Ann Hematol (1992) 65:238-239

Annals of

Hematology 9 Springer-Verlag 1992

Letter to the editor

Severe autoimmune hemolytic anemia in a patient with chronic lymphocytic leukemia responsive to fludarabine-based treatment* S. Tosti, R. Caruso, F. D'Adamo, A. Picardi, M. Ali Ege, G. Girelli, F.R. Mauro, L. Maurillo, and S. Amadori Section of Hematology,Department of Human Biopathology,UniversityLa Sapienza, Rome, Italy Received July 14, 1992/Accepted September 18, 1992

S/r, Fludarabine is an analogue of adenosine monophosphate which is relatively resistant to deamination by adenosinedeaminase and selectively inhibits DNA synthesis [5]. Recent clinical investigations indicate that the drug has significant single-agent activity against various lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphomas. In two separate trials of previously treated patients with CLL, this agent was found to induce response rates (complete + partial remission) of 32~ and 48%, respectively [3, 4]. In previously untreated patients the overall response rate may be as high as 80%, with approximately one third of the patients achieving complete remission [5]. Major toxicity on the currently used low-dose schedules consists of transient myelosuppression and infection. Recently, Bastion et al. reported on the occurrence of severe autoimmune hemolytic anemia (AIHA) in two patients with advanced CLL undergoing treatment with fludarabine [1]. We describe here an additional patient with advanced CLL whose fludarabine-based therapeutic program was complicated by severe AIHA. V.T., a 47-year-old man, was diagnosed at our institution as having B-CLL, Rai stage 0, in October 1989. In January 1991, because of progressive lymphocytosis (84000/ram 3) and splenomegaly (10 cm below the costal margin), the patient was started on daily chlorambucil and prednisone. Four months later, despite a reduction in the number of circulating lymphocytes (20 700/mm3), a significant spleen enlargement was still present and the patient was enrolled on a more aggressive chemotherapy program consisting of monthly courses of fludarabine (25 mg/sqm/day for 5 days) and prednisone (40 mg/sqm/ day for 5 days). Before the start of this regimen hemo* Supported by C.N.R., Progetto Finalizzato A.C.R.O., Contract No. 92.02125.PF 39 Correspondence to: S. Amadori, Section of Hematology,Department of Human Biopathology,UniversityLa Sapienza, Via Benevento 6, 00161 Rome, Italy

globin was in the normal range (13 g/dl), and hemolysis tests, including the direct antiglobulin test (DAGT), were negative. Response to the combination of fludarabine and prednisone was satisfactory, with complete normalization of the peripheral blood and significant reduction of splenomegaly observed after four courses of therapy. The patient continued to improve until the end of the sixth course, when he developed a severe hemolytic anemia (Hb 4.8 g/dl) characterized by a positive DAGT for IgM + complement and a high reticulocyte count (443 000/ mm3). A 2-week trial of corticotherapy (2 mg/kg/day of prednisone) was promptly initiated, with no evident improvement of the hemolytic process. For this reason, a course of high-dose intravenous immunoglobulins (400 mg/kg/day for 5 days) was added to the steroid therapy, with a significant and rapid effect on the hemoglobin level (10.4 g/dl on day + 10). A bone marrow aspirate and biopsy, performed 3 weeks later, showed massive erythroid hyperplasia with less than 5~ mature lymphocytes. A slow tapering of the prednisone dose was then initiated, and this was followed in 2 weeks by a recurrence of hemolytic anemia (Hb 5.7 g/dl), which was not controlled by the prompt reinstitution of full-dose corticotherapy combined with a second 5-day course of high-dose intravenous immunoglobulins. Addition of azathioprine (200 mg/day) resulted in a steady increase of the hemoglobin level and normalization of DAGT in 4 weeks. As previously reported by Bastion et al. [1], we describe a new case of AIHA occurring in a patient with B-CLL responsive to treatment with fludarabine and prednisone. This autoimmune complication is observed in approximately 10o70-20~ of patients and can develop at any time during the clinical course of the disease [2]. In most cases autoantibodies are warm-reactive, polyclonal IgG directed at the Rh system, usually against the C antigen. Interestingly, these antibodies are not secreted by the malignant B lymphocytes. It is unclear why patients with B-CLL tend to develop AIHA or other autoimmune complications. The prevailing opinion at the present time is that the high incidence of autoantibody production is mostly related to an imbalance of the

239 helper and suppressor T-lymphocyte subsets. Patients with C L L usually exhibit at diagnosis an inversion of the physiologic ratio o f C D 4 + to CD 8+ cells in the peripheral blood. In addition, patients with C L L may have decreased helper and excessive suppressor T-cell activity. These abnormalities of cellular immunity might be further exacerbated by the therapeutic use of cytotoxic agents, including prednisone, or radiation therapy. Fludarabine is a highly active agent for CLL. Its selective cytotoxicity for lymphocytes causes profound lymphopenia, depleting normal T lymphocytes more markedly than B lymphocytes. In particular, C D 4 + cells appear highly susceptible to the cytotoxic action o f the drug. It is conceivable that during fludarabine therapy the characteristic T-cell dysfunction associated with C L L may be further aggravated, especially in responding patients, thus increasing the chance for an autoimmune complication such as A I H A to develop. The clinical observations reported both by the French investigators and by our group do suggest that the use of

highly effective lymphocytotoxic agents such as fludarabine might be associated with an increasing occurrence of autoimmune phenomena in patients with C L L or other indolent lymphoproliferative malignancies.

References 1. Bastion Y, Coiffier B, Dumontet C, et al. (1992) Severe autoimmune hemolytic anemia in two patients treated with fludarabine for chronic lymphocytic leukemia. Ann Oncol 3:171-173 2. Foon KA, Rai KR, Gale RP (1990) Chronic lymphocytic leukemia: new insights into biology and therapy. Ann Intern Med 113: 525-539 3. Grever M, Leiby J, Kraut E, et al. (1990) A comprehensive phase-I and -II clinical investigation of fludarabine phosphate. Semin Oncol 17 [Suppl 8]: 39-48 4. Keating MJ (1990) Fludarabine phosphate in the treatment of chronic lymphocytic leukemia. Semin Oncol 17 [Suppl 8]" 49-62 5. Keating M J, Kantarjian H, Talpaz M, et al. (1989) Fludarabine: a new agent with major acitivity against chronic lymphocytic leukemia. Blood 74:19-25

Severe autoimmune hemolytic anemia in a patient with chronic lymphocytic leukemia responsive to fludarabine-based treatment.

Ann Hematol (1992) 65:238-239 Annals of Hematology 9 Springer-Verlag 1992 Letter to the editor Severe autoimmune hemolytic anemia in a patient wit...
166KB Sizes 0 Downloads 0 Views