The challenge of treating complex autoimmune cytopenias in chronic lymphocytic leukemia

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The presence of hemolytic anemia (AIHA) and immune-mediated thrombocytopenia (ITP) poses a significant challenge in treating patients with chronic lymphocytic leukemia (CLL). Treatment with purine analogs has been known to induce autoimmune cytopenias, typically hemolytic anemia, but these occurrences are seen de novo as well. The pathophysiology of these autoimmune processes is believed to result from a defect or paucity of normal Tregulatory cells [1‐4]. Not only can the arrest of the autoimmune process be difficult, but its presence can preclude the use of purine analogs—arguably the most effective agents in the treatment of CLL itself. Although autoimmune cytopenias can present at any time in the disease course, they are more frequently seen in the later stages [5], making the requirement of treating both the CLL disease and a concomitant autoimmune process (‘complex autoimmune cytopenias’) a relatively common and difficult scenario. Purine analogs notwithstanding, overlap does exist between the treatments of immune cytopenias and CLL disease. Corticosteroids, and more recently rituximab and alkylating agents, have been shown to be effective in the treatment of AIHA and ITP; these agents are mainstays in the treatment of CLL itself. Recently, we published the results of a retrospective study using the combination of rituximab, cyclophosphamide, and dexamethasone (RCD) in 21 patients with CLL-associated immune cytopenias. The immune cytopenias in all of these patients responded, with a median duration of response of 22 months. Though this combination is effective in the treatment of CLL itself, we did not report on these results [6]. In this issue of Leukemia and Lymphoma, Bowen and colleagues report on 20 patients using the combination of rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) in the treatment of progressive CLL complicated by autoimmune cytopenias (complex autoimmune cytopenias) [7]. The response rates achieved for both the immune phenomena as well as the progressive CLL are promising. A substantial number of complete responses (CRs) in each condition were achieved as well. The small sample size and the relatively short durations of response are obvious limitations to both the study and the therapy. Despite the limitations, the work of Bowen and colleagues provides an important evidence-based recommendation for treating autoimmune phenomena and CLL simultaneously. To our knowledge, little or no evidencebased guidance in the literature exists for dealing with the practical challenge posed by ‘complex autoimmune cytopenias’ faced by clinicians treating CLL. Additional combinations and newer agents will likely prove useful in these patients. Antibodies affecting the autoimmune phenomena are believed to be polyclonal, and not directly originating from the CLL clone. Nevertheless, newer therapies targeting B-cells in CLL will also likely decrease the activities of the aberrant polyclonal B-lymphocytes. The recent approval of ofatumumab, and the fast-coming addition of other monoclonal agents targeting B-cell antigens, broaden the potential options for new approaches in complex autoimmune cytopenias.