Allogeneic Hematopoietic Cell Transplantation in Patients with Therapy-Related Myeloid Neoplasm Following Treatment for Lymphoma: A Study of the Chronic Malignancies Working Party of the EBMT

Introduction: Therapy-related myeloid neoplasms (t-MNs) represent group of myeloid neoplasms arising after treatment for an antecedent cancer or autoimmune disease and historically present a dismal prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for t-MN. The Chronic Malignancies Working Party of EBMT previously reported outcomes for t-MN following breast cancer treatment demonstrating comparable outcomes to de novo disease and the crucial role of oncological surveillance due to risk of relapse of primary cancer. In this retrospective registry-based study, we analyzed the outcomes and complications of patients with t- MN arising secondary to lymphoma treatment who underwent allo-HCT.

Methods: Patients ≥18 years old receiving a first allo-HCT for t-MN [either therapy-related Myelodysplastic syndrome (t-MDS) or t-Acute myeloid leukemia (t-AML)] between 2006 and 2017 were included in this analysis. Both t-MN arising after completion of treatment for Hodgkin and Non-Hodgkin Lymphoma were included.

Results: In the EBMT registry, we identified 378 patients from 47 centers. t-MDS was the indication for allo-HCT in 222 (59%) and t-AML in 156 patients (41%), respectively, with a median age at allo-HCT of 58 years and males representing 62% of cases. Most of the patients were previously treated for Follicular Lymphoma (22%), followed by Hodgkin's Lymphoma (22%) and Diffuse large B-cell Lymphoma (16%). Autologous HCT was a prior line of therapy in 38% of cases, and at the time of allo-HCT 15% of lymphomas were not in complete remission (CR). For t-MN, CR was recorded at the time of allo-HCT in 46% of cases, with a Karnofsky status >80 in 66%. The conditioning regimen was reduced intensity in 70% of patients, 22% received TBI and 65% received T-cell depletion. Stem cell source was peripheral blood in 90% of cases. Donor was matched related (MRD) in 26%, matched unrelated (MUD) in 46%, mismatched related (MMRD) in 4% of cases, and mismatched unrelated (MMUD) in 20% of cases, respectively. Median follow-up was 72 months, and the 5-year overall survival (OS) was 32%. In univariate analysis, OS was worse for patients transplanted for t-MDS (26 vs 41% for t-MDS vs t-AML, p=.032), not being in remission for t-MN at the time of allo-HCT (24% vs 38% for CR vs 34% for untreated, p=.013), and patients with a longer interval from lymphoma diagnosis to allo-HCT (23% for >10 years vs 37% for 5-10 years vs 36% <5 years, p=.028). Five-year t-MN progression-free survival (PFS) was 28%: patients with active t-MN at allo-HCT presented with lower PFS (33% vs 20% for CR vs 31% for untreated, p=.003) as did patients with t-MDS (22% vs 36% for t-AML, p=.022). t-MN Relapse incidence (RI) and Non-relapse mortality (NRM) at 5 years were 35% and 37%, respectively. Uncontrolled t-MN was associated with higher RI (42% vs 35% for CR vs 25% for untreated, p=.025); having an MRD was associated with a worse RI (48%, 33%, 25%, 31% for MRD, MUD, MMRD, and MMUD, p=.009), but to a significantly lower NRM (21%, 35%, 47%, 52% for MRD, MUD, MMRD, and MMUD, p<0.001). A higher NRM was observed in patients older than 60 years (44% for >60 years vs 34% for 50-60 years vs 27% for <50 years, p=.034) and in those with heavily pretreated lymphoma, (32% for 1st CR vs 40% for 2nd CR vs 61% for ≥3rd CR vs 45% for not in CR, p=.028). Acute grade II-IV GVHD occurred in 33% of patients (14% grade III-IV), with a 12-months incidence of chronic GVHD of 32% (18% of extensive grade). By 5 years post allo-HCT, the relapse incidence of lymphoma was 3% at 60 months, while the rate of secondary malignancies was 8%. On multivariable analysis, compared to t-MN in CR, uncontrolled t-MN was associated with significantly worse OS, PFS, and NRM. Age was correlated with better OS, PFS, and higher NRM (all p-values<0.04). MRD was associated with higher RI (p=.03) and worse NRM (p=.02).

Conclusions: This analysis shows encouraging results for patients treated with allo-HCT for t-MN arising secondary to lymphoma treatment, however significant rates of NRM and relapse remain of concern. Lymphoma recurrence represents a rare event, but when considered together with the relatively high rate of secondary malignancies (8%) necessitates vigilance. Of note, our cohort was exposed to conventional chemotherapeutic agents for lymphoma treatment, and further efforts should explore supplementary variables in addition to the impact of novel therapies.

Nabergoj:Abbvie: Speakers Bureau; Jannsen: Other: travel sponsor. Platzbecker:Abbvie: Honoraria; Geron: Honoraria; Silence Therapeutics: Honoraria; Takeda: Honoraria; Novartis: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Jazz: Honoraria. Sockel:BMS: Consultancy, Honoraria; Active Biotech: Research Funding; Gilead: Honoraria; SOBI: Honoraria; Novartis: Consultancy, Honoraria. Finke:Riemser Pharma: Research Funding. Kröger:Takeda: Consultancy, Honoraria; Sanofi: Honoraria; Kite: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; DKMS: Research Funding; Amgen: Honoraria; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Honoraria. Forcade:GSK: Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support; Sanofi: Other: Travel Support; Jazz: Other: Travel Support, Speakers Bureau; Novartis: Speakers Bureau. Kuball:Miltenyi Biotech: Patents & Royalties: novel CAR T and engineering isolation strategies, Research Funding; GADETA: Current equity holder in private company, Patents & Royalties: on gdTCR engineering strategies and targets , Research Funding; Novartis: Research Funding. Wilson:Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Mathilde:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Clinigen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees. Helbig:Novartis: Honoraria. Mussetti:TAKEDA: Honoraria; BMS: Consultancy; JAZZ PHARMACEUTICALS: Consultancy; GILEAD: Research Funding. Scheid:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. McLornan:CELGENE BMS: Research Funding, Speakers Bureau; ABBVIE: Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Research Funding, Speakers Bureau. Robin:MEDAC, ASTEX: Research Funding. Yakoub-Agha:Janssen: Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria.