Risk of Acute Leukemia Post-Autologous Stem Cell Tranplant (ASCT) for Hodgkin’s Lymphoma (HL) Depends on Choice of Salvage Chemotherapy and Use of Radiation.
Authors: Dhani N.C. , Roberts T. , Pintilie M. , Kuruvilla J. , Franke N. , Nagy T. , Tsang R. , Keating A. , Crump Michael 
Published: April 2020

Abstract
Background: Late treatment-related mortality (TRM) and second cancers (SC) have an important impact on the long-term outcome of patients (pts) with HL. The optimum salvage regimen (based on efficacy and acute and late toxicity) as part of second-line therapy with ASCT is not known. Pts undergoing ASCT are at high risk of both solid tumors and leukemia (Proc ASCO 2007 abstr #8016). We analyzed our single-institution data to determine the contribution of the components of salvage therapy to leukemia risk post-transplant.
Methods: From Dec 1986 to Nov 2005, 321 pts with relapsed/refractory HL after doxorubicin-based primary chemotherapy (+ involved/extended field radiation [RT]: 46%) received salvage chemotherapy to best response, followed by etoposide 60 mg/kg day-4 and melphalan 160–180 mg/m2 [day-3] supported by autologous bone marrow (46%), mobilized PBSCs (49%) or both (5%) [day 0]. 27% received involved field RT post-ASCT. Risk of treatment failure and second cancers was estimated using competing risks methods. Leukemia risk with time was determined by cumulative incidence function.
Results: Patient characteristics: male: 61%; median age 33 yrs (range16–67). No. of salvage regimens pre-ASCT: 1: 76%; 2: 19%; ≥3: 5%. Salvage chemotherapy: BCNU, etoposide, cytarabine, melphalan (miniBEAM, [MB]) 162 (50%); cisplatinum-based regimens (dexamethasone, cytarabine, cisplatin [DHAP] or gemcitabine, dexamethasone, cisplatin [GDP]) 128 (40%); other 10%. Disease status post-salvage chemotherapy: CR 28%, PR 66%. With a median follow-up of 4.7 yrs post-ASCT (range 1–17), estimates of OS, PFS and disease relapse are 53%, 53% and 46% at 5 years, and 39%, 51% and 48% at 10 yrs. The cumulative incidence of treatment-related death (from toxicity or SC) continues to increase from 9% (6–13) at 3 years to 15% (11–20) 10 yrs post-ASCT. The probability of SC is 5% (2.8–7.8) at 3 years and 12% (7.9–16.7) at 10 years (leukemia risk: 7%, solid tumour risk: 5%). There have been a total of 154 deaths, 104 from progressive HL alone and 37 from treatment-related events - 14 (9%) of these were from SC with no evidence of relapsed HL. There were an additional 11 deaths from a combination of causes (relapsed HL and other), 9 (6%) of these were related to SC. 30 SC were identified, 12 solid tumors and 18 AML/MDS. The risk of secondary acute leukemia differs according to salvage chemotherapy received - 0.9% (0.1–6.2) and 3.4% (0.7–15.1) at 3 and 10 yrs respectively in DHAP/GDP pts, compared to 4.6% (2.2–9.4) and 9.1% (5.4–15.3) in pts treated with MB [p=0.051]. Pts who received radiation (pre- or post-ASCT) have a leukemia risk of 4% (1.8–8) at 3yrs increasing to 8.5% (4.9–14.4) at 10yrs, while pts who never received radiation had a stable leukemia risk of 1.8% (0.3–12%) [p=0.19].
Conclusions: In this single institution experience with HL pts undergoing ASCT with a consistent salvage therapy strategy, long-term survivors have an on-going increasing risk of SC and leukemia which contributes to late mortality. Specific components of therapy appear to influence this risk. Our observation of an unexpected increased risk of AML in HL patients receiving miniBEAM salvage prior to transplant suggests that the contribution of other salvage regimens to late adverse effects warrants further investigation.