Ayala, Ernesto

Introduction: NGS is increasingly being utilized to identify pathogenic somatic and targetable variants in patients with newly diagnosed AML and MDS. Patients with high-risk disease are typically recommended to undergo allo-HCT as consolidation, upon achieving morphological complete remission (CR). But, despite achieving hematologic CR, patients often have detectable somatic variants pre allo-HCT that predict for increased risk of disease relapse. Longitudinal monitoring of somatic variants via NGS at diagnosis, pre-allo-HCT and post allo-HCT can assist in prognostication and identify patients that remain at high risk of relapse despite allo-HCT. Methods: Patients with AML or MDS who underwent a first allo-HCT and completed NGS testing at day +100 between years 2016 to 2021 were identified from the transplant registry of Mayo Clinic in Florida. The primary aim of the study was to evaluate the prognostic impact of detectable variants via NGS at day +100 days post allo-HCT on the following outcomes: 1) overall survival (OS), 2) relapse, 3) progression-free survival (PFS), and 4) non-relapse mortality (NRM). Disease risk was assessed based on European Leukemia Network (ELN) 2022 risk classification for AML and Revised International Prognostic Scoring System (R-IPPS) for MDS. Baseline variables were compared between patients with and without mutation at day +100 days post allo-HCT using Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. Kaplan-Meier (KM) method was used to estimate freedom from events at different time points and draw corresponding survival curves. Results: 105 patients who underwent allo-HCT for AML and MDS and completed NGS testing at day +100 were included in the study population. Median age of the study population was 63 years (22-74) and 58% were of the male gender. Median HCT comorbidity score (HCT-CI) and KPS Karnofsky performance score (KPS) were 3 (0-8) and 90 (60-100), respectively. Matched unrelated donor (50%) and peripheral blood stem cells (98%) were the most common donor and graft source, respectively. Median number of lines of therapy pre allo-HCT was 1(0-6) and 52 (50%) patients had detectable variants after completion of chemotherapy and prior to allo-HCT. Seventeen (16%) had detectable variants via NGS on day +100. Eleven (65%) of these 17 had variants pre-allo-HCT and amongst the 88 patients with no variants post allo-HCT, 41 (47%) had detectable variants pre allo-HCT. There was no significant difference in baseline characteristics between patients with detectable variants at day+100 versus those who did not except for a higher KPS in patients with no variants at Day +100 of 90 (60-100) vs. 80 (60-100) (p=0.003). At a median follow up of 1.4 years (0.1-5.5), presence of a variant at day +100 was associated with inferior 4-year OS (32% vs. 69%, p<0.001) and higher relapse risk (64% vs. 23%, p<0.001). In univariate models, a lower KPS and presence of variants post allo-HCT were significantly associated with inferior OS, high relapse risk and worse PFS. Presence of variants pre allo-HCT was associated with an inferior PFS but did not impact OS or relapse risk. In multivariate models, KPS remained significant for OS, PFS and NRM; presence of variants at day +100 post allo-HCT approached significance for OS (p=0.06) and PFS (p=0.08) and was significant for relapse risk (p=0.002) (Table1) (Figure 1). Data regarding longitudinal evolution of variants and impact of individual variants on long term outcomes will be included at the time of presentation. Conclusion: These results indicate that presence of detectable somatic variants at day +100 is associated with poor long-term outcomes and predicts for high risk of disease relapse. Longitudinal monitoring of somatic variants via NGS should be consistently incorporated in the management of patients with high-risk AML and MDS undergoing allo-HCT. Patients with detectable somatic variants post allo-HCT should be considered for additional intervention to mitigate relapse risk.

Purpose The predominant pattern of relapse for patients with B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) involves sites previously involved by NHL. Bridging radiotherapy (BRT) has shown to be an effective bridging treatment with excellent local control rates. Our previous work defined limited/oligometastatic lymphoma as disease involving <5 sites. This study is the first to report on the role of BRT for patients with limited (<5 involved sites) disease prior to CART. Methods Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 Mayo Clinic sites (Arizona, Florida, and Minnesota) was performed and identified 139 patients with relapsed/refractory (r/r) B-cell NHL without bone marrow involvement who received CART and had <5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. An involved disease site included the Ann Arbor anatomical lymph node region(s) harboring the pathological lymph node(s) or any extranodal lesion. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. The primary endpoint was event-free survival (EFS),defined from CART infusion to any disease progression or initiation of post-CART consolidative/salvage therapy. Secondary endpoints included progression -free survival (PFS),defined from CART infusion to any disease progression, and overall survival (OS), defined from CART infusion to death. Results Prior to CART infusion, 44 (32%) patients received BRT and 95 (68%) did not. Bridging systemic therapy was given to 5 (11%) and 34 (36%) patients in the BRT and no BRT groups, respectively (p=0.003). The median number of involved disease sites prior to leukapheresis was 2 (range: 1-4). There was no significant difference in the baseline characteristics prior to CART infusion between the BRT and no BRT groups, except for extranodal involvement that was more common in the BRT group (Table 1). The median equivalent 2 Gy dose was 27 Gy (Interquartile range 23-34), and the most common BRT regimen was 20 Gy in 5 fractions. Among the 44 BRT patients, 34 received radiation to all visible PET-avid disease sites, and 10 received radiation to some but not all disease sites. The median follow-up was 20 months. The rate of grade ≥2 cytokine release syndrome was 41% in both groups (p=0.99). The rate of grade ≥2 immune effector cell-associated neurotoxicity syndrome was 21% and 37% in the BRT and no BRT groups, respectively (p=0.059). There were no observed grade ≥3 BRT-related toxicities. Objective response rate by PET 5 point scale was higher in the BRT group (93% versus 79%; p=0.036). Crude rates of progression were 30% in BRT and 55% in no BRT patients, with 9/13 (69%) and 43/52 (83%) patients relapsing in pre-existing sites of disease present prior to CART infusion in the BRT and no BRT group, respectively. Seven (16%) BRT patients relapsed in the radiation field. The 2-year EFS was 50% in the BRT group and 39% in the no BRT group (p=0.01). The 2-year PFS was 55% in the BRT group and 45% in the no BRT group (p=0.017). The 2-year OS was 55% in the BRT group and 62% in the no BRT group (p=0.7). Intriguingly, patients who received BRT to all visible PET-avid disease sites (n=34) had further improvement in 2-year EFS (67% vs 39%, p=0.003) and 2-year PFS (71% vs 46%, p=0.008) compared to no BRT or patients who received BRT to some but not all visible disease sites (n=105). Nine patients (2 in BRT and 7 in no BRT groups) received consolidative radiotherapy for day 30 residual disease with only one patient subsequently experiencing progression. Twenty-five patients (6 in BRT and 19 in no BRT groups) received salvage/palliative RT for post-CART relapsed disease. Thirty-seven (39%) patients in the no BRT group remained without disease progression and did not receive radiation in the bridging, consolidative or salvage/palliative setting. Conclusion Bridging radiotherapy prior to CART infusion for patients with limited (<5 involved disease sites) r/r NHL appears to improve response rate, EFS, and PFS without causing significant toxicities. Approximately one third of patients who do not receive BRT will require subsequent post-CART radiation, and another third will remain free of radiation and disease progression.

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2–3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2–3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2–4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.

Abstract Intravascular lymphoma (IVL) is a rare extranodal non‐Hodgkin lymphoma. We performed a retrospective analysis of 55 IVL patients who were treated at our institution 2003–2018. Median age at diagnosis was 68 years, and 64% were males. The most frequent presenting symptoms were skin rash 43% and weight loss 30%. MRI brain on IVL patients with CNS involvement (CNS‐IVL) showed multifocal involvement in 76% (13/17). 89% (17/19) of non‐CNS‐IVL patients with abnormal FDG‐PET had biopsy of an avid lesion resulting in definitive diagnosis. The top diagnostic biopsy site was the bone marrow (45%). 56% had multiorgan involvement. Based on CNS involvement, 36.5% (20/55) had CNS‐IVL and 63.5% (35/55) had non‐CNS‐IVL. CNS‐IVL group consists of clinically isolated CNS involvement (CNS‐only IVL) (22%;12/55) and mixed clinical CNS and peripheral site involvement (M‐IVL) (14.5%; 8/55). Non‐CNS‐IVL group consists of clinically isolated skin involvement (skin‐only IVL) (9%; 5/55) and peripheral IVL with or without skin involvement (P‐IVL); (54.5%; 30/55). Skin involvement was predominantly in the lower extremities. Pathologically, 89% (48/54) were B‐cell IVL. Rituximab + high‐dose methotrexate‐based regimen were used in 75% (12/16) of CNS‐IVL patients and RCHOP in 60% (17/28) of non‐CNS‐IVL patients. Estimated 5‐year progression free survival (PFS) and overall survival (OS) for the entire cohort were 38.6% and 52%, respectively. Skin‐only IVL was associated with excellent survival. Platelet count <150x10 9 /L, age > 60Y, and treatment without Rituximab were poor prognostic factors. Further research is necessary to identify novel therapies.

Abstract Background: AHCT is a standard of care treatment for eligible patients (pts) with MM. Most consensus guidelines recommend that at the time of first AHCT, enough APBHC should be collected to perform two AHCT. However, recent studies have shown that with each decade after 1990, the use of cryopreserved APBHC for a salvage AHCT has declined and is now in the range of 4.6-15% in the decade between 2010-2018. The collection and storage of APBHC for two AHCT incurs additional costs and a prior single center cost analysis revealed that having had collected for just one AHCT in a cohort of 726 MM pts would have saved 3.8 million USD between 1993 and 2011. 1 Most centers that perform AHCT for MM pts continue to collect and store PBAHC for 2 AHCT. Herein we evaluate utilization trends and costs associated with cryopreserved APBHC in patients with MM. Methods: We retrospectively evaluated the clinicopathologic data from 440 patients with MM who underwent APBHC mobilization and collection at Mayo Clinic Florida between 2010 and 2019. The number of apheresis/collection sessions and APBHC product collection yields were determined for patients who were mobilized by any method. We estimated the costs involved in PBSC collection (apheresis) and cryopreservation storage based on our institution-specific charges as of May 2021. The cost of 1 session of APBHC collection/apheresis was $4,680 and the cost of 1 year of APBHC cryopreservation was $4,790 per patient. Statistical analysis was performed using JMP Pro 15 (SAS). Chi-square and Fischer exact tests were used to carry out univariate analysis for categorical variables and Wilcoxon rank sum/Kruskal Wallis for continuous variables. Results: Patient demographics are shown in Table 1. 440 pts underwent at least one collection session and 347 underwent at least 1 AHCT. The median number of mobilization sessions was 1 (95% CI 1.0-1.03), the median number of collection/apheresis sessions was 2.0 (95% CI 2.39-2.59), 84.3% (n=371) required ≥1 collection session. The median number of CD34 stem cells collected was 7.6 x10 6 (95% CI 7.76-8.19 x10 6), and the median number of infused CD34 cells was 4 x10 6(95% CI 4.13-4.37x10 6). The median cost of total collection sessions (defined as # of apheresis/collection sessions x $4,680) was $9,360 per pt (95% CI $11,181-$12,100). The median cost of cryopreservation (defined as # of years of storage x $4,790) was $19,160 per pt (95% CI $9,682-$22,252). The median number of years of storage was 4 (95% CI 4.11-4.65). 77(17.5%) pts have had APBHC in storage for &lt;2 years, 218 (49.5%) have had APBHC in storage for 2-5 years, and 145 (33%) had have APBHC in storage for &gt;5 years. The median time from MM diagnosis to AHCT was 9.0 months (range 13.8-18.5). 82% of patients collected enough APBHC (≥6x10 6, at least 3x10 6 per AHCT)for 2 AHCT. 8% of patients had all APBHC infused during their first AHCT, 83.5% had half of their APBHC infused during their first AHCT, and 8.1% had a different amount of APBHC infused during their first AHCT thus 91.6% of patients who collected APBHC had cells in storage. The median OS for the entire cohort after AHCT was 94.7 months (95% CI 88.6-100). Out of 347 patients who had stem cells in cryopreservation, 5 (1.4%) underwent a salvage AHCT and 3 (0.9%) underwent a tandem AHCT. 61% percent of patients had ≥1 excess collection sessions for APBHC that ultimately went unused. The median cost of excess collection sessions was $4,680 per pt (range, $4,680-$32,760) and the median total cost for excess collection sessions plus costs for storage was $23,840 per pt (range, $4,680-$85,450). The sum of costs of excess collection sessions was $2,077,920 and the sum of costs of cryopreservation was $5,812,665. Conclusion: The results of this single center analysis show that only 1.4% of patients underwent a salvage AHCT between 2010 and 2019 while 91.6% had APBHC left in storage which confirms the increase in storage of cryopreserved APBHC and declining trend in the use of stored APBHC for salvage AHCT in pts with MM. This is likely due to the advent of next generation novel therapies such as monoclonal antibodies, proteasome inhibitors and immunomodulatory agents. Excess collections, and cryopreservation of unused APBHC incur a cost of nearly $8 million. Institutional policies regarding universal APBHC collection and long-term storage should be reevaluated. 1Phipps C, et al. Bone Marrow Transplantation 2015:50;663-667. Figure 1 Figure 1. Disclosures Murthy: CRISPR Therapeutics: Research Funding. Ailawadhi: Sanofi: Consultancy; Medimmune: Research Funding; Genentech: Consultancy; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Xencor: Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy; Beigene: Consultancy; GSK: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy; Cellectar: Research Funding; Karyopharm: Consultancy.

Abstract Introduction: Intravascular lymphoma (IVL) is an extra nodal non-Hodgkin lymphoma with tropism for vascular endothelium. It is characterized by growth of large cells within the lumen of small to medium sized blood vessels. Central nervous system (CNS) and skin are predominantly involved. This report represents a retrospective single-institution review of IVL. Methods: We identified patients (pts) with IVL evaluated at Mayo Clinic Cancer Center between January 2003 and December 2018. Demographic, clinical, radiologic, pathologic, and therapeutic data were extracted. Statistical analysis of overall survival (OS) and progression free survival (PFS)] was performed using Kaplan-Meier method. Results: Total number of pts was 55; 22% (12/55) had CNS-only IVL, 14.5% (8/55) had CNS and non-CNS IVL, and 63.6% (35/55) had non-CNS IVL. Eighty seven percent (47/54) pts were B cell type, 11% (6/54) were T cell type, one pt had NK cell type IVL and another was unknown. Four pts were diagnosed by autopsy. Median age at diagnosis was 68 years (range, 40-85). Sixty-four percent were males. ECOG performance status was &lt;2 in 66%. The median follow-up time from diagnosis was 63 months [CI 95%, 9-NR], and 47% (26/55) were alive. The most common diagnostic biopsy sites were bone marrow (BM) 45% (25/55), skin 25% (14/55), and brain 29% (16/55). Twenty-nine patients had a PET scan. Seventy nine percent (23/29) had abnormal PET findings, with mean SUV of 8.6 (range 2.5-19.1). Of the 35 pts with non-CNS IVL, 76% (16/21) had abnormal PET; furthermore, the diagnosis was made with biopsies of the following sites: bone marrow 54% (19/35), skin 40% (14/35), lung 14% (5/35), liver 5.7% (2/35), spleen 2.8% (1/35), and omentum 2.8% (1/35). Forty-six percent (13/28) received CNS prophylaxis and ten percent (3/55) had relapse in CNS. Two out of the three pts who had CNS relapse had received CNS prophylaxis. The median time to CNS relapse in non-CNS IVL was 9 months. The most common first-line regimen was high-dose methotrexate+ rituximab containing regimen 62% (10/16) in IVL with CNS involvement and RCHOP (60%) (17/28) in non-CNS IVL. Seventeen percent of (8/48) pts received autologous stem cell transplant (ASCT) and 63% (5/8) pts were transplanted in first complete remission (CR1), and 3 pts after the first relapse. Median OS (mOS) for the whole cohort was 57 months, [CI 95%, 9-NR], and median PFS was 7 months [CI 95%, 2-NR]. There was no significant difference in mOS between groups; CNS-only IVL- 9 months (CI 95%, 1-NR), non-CNS IVL -62 months (CI 95%, 20-NR) vs combined CNS and non-CNS IVL- 4 months (CI 95%, 3-NR). mOS for those who received ASCT in CR1 was not reached (CI 95%, 10-NR) vs 51 months in non-transplant group (CI 95%, 3-NR) p=0.24. In pts with non-CNS IVL, there was no significant difference in mOS between CNS prophylaxis subgroup (NR: CI 95%, 57-NR) vs no-CNS prophylaxis subgroup (20 months: CI 95%, 0-NR), p=0.12. In those with CNS IVL mOS for early diagnosis (0-30 days from symptom onset to diagnosis was NR (CI 95%, 3-NR) vs mOS for late diagnosis (&gt;30 days {31-14,440})-5months (CI 95% 1-NR), p=0.29]. Conclusion: 1. BM was most frequently involved in our patients. We suggest that BM biopsy should be part of diagnostic testing when IVL is suspected. 2. Most cases are of B-cell linage, consistent with reported literature. All non-B cell cases were in non-CNS locations. 3. PET scans were abnormal in more than 70% of cases indicating that this imaging modality is vital in the diagnosis due to odd location and small size of lesions. 4.Overall prognosis in the literature was poor with most patients surviving &lt;1 year. Our cohort has mOS of 57 months. The reason(s) for better survival in our cohort could not be definitively determined. 5. CNS involvement had an overall trend towards poor prognosis; however, those diagnosed early had better outcomes; this did not reach statistical significance due to small sample size. 6. mOS was not reached for those transplanted CR1. There was a trend towards a better survival associated with CNS prophylaxis versus no prophylaxis in non-CNS IVL. 7. We suggest that CNS-centric therapeutic approach and intensive consolidation with ASCT should be considered in managing IVL. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Habermann: Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Tun: Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding; Gossamer Bio, Acrotech: Consultancy.

Abstract Background: Haploidentical allogeneic hematopoietic cell transplantation (haplo) has expanded applicability of the procedure to patients for whom a suitable HLA compatible donor was not available in the past. A small multicenter retrospective study of 185 patients with hematologic malignancies who received a nonmyeloablative preparative regimen followed by infusion of bone marrow (BM) hematopoietic cells from haploidentical donors showed no significant association between the number of HLA mismatches (HLA-A, -B, -C, and -DRB1 combined) and risk of acute grade 2-4 graft-versus-host disease (GVHD) (hazard ratio [HR]=0.89; P=0.68 for 3-4 mismatches vs fewer antigen mismatches). This haploidentical transplant platform has certainly evolved. Nowadays, G-CSF mobilized peripheral blood stem cells (PBSC) are commonly used owing to its increased convenience vis-à-vis performing a BM harvest. Study population: Here, we evaluate post transplant outcomes when using haploidentical donors with T-replete PBSC and PTCy in AML in CR1. A total of 494 patients (4/8 HLA mismatch (group 1)=360, 2-3/8 HLA mismatch (group 2)=134) underwent the procedure at an EBMT participating center. The primary endpoints were cumulative incidences of grade 2-4 acute GVHD and chronic (all grades) GVHD. Secondary endpoints included cumulative incidence of relapse (RI), non-relapse mortality (NRM), leukemia-free (LFS) and overall survival (OS) and GVHD-free relapse-free survival (GRFS). Results: Group 1 and group 2 were not statistically different in regards to median age at allografting (54.1 vs. 56.1 years, p=0.51), median year of haplo transplantation (2018 vs. 2018, p=0.36), incidence of de novo AML (86.4% vs. 88.1%, p=0.63), Karnofsky equal or more than 90 (77.5% vs. 79.1%, p=0.70), and use of myeloablative conditioning (MAC) (44.7% vs. 48.5%, p=0.45). Patients in group 1 had a longer time from diagnosis to haplo-transplantation (5.3 vs. 4.9 months, p=0.03). In multivariate analysis, group 1 and group 2 did not differ in cumulative incidence of grade 2-4 acute GVHD (Hazard ratio (HR)=0.89 (95%CI=0.62-1.26), p=0.51) but group 1 had a significantly higher incidence of chronic (all grades) GVHD (HR=1.49 (95%CI=1.02-2.16), p=0.04). There was no difference in RI (HR=0.73 (95%CI=0.47-1.14), p=0.17), NRM (HR=1.25 (95%CI=0.78-2.02), p=0.36), LFS (HR=0.95 (95%CI=0.69-1.31), p=0.76), OS (HR=1.09 (95%CI=0.76-1.55), p=0.64) and GRFS (HR=1.07 (95%CI=0.81-1.42), p=0.64) between the groups. Presence of adverse cytogenetics was independently associated with higher RI (HR=1.90 (95%CI=1.20-2.99), p=0.006), inferior LFS (HR=1.59 (95%CI=1.15-2.19), p=0.005), inferior OS (HR=1.48 (95%CI=1.05-2.08), p=0.03), and worse GRFS (HR=1.54 (95%CI=1.17-2.04), p=0.002). Conclusion: Results show that patients undergoing haplo-transplantation with 4/8 (vs. 2-3/8) HLA mismatches have a higher incidence of chronic GVHD (all grades) without adversely affecting acute grade 2-4 GVHD, RI, LFS, OS and GRFS. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forcade: Novartis: Other: travel grant. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Takeda: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria.

Abstract Introduction Post-transplantation cyclophosphamide (PTCy) and calcineurin inhibitor (CNI) based GVHD prophylaxis has shown lower rates of acute and chronic GVHD when compared with the traditional prophylaxis of calcineurin inhibitor (CNI) and methotrexate (MTX) in matched donor (related and unrelated) allo-HCT. The combination of PTCy with sirolimus as a calcineurin inhibitor-free GVHD prophylaxis has shown promising results with cumulative rates of grade II-IV acute and chronic GVHD in the range of 15-27% and 20-27% respectively in patients undergoing matched and haploidentical allo-HCT. We report a single center, nonrandomized comparison of patients undergoing matched donor allo-HCT receiving PTCy in combination with sirolimus (PTCy/Siro) with those receiving the standard GVHD prophylaxis of tacrolimus and MTX (Tac/MTX). Methods One hundred and sixteen consecutive patients who had undergone a MRD or MUD allo-HCT between January 2018 to January 2021 and received either PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimens were eligible for inclusion. The selection of PTCy with sirolimus or tacrolimus with methotrexate as GVHD prophylaxis regimen was based on physician choice. Primary endpoints were cumulative incidence of acute (grade II to IV) and chronic GVHD. Secondary endpoints were a) neutrophil and platelet engraftment; b) overall survival (OS); c) non-relapse mortality (NRM); d) relapse; e) clinical infections and f) time to immunosuppression (IS) withdrawal. Kaplan-Meier method was used to estimate 1-year and 2-year freedom from long term adverse events, including chronic GVHD, relapse, NRM and OS. All tests were two-sided with alpha level set at 0.05 for statistical significance. Results Out of a total of 116 patients undergoing MRD and MUD allo-HCT, 29 received PTCy/Siro and 87 Tac/MTX. Baseline characteristics were similar between the two arms except patients in PTCy/Siro were younger with median of 48 (range: 24-69) years vs. 61 (range: 20-73) years (p=0.004) in Tac/MTX. There was difference in primary indication for allo-HCT between the two arms with non-hodgkin lymphoma (NHL) being the most common in PTCy/Siro and acute myeloid leukemia (AML) in the Tac/MTX group. Patients receiving PTCy/Siro had a significantly higher median CD3 day 100 chimerism at 100 (90-100) vs. 90 (40-100) % (&lt;0.001) and a significantly shorter median time to IS withdrawal at 138 (37-312) vs 232(66-1120) days for patients receiving Tac/MTX. There was no difference between the two arms for length of hospital stay and time to neutrophil engraftment, but PTCy/Siro had a significantly longer median time for platelet engraftment at 17.5 (12-74) vs.14 (11-38) days (p= 0.001). No significant difference was observed between the two arms for incidence of grade II to IV acute GVHD, grade III to IV acute GVHD, steroid refractory acute GVHD or clinical infections (Table 1). After a median follow up of 1.1 (range: 0-1.8) years, patients receiving PTCy/Siro were significantly less likely to have chronic GVHD with 2-year freedom from GVHD of 75% (95%CI: 58-98%) vs 20% (95%CI 10-40%), p=0.005 (Figure 1). There was no difference between the two arms for OS, disease relapse or non-relapse mortality (Table 2). Conclusion In this study, the combination of PTCy/Siro is associated with a significantly lower risk of chronic GVHD when compared against the traditional GVHD prophylaxis of CNI and methotrexate, despite significantly earlier IS withdrawal. Other long-term outcomes of interest remained comparable between the two arms. Chronic GVHD contributes to significant morbidity and mortality in patients undergoing allo-HCT. Newer strategies to limit the impact of chronic GVHD are needed. The results of our study warrant validation in a large, multicenter, randomized prospective trial. Figure 1 Figure 1. Disclosures Murthy: CRISPR Therapeutics: Research Funding. Foran: gamida: Honoraria; takeda: Research Funding; novartis: Honoraria; trillium: Research Funding; boehringer ingelheim: Research Funding; OncLive: Honoraria; abbvie: Research Funding; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; taiho: Honoraria; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; pfizer: Honoraria; actinium: Research Funding; aptose: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

Abstract Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.