Second Cancers after Autologous Hematopoietic Stem Cell Transplantation (ASCT) for Relapsed/Refractory Aggressive Non-Hodgkin’s Lymphoma (NHL).
Authors: Seshadri Tara , Pintilie Melania , Tsang Richard , Kuruvilla John , Zadeh Sahar , Keating Armand , Crump Michael 
Published: April 2020

Abstract
ASCT results in long-term disease free survival for approximately 40–50% of patients (pts) with relapsed−/− refractory aggressive NHL who respond to second-line chemotherapy. The incidence of second cancers (SC) in long-term survivors and risk factors in this pt population has not been well studied. We performed a retrospective analysis of 372 pts undergoing ASCT at our institution from May 1987 to Dec 2006 for relapsed−/− refractory aggressive NHL after primary therapy. Second-line chemotherapy was given to best response, followed by high dose therapy for pts with chemotherapy-sensitive disease. Intensive therapy was melphalan 180mg/m2 + etoposide 60mg/kg in 86%; regimens including total body irradiation (TBI) 12 Gy were received in 16%. Stem cell source: autologous bone marrow (27%), peripheral blood (63%) or both (10%); 7% received post-ASCT involved field RT to sites of bulky disease. Estimates of SC risk were determined adjusting for competing risks. The incidence of SC was compared to the general population in Ontario from 1987 to 2002. Of 372 pts, 59% had diffuse large B cell lymphoma, 24% transformed from prior indolent NHL, 16% T cell lymphoma, 1% undefined aggressive NHL. Median age at ASCT was 50 years (range 19–70); female 44%. The majority of patients (74%) received 2 chemotherapy regimens prior to ASCT (range 1–8); all pts with de novo DLCL received CHOP or equivalent regimen as primary therapy. For first salvage therapy cytarabine/platinum combinations were used in 205 (55%) pts, miniBEAM (melphalan, etoposide, cytarabine, BCNU) in 40 (11%), gemcitabine/dexamethasone/cisplatinum in 37 (10%); CHOP or equivalent was used in 42 pts (11%). Median follow up is 4.3 years and 27/185 (15%) have been followed more than 10 years. 184 pts (49%) have experienced disease relapse and 32 (9%) have developed a SC (17 MDS/AML, 13 solid tumors, 1 chronic lymphocytic leukemia and 1 acute lymphoblastic leukemia). During the follow up period 187 (50%) patients have died (126 from relapsed lymphoma, 30 from treatment-related toxicity, 14 from second cancer, 5 unrelated medical condition, 7 unknown). The probability of SC is 5% (95% CI: 3%-8%) 3 years post-ASCT and 14% at 10 years (95%CI: 10%-20%). Age at ASCT, sex, receipt of TBI, number of chemotherapy regimens, prior RT, graft source and lymphoma subtype were not associated with development of a second malignancy. Use of miniBEAM as part of salvage therapy was significantly associated with the development of a second cancer (p=0.001). The incidence of malignancy in survivors of ASCT is 32 per 1180 person years of follow-up. When compared to the general population (AML and solid tumors only) the relative risk (RR) for developing AML or a solid tumor is 13.5 (p&lt;0.0001, 95% CI 5.4–27.8) and 2.4 (p=0.0013, 95% CI 1.3–4.0) respectively. The risk of developing a SC in pts treated with ASCT for relapsed aggressive NHL is substantially higher compared to the general population. Second cancers appear to develop both in the early and late post ASCT period and contribute to late mortality. Our observation of an unexpected increased risk of SC in ASCT patients receiving prior miniBEAM salvage suggests that the contribution of other salvage regimens to late adverse effects after ASCT warrants further investigation.