Incidence of Secondary Myelodysplastic Syndrome/Acute Leukemia in 1,266 Lymphoma Patients Following High-Dose Therapy and Autograft: A Study from GITIL (Gruppo Italiano Terapie Innovative nei Linfomi).
Authors: Zanni Manuela , Magni Michele , Rambaldi Alessandro , Benedetti Fabio , Rosato Rosalba , Passera Roberto , Patti Caterina , Ciceri Fabio , Gallamini Andrea , Cortelazzo Sergio , Majolino Ignazio , Mirto Salvatore , Corradini Paolo , Boccadoro Mario , Andreini Angelo , Barbui Tiziano , Gianni Alessandro M. , Tarella Corrado 
Published: October 2019

Abstract
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 malignancies, particularly myelodysplastic syndrome/acute leukemias (sMDS/AL), is a critical issue, representing a major cause of failure in patients potentially cured after hd-chemotherapy.
Aim of the study. To evaluate: frequency-cumulative incidence-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 1,266 lymphoma patients treated in the last two decades at 10 Centers, associated to GITIL. All patients received either the original or modified HDS regimens with autograft; PBPC were usually collected after hd-cyclophosphamide, or, in a subgroup, after a 2nd round of mobilization, with hd-Ara-C. The series included 213 HL and 1,053 NHL (423 low-grade); median age was 46 yrs; 57% were male. Overall, 595 (47%) patients received HDS front-line, and 671 patients as salvage treatment. Most patients were autografted with PBPC (median CD34+ cells: 8×106/kg), few patients received BM cells; 158 (12%) patients were unable to complete the program with autograft; among 1,108 autografted patients, a TBI-conditioning regimen was employed only in 79 patients. All patients have been monitored during routine follow-up; phenotypical and cytogenetic studies were usually employed to characterize sMDS/AL.
Results: At a median follow-up of 5 yrs, Overall Survival (OS) projections at 5 and 10 yrs are, respectively: 64% and 55% for the whole series, 72% and 63% for patients treated at diagnosis, 56% and 47% for those receiving salvage HDS. Overall, 38 (3%) patients developed s-MDS/AL, with a cumulative incidence of sMDS/AL of 4.2% at 5 yrs. Median time of s-MDS/AL occurrence was 2.2 yrs since autograft. Several clinical parameters, including age, sex, histology, disease status, BM involvement, were assessed and found negative for possible association with sMDS/AL occurrence; patients autografted with PBPC of the 2nd round of mobilization had a higher risk of sMDS/AL development compared to those autografted with PBPC of the 1st collection; on multivariate analysis, this was the only parameter associated, marginally, with sMDS/AL occurrence (OR 1.93, c.i. 0.92–4.05, p=0.08).
Conclusions. Overall, the incidence of sMDS/AL observed following HDS is among the lowest reported so far in lymphoma patients treated with hd-therapy and autograft; the large quantities of CD34+ cells employed for autograft and the preferential use of TBI-free conditioning regimens might have lowered the risk of sMDS/AL. In addition, the study suggests that the type of graft employed may be critical for sMDS/AL development.