Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha

Abstract

Treatment-related myelodysplasia (t-MDS IntroductionAlkylating agent therapy does not cure patients with indolent lymphoma and can result in late morbidity such as treatmentrelated myelodysplasia (t-MDS). 1 Alternatives to alkylators include biologic agents and purine nucleoside analogs, which have a low reported frequency of t-MDS. 2 The combination of fludarabine, mitoxantrone, and dexamethasone (FND) is an effective regimen for patients with indolent lymphoma. [3][4][5] Recently, we combined rituximab with FND, either concurrently (R-FND) or sequentially (FND3R), followed by interferon alpha (IFN-␣) maintenance, for patients with stage IV indolent lymphoma. Preliminary reports have described good short-term safety and efficacy of this program, including a 3-year failure-free survival rate of greater than 65% and a 3-year survival rate of 95%. 6,7 The current report describes the occurrence of t-MDS in 8 patients in this trial. The lymphoma protocol included FND for the majority of patients, either concurrently with rituximab or followed by rituximab. Patients also received IFN-␣ maintenance. The doses of FND were as follows: fludarabine 25 mg/m 2 intravenously days 1 to 3, mitoxantrone 10 mg/m 2 intravenously on day 1, and dexamethasone 20 mg orally or intravenously days 1 to 5, every 4 weeks for 8 cycles. In R-FND, rituximab 375 mg/m 2 was given intravenously on days 1 and 8 of course 1; in courses 2 to 5, it was given on day 1 only. Responding patients received maintenance with 3 million units/m 2 interferon alpha 2b subcutaneously daily on days 2 to 14 and dexamethasone 40 mg orally on days 1 to 3, given monthly for 1 year. In FND3R, rituximab 375 mg/m 2 was given intravenously once monthly for 6 doses, starting at month 12. Patients and methods PatientsPatients with follicular lymphoma without BCL2 gene rearrangement 8 received alternating triple therapy (ATT) with concurrent rituximab, followed by maintenance IFN-␣. ATT is a rotation of 3 regimens, CHOD-Bleo (cyclophosphamide, doxorubicin, vincristine, dexamethasone, bleomycin), ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin), and NOPP (mitoxantrone, vincristine, prednisone, procarbazine), for 12 courses (3-4 courses of each); doses have previously been reported. 4 Six doses of rituximab (375 mg/m 2 ) were included with ATT: 2 in courses 1 and 3 and 1 dose in courses 4 and 6. Diagnosis of t-MDS and t-AMLThe diagnosis of t-MDS, using World Health Organization criteria, 9 was considered when the bone marrow contained excess blasts (Ͼ 5%) or was dysplastic or when unexpected cytopenias occurred. Marrow assessment was done pretreatment and every 3 to 6 months if initially positive. However, neither pretreatment nor follow-up cytogenetic monitoring was part of the study design; cytogenetics was performed only when MDS was The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 U.S.C. section 1734. Statist...

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

“…26,27 However, the incidence of therapy-related myeloid neoplasms is significantly higher in the setting of fludarabine combination therapy. [13][14][15][16]26,28 It has been postulated that fludarabine inhibits DNA repair 29 and acts synergistically with DNA-damaging agents, such as cyclophosphomide. As a result, genetically altered stem cells may escape DNA integrity check and gain survival advantage in the setting of genotoxic therapy.…”

Therapy‐related acute lymphoblastic leukemia is more frequent than previously recognized and has a poor prognosis

“…2,5 Most secondary leukemias are myeloid, which represent 5% to 10% of all acute myeloid leukemia (AML). 1,2 In contrast, the occurrence of acute lymphoblastic leukemia (ALL) after CT/RT is rare; previous reports indicate that these represent 1.2% to 2.5% of adult ALL.…”

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial

“…49 The risk of sMDS/AL seems to rise with the use of novel regimens including fludarabine and/or rituximab. 50,51 It is commonly accepted that high-dose chemotherapy with autograft may increase the risk of sMDS/AL, although the incidences reported in different studies are variable, with actuarial risk ranging from 3 to 10% and even up to 20% at 10 years. [24][25][26] The discrepancy among studies can be explained by differences concerning patient inclusion criteria, source of hemopoietic cells for autograft, induction treatments and conditioning regimens.…”