number or circulating lymphocytes.

CR = complete response; nPR = same as CR with presence of lymphoid aggregates in bone marrow biopsy; PR = partial response; SD = stable disease; PD = progressive disease.

represent either leukemic or nonneoplastic T cells. In other words, some patients considered to be in CR by current criteria can still harbor leukemic cells, whereas others who are deemed to be in partial remission (PR) may have achieved CR.

A step forward in evaluating the response in CLL has been the assessment of MRD by either allele-specific polymerase chain reaction (PCR) or four-color cytofluorometry, classical combinations being CD19/CD5/CD79b/CD20 or CD19/CD5/CD43/C20.3-5 However, these combinations are less effective in situations where leukemia cells lack CD20, e.g., in patients treated with combinations including rituximab. Antigenic combinations that circumvent that problem include CD79b/CD43/CD19/CD5; CD81/CD22/CD19/ CD5; and CD20/CD38/CD19/CD5.6 Although PCR has a slightly higher sensitivity than four-color cytofluo-rometry, both methods are similarly useful from the clinical point of view, and four-color cytofluorometry is cheaper and more widely applicable.

Analyzing MRD may be useful for assessing and monitoring the response to therapy. There is already proof that eradicating MRD results not only in longer freedom-from-progression but also longer survival,37-9 making the MRD eradication a desirable goal in CLL therapy.

Note that some patients considered in NCI-WG PR because of treatment-related cytopenias (normalization of peripheral blood cell counts is a requisite for CR in classical response criteria) may have achieved an MRD-negative status, and these patients have a better prognosis than those in CR by NCI-WG criteria but with persistent MRD.9 This indicates that MRD status may be more important than NCI-WG criteria to predict outcome after therapy.

A practical point is, therefore, that with the newer, more effective, but also more myelotoxic treatments, a time window of 2-3 months that would allow patients to recover from treatment-related cytopenias should be required before evaluating response and that treatment-related cytopenias should not necessarily disqualify for CR. Also, and more importantly, MRD-neg-ative CR should be incorporated as a new response category in the assessment of CLL therapy.

Another criticism to current response criteria is that the disappearance of immunologic abnormalities that may be present before treatment (e.g., hypogammaglobulinemia, autoimmune hemolytic anemia (AIHA), positive Coombs test) is not considered as a criterion for CR. This is not an easy issue since current therapies cause a profound immunosuppression and may trigger autoimmune phenomena.10 However, whether the outcome of patients in whom the immunologic abnormalities are corrected upon treatment is better than those in whom such abnormalities persist should be investigated.

Finally, the assessment of lymphadenopathy, splenomegaly, and hepatomegaly is made clinically both when assessing clinical stage and when evaluating response to therapy. The role of imaging studies (e.g.,

CT scans) in staging and response to therapy evaluation should be evaluated.

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