Disease Risk Index Is Independently Associated with Long-Term Outcomes of Allogeneic Transplantation Post Reduced-Intensity Conditioning in Lymphoid Malignancies

Introduction: Allogeneic hematopoietic cell transplantation (alloHCT) with reduced-intensity conditioning (RIC) has been used in heavily pretreated lymphoma patients with the promise of decreased treatment-related mortality. Despite overall improvements in outcomes of patients with lymphoid malignancies, several new agents are emerging as potential therapies. However, investigation is ongoing. Therefore, we aimed to describe our long-term experience in Hodgkin (HL), non-Hodgkin lymphomas (NHL) and chronic lymphocytic leukemia (CLL).

Methods: In this retrospective study, we enrolled consecutive patients who underwent allo-HCT for lymphoid malignancies in our institution between 2001-2018. We performed a retrospective review of data in our prospectively acquired database.

Results: In total, 50 patients (male=35, female=15, median age 36 years, range 15-64) underwent allo-HCT for HL (n=24), NHL (n=21, including mantle cell n=12, follicular n=3, aggressive B-NHL n=4, T-NHL n=2) and CLL (n=5). The majority of patients were diagnosed at stage IV (48%), 34% had bone marrow involvement and 66% had previously undergone autologous HCT. Most patients were heavily pretreated (median treatment lines=4, range 1-11), 21 of them had received more than 4 treatment lines and at the time of transplantation only 14 had complete response of the disease, while 9 had partial response and 27 were refractory. According to Disease-Risk Index (DRI), patients were stratified at low (n=11, 23.4%), intermediate (n=12, 25.5%), high (n=20, 42.6%) or very high (n=4, 8.5%) category.

Among patients with Hodgkin lymphoma, Brentuximab vedotin was administered in 7, and 4 of them were effectively bridged to AHCT.

All patients received RIC, mainly Fludarabine (150mg/m²)-Cyclophosphamide (2g/ m²) in CLL and NHL and Thiotepa (10mg/kg)-Fludarabine (120 mg/m²)-Cyclophosphamide (60mg/kg) in HL from matched sibling (n=27), matched unrelated (n=15) or mismatched unrelated (n=8) donor. GVHD prophylaxis consisted of cyclosporine or tacrolimus and mycophenolate mofetil or short- term methotrexate and additional low dose antithymocyte globulin (5mg/kg) in unrelated donors. Peripheral blood was the main stem cell source (only two patients received bone marrow graft) and median number of CD34+ cells infused was 6.37 x10⁶ /kg (1.33-14.5). Two patients succumbed to advanced underlying disease before engraftment, in all other engraftment was successful. Median time until neutrophil engraftment was 10 days (7-23) and until platelet engraftment 12 days (7-28). Eighteen patients (36.7%) developed acute GVHD (grade I,n=1,grade II, n=12,grade III-IV, n=5), steroid sensitive in 10 (62.5%). Cumulative incidence (CI) of chronic extensive GVHD at first year was 78.2%, and 13 patients required more than one additional line of immunosuppression (range 1-5 lines). Ten patients presented CMV reactivation successfully treated with antiviral medication and 1 patient died from HSV7 encephalitis. With a median follow of 3 years (1-16 years), 10-year OS was 40.4%, 10-year non-relapse mortality CI 23.4% and 10-year DFS 32%. There was no difference in survival according to original disease (5yr, NHL=61.1%, HL=47.1%, CLL=30%%, p=0.67). Multivariate analysis revealed high and very high DRI as the single predicting factor for OS (HR 9.69, CI 1.55-60.55, p=0.015), when assessing impact of disease, DRI, number of prior treatment lines, cGVHD and bone marrow infiltration at diagnosis.

Conclusions: Our data suggest that RIC allo-HCT provides encouraging survival rates, potentially offers the chance of cure, with acceptable 10-year TRM in selected high risk patients with lymphoid malignancies, despite high risk of chronic GVHD. Disease risk index that is mainly associated with disease stage at transplant independently affects survival. Therefore, efforts need to continue to improve clinical application of novel agents targeting specific pathways with the aim of lowering disease stage pre-transplant. These therapeutic strategies merit further investigation in prospective studies in order to select potential therapeutic targets and best regimens for individual patients.