The Frequency, Manifestations and Duration of Prolonged Cytopenias after First Line Fludarabine-Combination Chemotherapy for Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma

The combination of fludarabine with other cytotoxic agents or rituximab is established in the treatment of lymphoid malignancies, with well-recognised efficacy and short-term toxicity. However, the presence and significance of prolonged cytopenias after completion of treatment have not been thoroughly described. In addition, recent guidelines on the management of chronic lymphocytic leukemia (CLL) highlight the importance of delineating the cause of post-treatment cytopenias. In order to address this important and under-reported aspect of treatment outcome, we evaluated 61 patients with indolent non-Hodgkin lymphoma or chronic lymphocytic leukemia treated in our institution with fludarabine with or without other agents as their first-line cytotoxic therapy. Post-treatment cytopenias (defined as hemoglobin < 130 g/L, neutrophils < 2.0 × 109/L or platelets < 140 × 109/L) persisting longer than 3 months were found in 43% of patients. Increasing patient age was found to be the only predictive factor (p= 0.02), whereas the presence of pre-treatment cytopenias, dose delivered, and requirement for dose delay during treatment were not. Patients failing to achieve complete count recovery by 3 months were more likely to experience post-treatment complications (infection, transfusion requirement, and bleeding) (p=0.03). The median time to resolution of anaemia, neutropenia and thrombocytopenia was 7, 9, and 10 months respectively, and the median hemoglobin, neutrophil count and platelet count were 94 g/L, 0.94 × 109/L and 86 × 109/L, respectively. Persistent cytopenias at 3 months did not impact on overall survival at 36 months. Bone marrow biopsies revealed residual disease infiltration and autoimmune aetiology in only 4% and 11% of patients, respectively, and there was no typical morphological appearance in the remaining 85%. After the completion of first-line fludarabine-based combination therapy for CLL and NHL, persistent cytopenias are frequent and clinically significant. Although cytopenias tend to resolve over time, treating physicians should be aware of these factors when considering fludarabine combination chemotherapy and when documenting post-treatment response status in CLL.