Ahn, Kwang Woo

SummaryIn young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

Abstract The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) vs chimeric antigen receptor T-cell (CAR-T) therapy in patients with diffuse large B-cell lymphoma (DLBCL) who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult patients with DLBCL who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by computed tomography or positron emission tomography scan. We compared the clinical outcomes between the 2 cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs 42%; P = .1) and the rate of 100-day nonrelapse mortality (4% vs 2%; P = .3) were not different between the 2 cohorts, but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs 53%; P = .05) and a superior overall survival (OS) (69% vs 47%; P = .004) at 2 years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (hazard ratio = 1.49; P = .01) and a superior OS (hazard ratio = 1.63; P = .008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard of care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.

Abstract Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P &lt; .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.

7521 Background: In MCL, outcomes are heterogeneous and the clinical significance of the timing of relapse following autoHCT and its impact on OS is not well defined. Using the CIBMTR database, we evaluate the effect of post-autoHCT time to relapse on OS over time. Methods: Adult MCL pts treated with up to two lines of rituximab-based induction therapy followed by first autoHCT within 1-year of diagnosis were identified between 2000-2018. Primary outcomes included OS and post-relapse OS. A dynamic landmark analysis was performed at 6-month intervals following autoHCT to evaluate the impact of relapse on OS while adjusting for significant patient- and disease-related variables. Post-relapse OS was evaluated in pts who experienced relapse. Results: Of the 461 pts included in the analysis, the median age was 60 years (range 29-78), 57% had a KPS of ≥ 90, 83% had stage III-IV disease at diagnosis, and 76% had extranodal involvement. BEAM was the most common conditioning regimen (58%) and 23% of pts received post-autoHCT maintenance rituximab. With a median follow-up of 67 months, the 5-year progression-free survival was 45.8% with a 5-year OS of 69.6%. On multivariate analysis, age ≥60 years was associated with worse OS (HR= 1.55, 95% CI 1.08-2.24, p=0.0191) at all landmark timepoints. Additionally, the impact of relapse on OS varied with time (p=0.006) and was greatest at the 6-month (HR=7.68), 12-month (HR=6.68), and 18-month (HR=5.81) landmark timepoints. The risk of death for relapsing pts decreased with time and was mirrored by an improvement in adjusted OS for both relapsing and non-relapsing pts. In total, 9.3% of patients relapsed prior to the 18-month landmark timepoint. Relapse at the 6-month, 12-month, and 18-month landmark timepoints correlated with a poor median post-relapse OS of 9 months, 24 months, and 34 months, respectively (Table). Conversely, patients relapsing after the 18-month landmark timepoint experienced a median post-relapse OS ranging from 44-67 months. Conclusions: In MCL, early relapse (< 18-months) following autoHCT defines a high-risk group with inferior post-relapse OS. This population should be considered for clinical trials or novel therapeutic approaches including early utilization of chimeric antigen receptor T-cell therapy.[Table: see text]

Introduction T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive malignancy with limited treatment options, frequent relapse, and poor long-term survival. Allogeneic hematopoietic cell transplantation (allo-HCT) is reported to be effective in T-PLL yielding durable remissions and improved survival. Rates of survival and non-relapse mortality vary; data is scant and limited to small retrospective series. Whether regimen intensity - a modifiable factor- is associated with outcomes is unknown. Here, we report an analysis of patients with T-PLL undergoing allo-HCT in 87 centers using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods A retrospective multicenter study was conducted utilizing the CIBMTR dataset, which captures all consecutive patients transplanted in participating centers. The study population included patients aged 18 or older with T-PLL who underwent allo-HCT between 2008 and 2018. All donor types, graft sources, and conditioning intensities are summarized (Table 1). Cox regression analysis was used to assess overall mortality, treatment-related mortality (TRM), relapse or progression, disease-free survival (DFS) and acute and chronic graft-versus-host disease (GVHD). Due to the strong correlation between regimen intensity and patients' age, a combined variable was constructed, and in all models, interactions between age/regimen and significant covariates were examined. Results A total of 266 pts were identified and included in this analysis (Table 1). Median follow up of survivors was 49 months (range 3-117); the completeness of survival data out to four years was 95%. In univariate analysis, the 4-year overall survival (OS) rate was 30% (95% confidence interval [CI]: 23.8-36.5%). The 4-year DFS, relapse, TRM rates were 25.72% (95%CI: 20-32%), 41.9% (95%CI: 35.5-48.4%), and 32.4% (95%CI: 26.4-38.6%), respectively. Cumulative incidences of grade 2-4 acute GVHD at day +180 and chronic GVHD at 1-year were 22.5%% (95%CI: 16.8- 28.9%) and 38.3% (95%CI: 32.9-44.9%), respectively. Multivariate analyses was performed using age (Age &gt;60 vs Age ≤60) and conditioning intensity (myeloablative [MAC] vs. reduced intensity/non-myeloablative [RIC/NMA]) as main effect (Table 2). Poor performance status was associated with inferior TRM, DFS and OS. Compared to MAC/Age ≤ 60, RIC/NMA/Age≤ 60 correlated significantly with less TRM (hazard ratio [HR] 0.28, 95% CI 0.14-0.55, p= 0.0022, superior DFS [HR 0.53, 95% CI 0.35-0.81, p= 0.0029; (Figure 3) and OS HR 0.49, 95% CI 0.32-0.75, p= 0.0009; (Figure 2). Similar trend was observed for RIC/NMA/ Age&gt; 60 for all 3 outcomes but did not reach statistical significance. Remission status at time of allo-HCT (stable disease or progression vs. complete remission) correlated with relapse (hazard ratio [HR] of relapse=2.13, 95%CI 1.23-3.71, p=0.0072), however degree of response (partial response vs. complete remission did not significantly correlate with relapse (HR of relapse=1.41, 95%CI 0.91-2.17, p=0.1257). In vivo T cell depletion with ATG (N=47) or alemtuzumab (N=2) was associated with worse TRM [HR 1.82, 95% CI 1.08-3.08, p= 0.0255] and inferior DFS [HR of death or progression=HR 1.50, 95% CI 1.05-2.15, p= 0.0276]. The most common cause of death was disease relapse (52%) followed by infection (15%) and GVHD (13%). Conclusion This CIBMTR study, with the largest cohort of allo-HCT in T-PLL to date, demonstrates allo-HCT is effective in providing durable remissions. MAC and poor performance status were predictive of inferior TRM and OS. Disease relapse was most common cause of death, and pre-allo-HCT remission inversely correlated with relapse rate. The data suggest that reduced intensity conditioning and avoidance of post-transplant ATG/alemtuzumab may be beneficial. Novel strategies are needed both pre and post-allo-HCT to further improve outcomes. Disclosures Dholaria: J&J: Research Funding; bms: Research Funding; Takeda: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding. Jagadeesh:Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Regeneron: Research Funding. Oran:Celgene: Consultancy; ASTEX: Research Funding; Arog Pharmaceuticals: Research Funding. Nakamura:Viracor: Consultancy; Celgene: Other: Support on seminar; Magenta Therapeutics: Other: Advisory board meeting; NapaJen Pharma: Consultancy; Alexion: Other: Support on a meeting presentation; Merck: Other: advisory board meeting; Kadmon Corporation: Other: Advisory board meeting; Kyowa-Kirin: Other: Support on a meeting presentation. Sauter:Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Celgene: Consultancy, Research Funding; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy, Research Funding. kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

INTRODUCTION Primary DLBCL of the CNS (PCNSL) is a rare, extra-nodal non-Hodgkin lymphoma with high risk of relapse without consolidation therapies. AutoHCT has emerged as an accepted consolidation strategy, especially with increasing use of CNS penetrant chemotherapy agents in transplant conditioning. However, studies defining the optimal conditioning regimen for PCNSL have not been performed. The use of two common conditioning regimens in the U.S., thiotepa/busulfan/cyclophosphamide (TBC) and thiotepa/carmustine (TT-BCNU), is supported by phase II trials, but lack comparative data. Extrapolating experience from systemic lymphomas, BEAM (BCNU/etoposide/cytarabine/melphalan) is also prescribed for PCNSL in the U.S. Using the Center for International Blood & Marrow Transplant Research (CIBMTR) registry, we compared outcomes for PCNSL patients undergoing autoHCT using the three most commonly employed conditioning regimens: TBC vs. TT-BCNU vs. BEAM. METHODS Six hundred and eight adult PCNSL patients who underwent a first autoHCT between 2010-2018 were included. Conditioning regimens included TBC (n = 265), TT-BCNU (n = 278), and BEAM (n = 65). The primary endpoint was progression-free survival (PFS). Secondary endpoints included (a) time to hematopoietic recovery, (b) relapse/progression, (c) non-relapse mortality (NRM), and (d) overall survival (OS). Kaplan-Meier method was used to estimate probabilities of PFS and OS. Cox proportional hazard analysis was used to identify prognostic factors for relapse, NRM, PFS, and OS. Variables considered in regression model include patient age, sex, race, performance status, HCT-comorbidity index (HCT-CI), rituximab use during conditioning, interval between diagnosis and HCT, and remission status. Covariates with a p&lt;0.05 were considered significant. RESULTS Baseline characteristics are presented in Table 1. The groups were comparable with regards to median patient age, gender, race, HCT-CI, and remission status. The cumulative incidences of neutrophil recovery at 1-month for the three conditioning regimens were: TBC 96% (95%CI 94-98%), TT-BCNU 100% (95%CI 98-100%), and BEAM 100% (95%CI 100%), (p &lt; 0.001). The cumulative incidence rate of relapse for TBC, TT-BCNU, and BEAM at 1-year were 6% (95%CI 3-9%), 10% (95%CI 7-14%), and 23% (95%CI 14-35%), respectively (p = 0.003). The corresponding cumulative incidence rate of relapse at 3-years were 11% (95%CI 7-16%), 15% (95%CI 10-20%) and 37% (95%CI 25-50%) (p &lt; 0.001) respectively. The adjusted NRM were higher for TBC: 100-day 7% (95%CI 4-10%) and 1-year 11% (95%CI 7-15%), compared to TT-BCNU: 100-day 2% (95%CI 0.2-3%) and 1-year 4% (95%CI 2-6%), and BEAM: 100-day 0% (95%CI 0%) and 1-year 4% (95%CI 0-9%) (1-year p=0.01). The 3-year adjusted PFS across the three conditioning regimens were: TBC 75% (95%CI 69-81%), TT-BCNU 76% (95%CI 70-82%), and BEAM 58% (95%CI 46-70%) (p = 0.03) [Figure 1a]. The adjusted OS at 3-years were: TBC 81% (95%CI 75-86%), TT-BCNU 78% (95%CI 72-85%) and BEAM 69% (95%CI 58-80%), (p = 0.17) [Figure 1b]. Relapse of primary disease was the most common cause of death in all three cohorts: TBC 38% (n=20), TT-BCNU 72% (n=33) and BEAM 76% (n=19). Other significant causes of death in the TBC group included infections 15% (n=8) and organ failure 21% (n=11). CONCLUSIONS In this CIBMTR analysis in patients with PCNSL, we found favorable outcomes with thiotepa-containing conditioning regimens. Adjusted 3-year PFS favored TBC and TT-BCNU over BEAM and suggest that use of BEAM should be discouraged in this specific setting. Whether TBC or TT-BCNU is the optimal conditioning regimen requires further inquiry in a prospective clinical trial. Disclosures Scordo: McKinsey & Company: Consultancy; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board; Angiocrine Bioscience, Inc.: Consultancy, Research Funding. Kharfan-Dabaja:Pharmacyclics: Consultancy; Daiichi Sankyo: Consultancy. Herrera:Pharmacyclics: Research Funding; Karyopharm: Consultancy; Bristol Myers Squibb: Consultancy, Other: Travel, Accomodations, Expenses, Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; AstraZeneca: Research Funding; Immune Design: Research Funding; Seattle Genetics: Consultancy, Research Funding. Hamadani:Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees. Sauter:Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharamaceuticals: Consultancy; Novartis: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Consultancy, Research Funding.

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only curative therapy for myelofibrosis (MF). In this large multicenter retrospective study, overall survival (OS) in MF patients treated with allogeneic HCT (551 patients) and without HCT (non-HCT) (1377 patients) was analyzed with Cox proportional hazards model. Survival analysis stratified by the Dynamic International Prognostic Scoring System (DIPSS) revealed that the first year of treatment arm assignment, due to upfront risk of transplant-related mortality (TRM), HCT was associated with inferior OS compared with non-HCT (non-HCT vs HCT: DIPSS intermediate 1 [Int-1]: hazard ratio [HR] = 0.26, P &lt; .0001; DIPSS-Int-2 and higher: HR, 0.39, P &lt; .0001). Similarly, in the DIPSS low-risk MF group, due to upfront TRM risk, OS was superior with non-HCT therapies compared with HCT in the first-year post treatment arm assignment (HR, 0.16, P = .006). However, after 1 year, OS was not significantly different (HR, 1.38, P = .451). Beyond 1 year of treatment arm assignment, an OS advantage with HCT therapy in Int-1 and higher DIPSS score patients was observed (non-HCT vs HCT: DIPSS-Int-1: HR, 2.64, P &lt; .0001; DIPSS-Int-2 and higher: HR, 2.55, P &lt; .0001). In conclusion, long-term OS advantage with HCT was observed for patients with Int-1 or higher risk MF, but at the cost of early TRM. The magnitude of OS benefit with HCT increased as DIPSS risk score increased and became apparent with longer follow-up.