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© 2003 American Society for Clinical Oncology
In Reply:Veterans Administration Medical Center, Minneapolis, MN As noted by Dr Astrow,1 we are reminded of the significance of therapy-related dysplasias in patients with lymphoproliferative disorders. Last year, we reported the occurrence of therapy-related myelodysplastic disorders (t-MDS) and therapy-related acute myeloid leukemia (t-AML) in a series of patients with chronic lymphocytic leukemia (CLL), who received initial cytotoxic therapy on an intergroup trial.2 In this series, five of six cases of t-MDS or t-AML occurred in patients treated with concomitant fludarabine and chlorambucil. The remaining case occurred in a patient who received single-agent fludarabine therapy, followed by chlorambucil with prednisone. These findings raised the possibility that combination purine analog-alkylator therapy may increase the risk of therapy-related dysplasias. However, similar findings of t-MDS or t-AML have not yet been forthcoming from either large single-institution, or cooperative group trials of therapy with fludarabine plus cyclophosphamide for CLL. Ideally, longer periods of follow-up are warranted in these trials to observe patients for this complication. For more than two decades, fludarabine has been used for the therapy of patients with a variety of lymphoproliferative disorders. However, reports of second malignancies have generally not included therapy-related dysplasias.3 In the case of t-AML reported by Astrow, the patient developed this disorder after therapy with fludarabine followed by rituximab for a nodular mixed non-Hodgkin’s lymphoma (NHL). Similar to some cases that we reported, cytogenetic analysis of bone marrow was not performed initially at the diagnosis of lymphoma, though cytogenetics at the time of transformation to t-AML revealed an abnormality on chromosome 7, typical of a therapy-related dysplasia. Since our initial report, anecdotal cases of t-MDS and t-AML following fludarabine therapy have been reported. A case of a probable fludarabine-induced t-MDS in a patient with low-grade NHL was described by Misgeld et al.4 In this patient, marrow findings compatible with t-MDS were found approximately 18 months after initiation of fludarabine therapy. Cytogenetic findings at this time revealed deletions in chromosomes 5 and 7. Two cases of t-MDS have also been reported from England, occurring approximately 9 months after therapy with fludarabine and cyclophosphamide (S. Basu, personal communication, September 2002). Among 492 patients with NHL who underwent high-dose therapy followed by autologous bone marrow transplantation from a single-institution series, 22 cases of t-MDS or t-AML were reported.5 In this report, prior fludarabine therapy was found to be a significant risk factor for the development of this complication in a univariate analysis. Finally, in our recent report of 104 patients with CLL receiving initial therapy with either concurrent or sequential fludarabine-rituximab therapy, to date, no cases of t-MDS or t-AML have been reported.6 Several cases of lymphomatous transformation following fludarabine therapy have also been reported recently. Cohen et al7 noted the occurrence of large-cell transformation of CLL or follicular NHL in nine patients either during or shortly after therapy with fludarabine + rituximab–containing regimens. Likewise, Abruzzo et al8 reported five cases of Epstein-Barr virus–positive B-cell lymphoproliferative disorders arising in patients with either CLL or splenic marginal zone lymphoma who received fludarabine therapy; three of these patients also received campath-1H. These disorders were diagnosed from 2 to 12 months after completion of fludarabine therapy, and were morphologically like lymphoproliferative disorders occurring in the posttransplant setting. In addition, two cases of aggressive epithelial carcinomas following treatment with either fludarabine or 2-chlorodeoxyadenosine for CLL and hairy cell leukemia, respectively, were reported by Larsen et al.9 The authors postulated that the T-cell depletion caused by these agents accounted for the aggressive clinical course of these epithelial malignancies. These reports underscore the importance of evaluating various aspects of outcome when new therapies for lymphoproliferative disorders are examined. The traditional outcome parameters of response rate, remission duration, and survival will remain of primary importance in future therapeutic trials. However, infectious complications have certainly been demonstrated to be of significance in the utilization of purine analogs or agents such as alemtuzumab. Lastly, as shown by Astrow and others, the impact of late effects, particularly second malignancies such as t-MDS and t-AML, must also be considered in the more widespread use of agents such as fludarabine, either as a single agent or as part of a combination regimen, in the therapy of lymphoproliferative disorders. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Astrow AB: Fludarabine-related myeloid leukemia. J Clin Oncol 21: 3709, 2003
2. Morrison VA, Rai KR, Peterson BL, et al: Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: Results of an intergroup study — Cancer and Leukemia Group B 9011. J Clin Oncol 20:3878–3884, 2002
3. Keating MJ, O’Brien S, Lerner S, et al: Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy. Blood 92:1165–1171, 1998 4. Misgeld E, Germing U, Aul C, et al: Secondary myelodysplastic syndrome after fludarabine therapy of a low-grade non-Hodgkin’s lymphoma. Leuk Res 25:95–98, 2001[CrossRef][Medline]
5. Hosing C, Munsell M, Yazji S, et al: Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma. Ann Oncol 13:450–459, 2002
6. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6–14, 2003 7. Cohen Y, Da’as N, Libster D, et al: Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine-rituximab-containing regimens: Natural history- or therapy-related complication? Eur J Hematol 68:80–83, 2002[CrossRef][Medline] 8. Abruzzo LV, Rosales CM, Medeiros LJ, et al: Epstein-Barr virus-positive B-cell lymphoproliferative disorders arising in immunodeficient patients previously treated with fludarabine for low-grade B-cell neoplasms. Am J Surg Pathol 26:630–636, 2002[CrossRef][Medline] 9. Larsen CR, Hansen PB, Clausen NT: Aggressive growth of epithelial carcinomas following treatment with nuceloside analogues. Am J Hematol 70:48–50, 2002[CrossRef][Medline]
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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