Superiority of Thiotepa-Containing Conditioning Regimens in Patients with Primary Diffuse Large B-Cell Lymphoma (DLBCL) of the Central Nervous System (CNS) Undergoing Autologous Hematopoietic Cell Transplantation (autoHCT)

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<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 < 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 < 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.

Development of Optimal Conditioning Method to Improve Economic Efficiency of Polymer Electrolyte Membrane (PEM) Fuel Cells

This study presents an economical conditioning method for polymer electrolyte membrane (PEM) fuel cells through a parametric study investigating the factors affecting online conditioning methods. First, we compared the operating conditions between constant current (CC) mode and constant voltage (CV) mode conditioning to understand the effects of current and potential differences on conditioning. We found that CV mode conditioning is at least one hour faster at the same load. This is because unlike CV mode conditioning, which has a constant load over the entire range of the membrane electrode assembly (MEA), CC mode conditioning features current flow through the existing passage of the pre-activated triple phase boundary of the MEA so that the electronic load is not entirely used in the conditioning process. Second, the optimization of CV mode conditioning was conducted by controlling the conditioning temperature. Lastly, the economics of the proposed method were analyzed by comparing it with existing conditioning methods. Using this optimal conditioning method can reduce the consumption of hydrogen during conditioning by ~87.5% compared to previous methods. The findings from this study provide the means to lower the actual production cost of fuel cells, thereby ensuring market access.

Is there an optimal conditioning for older patients with AML receiving allogeneic hematopoietic cell transplantation?

The optimal conditioning regimen for older patients with acute myeloid leukemia (AML) remains unclear. In this study, we compared outcomes of AML patients >60 years of age undergoing allogenic hematopoietic stem cell transplantation at our institution. All 404 consecutively treated patients received 1 of the following conditioning regimens: (1) fludarabine+melphalan 100 mg/m2 (FM100), (2) fludarabine+melphalan 140 mg/m2 (FM140), (3) fludarabine+IV busulfan AUC ≥ 5000/d × 4 d (Bu≥20000), and (4) fludarabine+IV busulfan AUC 4000/d × 4 d (Bu16000). A propensity score analysis (PSA) was used to compare outcomes between these 4 groups. Among the 4 conditioning regimens, the FM100 group had a significantly better long-term survival with 5-year progression-free survival of 49% vs 30%, 34%, and 23%, respectively. The benefit of the FM100 regimen resulted primarily from the lower nonrelapse mortality associated with this regimen, an effect more pronounced in patients with lower performance status. The PSA confirmed that FM100 was associated with better posttransplantation survival, whereas no significant differences were seen between the other regimen groups. In summary, older patients with AML benefited from a reduced-intensity conditioning regimen with lower melphalan doses (FM100), which was associated with better survival, even though it was primarily used in patients who could not receive a more intense conditioning regimen.

Optimal Conditioning Regimen for Haplo-Identical Stem Cell Transplantation in Adult Patients with Acquired Severe Aplastic Anemia: Prospective De-Escalation Study of TBI and ATG Dose

Background Recent advances in controlling graft failure and graft-versus-host disease (GVHD) due to barrier of HLA incompatibilities in haplo-identical stem cell transplantation from related mismatched donor (Haplo-SCT) extended its application to severe aplastic anemia (SAA). Therefore, studies for searching optimal conditioning regimen and strategy of graft manipulations for SAA patients who receive Haplo-SCT are needed. This prospective study was aimed to explore the optimal conditioning regimen to ensure engraftment with minimal toxicity in adult patients with SAA who received Haplo-SCT. Methods We have explored a safe and sufficient dose of ATG in combination with 800 cGy TBI and fludarabine (Flu, 30 mg/m2/day) for 5 days using step by step dose de-escalation based on the transplant-related mortality (TRM) and toxicity. The dose of ATG was de-escalated from 10 mg/kg (group 1), 7.5 mg/kg (group 2), to 5 mg/kg (group 3) and from October 2014, the TBI dose also reduced to 600 cGy with fixed dose of Flu and ATG (5mg/kg) (group 4). If any patient developed TRM with engraftment in each group, we moved to next group. For GVHD prophylaxis, a combination of tacrolimus and short-course methotrexate was used. G-CSF mobilized PBSCs were used as stem cell source without manipulation. Considering the importance of both survival and GVHD rate when testing conditioning regimen, GVHD-free survival, defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, or death was addressed. Results Twenty-nine patients including 18 men and 11 women were enrolled. The median age was 31 (17-52) years. Median CD34+ cells transplanted were 5.84x106/kg (1.45-16.2). All patients achieved primary engraftment. Thirteen patients (7 of 10 in the group 1-3, 6 of 19 in the group 4) had CMV DNAemia requiring pre-emptive therapy including 3 patients with CMV disease (2 pneumonia, 1 colitis). Three patients (2 in the group 1, 1 in the group 2) developed EBV-associated PTLD, of whom two patients with monomorphic type received rituximab and chemotherapy. The incidence of acute GVHD (grade ≥2) and chronic GVHD (≥ moderate) were 24% and 17%, respectively. With a median follow-up of 41.4 (31.9-48.9) months in the group 1-3 and 10.1 (1.3-20.6) months in the group 4, probability of overall survival (94.1% in the group 4 vs. 70% in the group 1-3, P = 0.292) and GVHD-free survival (73.3% in the group 4 vs. 50% in the group 1-3, P = 0.161) were improved in the group 4. Conclusions This study explored the optimal conditioning with step by step de-escalation dose of ATG and TBI to reduce TRM with sustained graft function. TBI-600 cGy/Flu/low-dose ATG resulted in feasible outcomes of Haplo-SCT for adult patients with SAA. Disclosures No relevant conflicts of interest to declare.