Immune-Mediated Anemias and CLL: Who Gets It? What To Do?
Immune-Mediated Anemias and CLL: Who Gets It? What To Do?
Abstract & Commentary
By William B. Ershler, MD, Editor, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC.
Synopsis: Chronic lymphocytic leukemia is occasionally associated with hemolytic leukemia or pure red cell aplasia. In a series of 300 patients treated at MD Anderson with a combination of fludarabine, cyclophosphamide and rituximab, 6.5% developed one or the other of these conditions. Pre-treatment beta-2 microglobulin was the single laboratory measure that was significantly associated with the development of immune-mediated anemia. In general, treatment with steroids or other immunosuppressive measures was successful.
Source: Borthakur B, et al. Br. J Haematol. 2007;136:800-805.
Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are clinical manifestations of immune mediated cytopenia that occur with some frequency in association with chronic lymphocytic leukemia.1 Furthermore, the single most active agent for treatment of CLL, fludarabine, itself, has been implicated in the pathogenesis of hemolytic anemia in at least some CLL patients.2 In contrast, rituximab and cyclophosphamide have both been used to treat AIHA. Thus, there was rationale for the combination of fludarabine, rituximab, and cyclophosphamide for treatment for CLL with a reasonable expectation that there would be reduced immune cytopenia.
Over a five-year period at a single institution (MD Anderson Cancer Center in Houston) 300 patients with chronic lymphocytic leukemia requiring therapy were treated on a protocol that included these three agents. The details of this trial were previously reported3 and consisted of day one rituximab (375 mg/m2). The dose of rituximab on day one of subsequent cycles was 500 mg/m2. On days two, three, and four in the first cycle, and on days one, two, and three on subsequent cycles, the patients received fludarabine 25 mg/m2 per day and cyclophosphamide 250 mg/m2 per day, intravenously. A total of six cycles were planned.
Of the 300 patients who were treated with the FCR regimen, nine had shown evidence of immune anemia (eight with hemolytic anemia and one with pure red cell aplasia) prior to the start of therapy. An additional 19 patients developed immune anemia (hemolytic anemia in 17 and PRCA in two) on or after therapy with FCR. Eleven of the 28 patients with CLL and AIHA or PRCA required transfusion.
The diagnosis of AIHA was based on a hemoglobin of less than 10 g/dL and a positive direct antiglobulin test (DAT) in the absence of evidence for bleeding. For patients in whom the DAT was negative, the diagnosis was also considered on the basis of a hemoglobin of less than 10 g/dL and the presence of at least two indicators of hemolysis (increased indirect bilirubin, absolute reticulocyte count, LDH, and reduced haptoglobin) in the absence of evidence for bleeding. The diagnosis of PRCA was based on a hemoglobin of less than 10 g/dL, reticulocytopenia, and isolated absence of erythroid precursors in the bone marrow aspirate.
Twelve of the patients developed AIHA while receiving FCR chemotherapy and five developed the complication after completion of treatment. Of these 17 patients, seven responded to oral steroid treatment with a median duration of three months of steroid dosing. The remaining 10 patients required additional therapy; of these, two responded to cyclosporine whereas others required various combinations including intravenous immunoglobulin (IVIG), rituximab, erythropoietin, and splenectomy. FCR therapy was discontinued in patients who developed AIHA until resolution of the cytopenia.
High pretreatment levels of beta-2 microglobulin predicted the development of immune anemia. Other factors such as age, CLL stage, performance status, white blood count, or absolute lymphocyte count prior to treatment were not predictive. During treatment, no hemolytic crisis developed during FCR therapy in those eight patients with pre-existing AIHA. Thus, preexisting AIHA did not preclude frontline FCR therapy.
Commentary
Immune cytopenias are not uncommon in CLL, either at the time of presentation or after treatment, particularly with fludarabine. In this series, 6.5% of patients who were treated with FCR developed this complication. Thus, the initial hopeful expectation that the addition of cyclophosphamide and rituximab to fludarabine would reduce or eliminate immune anemias was not achieved. It was notable that 50% of the patients who developed AIHA were DAT negative. DAT has traditionally been considered a requisite for the diagnosis of CLL-AIHA and thus the 6.5% in this series may actually reflect a reduced incidence of treatment-related cytopenia. In this context, it is interesting to note that in a recent report of 14 patients with CLL and AIHA who received rituximab for treatment of the AIHA4, four patients converted from DAT positive to DAT negative after treatment.
An additional finding from the study of potential value for clinical oncologists is a rather robust finding that beta-2 microglobulin was a predictor for immune anemia development in patients with CLL. For those 19 patients who had immune anemia in this series, the beta-2 microglobulin was 6.1 mg/L (range 2.7 mg/L to 16.4 mg/L) compared to a level of 3.6 mg/L for the remainder of the patients who did not develop anemia. Thus, the beta-2 microglobulin serum assay may prepare the treating oncologist for vigilance regarding the development of immune-mediated anemia in patients with CLL undergoing treatments.
References
1. Diehl LF, Ketchum, LF. Autoimmune disease and chronic lymphocytic leukemia: autoimmune hemolytic anemia, pure red cell aplasia, and autoimmune thrombocytopenia. Semin Oncol. 1998;25(1):80-97.
2. Keating MJ, et al., Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood. 1998;92(4):1165-1171.
3. Keating MJ, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18): 4079-4088.
4. D'Arena G, et al. Rituximab therapy for chronic lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol. 2006;81(8):598-602.
Chronic lymphocytic leukemia is occasionally associated with hemolytic leukemia or pure red cell aplasia.Subscribe Now for Access
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