Historically, myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia have been recognized as significant complications of alkylating-agent-based chemotherapy for both indolent NHL and Hodgkin's lymphoma.1112 Topoisomerase inhibitors13 and purine analogs14 also clearly contribute to the risk of AML and MDS. With the recent introduction of alternative chemotherapy and immunotherapeutic modalities, autologous stem cell transplantation (ASCT) and radioimmunotherapy represent the lymphoma treatment modalities with the highest risk of developing MDS. In fact, MDS and AML have emerged as the major late complications of ASCT in patients with lymphoma.15 In this setting, these disorders have an exceedingly poor prognosis, and represent the leading cause of non-disease-related death in survivors of ASCT for lymphoma.
The true incidence of MDS after nonmyeloablative radioimmunotherapy with either iodine-131 tositu-momab16 (Bexxar, GlaxoSmithKline, Philadelphia, and Corixa, Seattle) or Y-90 ibritumomab tiuxetan17 (Zevalin, BiogenIdec, Cambridge) remains to be defined. In an analysis of 773 patients treated with I-131 tositumomab, 21 patients have developed MDS thus far, with an annualized incidence of 1.45%/year, which compares favorably to patients treated with alkylating agent chemotherapy.18 The incidence of MDS after Y-90 ibri-tumomab tiuxetan appears to be similar. However, long-term follow-up of large cohorts of patients is clearly required to definitively determine the incidence of this fatal complication in the modern treatment era of indolent lymphoma, and the degree to which radioimmunotherapy contributes to this risk.
There is a substantially greater understanding of clinical risk factors for subsequent development of MDS after ASCT for lymphoma. It is expected that these risk factors may be similar in patients treated with radioim-munotherapy. Acknowledging differences in methods used to identify cases and to estimate the cumulative incidence over time, up to 10% of NHL patients treated with ASCT may develop secondary MDS within 10 years of primary therapy.19 The majority of published studies are single-institution experiences. Important considerations in the interpretation of these studies are length and quality of patient follow-up, definition of MDS, and uniformity of treatment regimens. As expected, risk factors may differ between studies; however, the incidence over time in most studies is strikingly similar. Unlike secondary MDS from chemotherapy alone, the incidence post-ASCT appears to remain stable over time, without evidence of a plateau on the Kaplan-Meier curve.20
A representative series from the Dana-Farber Cancer Institute evaluated the risks and outcome of MDS in 552 patients with NHL receiving a standard conditioning regimen of 1200-1400 cGy total body irradiation (TBI) and cyclophosphamide, followed by monoclonal-antibody-purged ASCT with marrow as graft source. In this series, 41 patients developed MDS, strictly defined, a median of 47 months (range 12-129) from ASCT.21 At the time of diagnosis of MDS, 29 patients were in remission and 12 patients had relapsed with NHL; the majority of these patients had not received further cytotoxic therapy since transplant. The absolute risk of developing MDS after ASCT for NHL was 7.4%. The cumulative risk of development of MDS was 14.5% at 10 years posttransplant.22 In a logistic regression model, low number of stem cells infused per kilogram and prior localized irradiation were the only significant predictors of developing MDS.
The specific role of TBI conditioning in the development of MDS has been assessed by several other studies. Almost 5000 patients with lymphoma have undergone ASCT in the European Bone Marrow Transplant Registry, with 68 patients developing MDS.23 This incidence is lower than other series, perhaps as a consequence of underreporting of this complication. The median follow-up from the date of transplant was 6.7 years for patients who developed MDS, but only 2.9 years for the patients without MDS. Multivariate analysis revealed age at transplant, exposure to TBI in conditioning, long interval between diagnosis of lymphoma and transplant, and indolent histology as independent variables predicting for subsequent MDS. For patients with Hodgkin's lymphoma, female gender was identified as a risk factor. The amount of previous chemotherapy, including cumulative alkylating agent exposure, was not found to be a significant factor.
In a case-control study of 56 patients with MDS/AML after ASCT for lymphoma, and 168 matched controls who also underwent ASCT for lymphoma but did not develop MDS/AML, the separate contributions of pretransplantation and transplantation-related therapy were assessed.24 The intensity of pretransplant therapy did contribute to the risk of developing MDS. Transplant factors, including high-dose TBI, and peripheral blood stem cells as graft source also appeared to contribute to the risk of MDS.
It is therefore not possible to establish whether the increased risk of MDS in patients with lymphoma is truly a disease-related phenomenon, or secondary to other fac tors such as a tendency to use more TBI for conditioning, or exposure to high doses of alkylating agents pretransplant. The risk of MDS following ASCT for multiple myeloma25, breast cancer,26 27 and germ cell tumors28 appears to be less than that in similar populations of patients with NHL following ASCT. Reported risks of developing MDS after autotransplantation for Hodgkin's lymphoma are varied, with some studies suggesting a lower risk than in similar patients with NHL following ASCT,29-31 and others reporting a similarly high risk.32 Confounding most of the studies of Hodgkin's lymphoma is the use of mechlorethamine prior to transplantation, which may have a more profound effect on the development of MDS than the transplant itself has.2431 Standard, modern regimens for Hodgkin's lymphoma clearly have significantly less risk. Between 1981 and 1998, the German Hodgkin Study Group treated 5411 patients,33 of whom only 46 patients developed MDS/AML at a median follow-up of 55 months. Similar
MDS/AML after ASCT for NHL and HL
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