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

Alkylating agent therapy does not cure patients with indolent lymphoma and can result in late morbidity such as treatment-related 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.^3-5  Recently, we combined rituximab with FND, either concurrently (R-FND) or sequentially (FND→R), followed by interferon alpha (IFN-α) 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.

From 1997 to 2003, 202 evaluable patients with stage IV indolent lymphoma were treated on this trial; all signed informed consent in accordance with the University of Texas M.D. Anderson Cancer Center institutional review board regulations and the Declaration of Helsinki. With a median follow-up of 42 months (range, 6-70 months), 8 patients have been diagnosed with t-MDS or treatment-related acute myeloid leukemia (t-AML).

The lymphoma protocol included FND for the majority of patients, either concurrently with rituximab or followed by rituximab. Patients also received IFN-α maintenance. The doses of FND were as follows: fludarabine 25 mg/m² intravenously days 1 to 3, mitoxantrone 10 mg/m² 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/m² 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/m² 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 FND→R, rituximab 375 mg/m² was given intravenously once monthly for 6 doses, starting at month 12.

Patients with follicular lymphoma without BCL2 gene rearrangement⁸  received alternating triple therapy (ATT) with concurrent rituximab, followed by maintenance IFN-α. 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/m²) were included with ATT: 2 in courses 1 and 3 and 1 dose in courses 4 and 6.

The diagnosis of t-MDS, using World Health Organization criteria,⁹  was considered when the bone marrow contained excess blasts (> 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 suspected. Cytogenetic data were reported using the International System for Human Cytogenetic Nomenclature (ISCN).¹⁰ 

The time to development of t-MDS was measured from the time of lymphoma therapy until the t-MDS diagnosis. The actuarial incidence was calculated by the method of Kaplan and Meier.¹¹ 

Eight of 202 patients developed t-MDS or t-AML (crude incidence 4%), as categorized in Table 1. In all cases, the t-MDS was first suspected based on cytopenias (n = 7) or overt leukemia (n = 1) on routine hematology survey. The median age of the MDS patients was 57 years (range, 42-75 years), with 3 males and 5 females. MDS was diagnosed a median of 32 months after the lymphoma therapy (range, 15-59 months). Figure 1 shows the actuarial incidence of t-MDS.

The initial lymphoma treatment for these 8 patients included R-FND for 5, FND→R for 1, and ATT+R for 2 (Table 1). Two R-FND patients who attained only partial remission received salvage therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) before developing t-MDS. The other 6 patients attained complete remission (CR) with the lymphoma therapy. One patient was still on IFN-α maintenance when MDS was diagnosed, 5 others were off therapy 12 to 40 months. Five patients were in ongoing CR from the lymphoma standpoint when the t-MDS was diagnosed.

All had cytogenetic abnormalities commonly seen following alkylating agent therapy, including abnormalities of chromosome 5 and/or 7 in 6 patients (Table 1). Two patients had del(12)(p11p12). None had abnormalities of 11q23.

The median survival after the development of AML or MDS was 9 months (range, 2-17 months).

Management options for indolent lymphoma are numerous. The risks of the lymphoma need to be weighed against those of the therapy. In our stage IV protocol, a risk-adapted approach was taken, with ATT reserved for those considered to be poor risk.⁸  MDS has been previously described following ATT.⁴ 

The risk of t-MDS in patients who received only FND, IFN-α, and rituximab was expected to be minimal. MDS has been described rarely following IFN-α,¹²  never with rituximab, and only infrequently with the nucleoside analogs or other antimetabolites.^2,13-16  Mitoxantrone is an intercalator and a topoisomerase II inhibitor, which has only infrequently been associated with MDS.¹⁷  MDS can occur following CHOP-like therapy,¹⁸  which is a potentially confounding factor in 2 of our patients who received R-CHOP salvage therapy; it is plausible to suspect that the primary therapy contributed to the risk of MDS in those cases.¹⁹ 

The cytogenetic abnormalities in these patients were complex (Table 1). Six patients had abnormalities of chromosome 7, as commonly observed following exposure to DNA-damaging agents. Two patients had del(12)(p11p12). Abnormalities of chromosome 12 are seen in a broad spectrum of hematologic malignancies, including in secondary leukemias after mutagenic agents, and are generally associated with a poor outlook.²⁰  The 11q23 abnormality, classically observed with topoisomerase II inhibitors, was not observed in our 8 cases.²¹ 

Fludarabine inhibits the DNA repair process, thereby enhancing the antineoplastic effect of an agent like cyclophosphamide.²²  This synergism has been exploited successfully in the treatment of chronic lymphocytic leukemia (CLL); an analogous synergism may exist for fludarabine and mitoxantrone. But there could also be augmented adverse effects. MDS has been reported following fludarabine plus chlorambucil for CLL.²³  Antitumor synergism exists between rituximab and several chemotherapeutic agents,²⁴  but rituximab selectively targets B cells so an impact on myeloid cells would not be expected.

The risk of t-MDS is calculated variably in the literature: crude incidence figures (4% in our report) underestimate the risk, whereas Kaplan-Meier plots (as in Figure 1) overestimate the risk.²⁵  Overall, up to 10% of lymphoma patients treated with standard chemotherapy may develop t-MDS.²⁵  Prolonged exposure to cytotoxic agents increases the risk. Patients in the current report received 6 to 8 courses of FND or 9 to 12 courses of ATT. Shorter-duration therapy might lessen the risk. Others who use 4 to 6 courses of FND and variants in the front-line setting have not noted a high frequency of t-MDS (E. Montserrat, J. Seymour, V. Jain, P.L. Zinzani, W. Hiddemann, S. Gregory, personal communications, July 2004). Since t-MDS following FND with or without rituximab and IFN-α appears to be infrequent, routine cytogenetic monitoring may not be warranted. But based on the current report, t-MDS occurring 1 to 5 years after therapy must be considered a risk of FND or R-FND plus IFN-α therapy, particularly if protracted treatment is given.

The authors thank Joyce Palmer-Brown for preparation and editing of the manuscript and Mark Hess for the Kaplan-Meier curves.