92 Hematological toxicity grades 3–4 were observed in 12 patients (41%), including grade 4 neutropenia in four (14%). Seventeen patients (59%) experienced grade 1–3 infection. All infections were successfully treated except for one old, frail non-responder who died of pneumonia after nine months. Three patients (10%) suffered herpes zoster reactivation, but Pneumocystis jirovecii pneumonia or infection grade 4 was not observed.

Fludarabine-induced warm-antibody AIHA did not occur, but three patients (10%) experienced a transient, mild exacerbation of CAD precipitated by infection. [39] and [92] The study was not designed to address the risk of myelodysplasia or late-occurring hematological malignancies. Although not specific

to nucleoside analogues, such late events have been reported after fludarabine-based therapy for WM. 90 This concern should not be IWR-1 concentration prohibitive to the use of the combination Akt inhibitor therapy, but lead to a balanced, individualized consideration of risk versus benefit. There seems to be a discrepancy between the restrictive attitude to pharmacological therapy for CAD often found in the literature and the real requirement for therapy.6 Recommendations to avoid medications may simply reflect the fact that in the past, treatment was ineffective. Underestimation of the severity of anemia and clinical symptoms in this particular patient population may also have influenced the attitudes. In selected patients, actually, the circulatory symptoms may be sufficiently disabling to justify therapy even if the hemolysis is fully compensated.[10] and [92] Some patients, however, do have a mild disease in which the anemia is slight and the

circulatory symptoms modest or absent. In consequence, CAD should not be regarded an indication for therapy in every patient, and the decision to treat should be based on an individualized Y-27632 2HCl assessment. Reasonable criteria for starting drug therapy are symptomatic anemia, transfusion dependence, and/or disabling circulatory symptoms.[10], [87] and [92] Corticosteroids should not be used to treat primary CAD.[6], [15], [31] and [69] Outside clinical trials, the fludarabine and rituximab combination should be regarded the most efficient treatment to date and should be considered in elderly patients requiring therapy if they are otherwise reasonably fit and have no relevant co-morbidity. The combination has proved useful even in patients non-responsive to monotherapy with rituximab.92 Given the toxicity, however, a balanced assessment of risk versus benefit should be undertaken in every case. In the occasional young patients as well as the very old and co-morbid ones, rituximab monotherapy should be considered first-line treatment. Those who relapse after having responded to rituximab as single agent therapy may, depending on an individualized assessment, receive another course of rituximab or proceed to combination therapy.