The Risk of Secondary Myelodysplastic Syndrome/Acute Leukemia Following Intensive Therapy and Autograft Correlates with the Type of Cells Grafted: A Survey on 1,347 Lymphoma Patients Receiving the High-Dose Sequential (HDS) Program.

Introduction. High-dose (hd) therapy with stem cell autograft is an effective treatment for both non-Hodgkins (NHL) and Hodgkins Lymphoma (HL). However, the occurrence of secondary myelodysplastic syndrome/acute leukemia (sMDS/AL) is a critical issue, representing a major cause of failure in patients potentially cured after hd-therapy. Aim of the study. To evaluate incidence and risk factors of sMDS/AL in a large series of lymphoma patients, treated with the hd-sequential (HDS) chemotherapy approach, followed by peripheral blood progenitor cell (PBPC) autograft.

Patients and Methods. Data have been collected on 1,347 lymphoma patients treated in the last two decades at 11 Centers, associated to GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). The series included 234 HL and 1,110 NHL (276 low-grade); median age was 46 yrs; 771 were male; 640 (47.5%) patients received HDS front-line, 707 as salvage treatment. All patients received either the original or the modified HDS regimen: 152 (13%) patients were unable to complete the program with autograft; among 1,171 autografted patients, only 79 received a TBI-conditioning regimen. Nearly all patients (97%) were autografted with PBPC (median CD34+ cells: 8 × 10⁶/kg), only a few received BM cells; PBPC were usually collected after hd-cyclophosphamide, or, in a subgroup (28%), after a 2^nd round of mobilization, with hd-Ara-C; there were no significant differences in the amount of infused cells between PBPC of the 1^st vs. the 2^nd mobilization course. HDS was supplemented with Rituximab in 525 (39%) patients.

Results. At a median follow-up of 5.5 yrs, Overall Survival projections at 5 and 10 yrs are, respectively, 62% and 54% for the whole series, 69% and 61% for patients treated at diagnosis. Overall, 46 (3.4%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 3.2%, 4.7% and 8.4% at 5, 10 and 20 yrs, respectively. Median time of s-MDS/AL occurrence was 35 months since autograft. In competing risk univariate analysis, a few clinical parameters, including age > 45 yrs, male sex, advanced stage, Rituximab administration, autograft with PBPC of 2^nd round of mobilization, displayed a variable increase in the cumulative incidence of sMDS/AL; however, on multivariate analysis, only male gender and reinfusion of PBPC of the 2^nd mobilization course were associated with sMDS/AL occurrence (SDHR: 2.93, p=0.007 for male gender; 2.54, p=0.004 for graft with PBPC collected at the 2^nd round).

Conclusions. Overall incidence of sMDS/AL in HDS-treated patients is analogous to that reported in other recent surveys on lymphoma patients treated with hd-therapy and autograft, with a higher risk recorded among males; furthermore, the study suggests that the quality of CD34+ve cells employed for autograft may be critical for the post-graft development of sMDS/AL.