Abstract: Intro: Assessment of induction mortality risk in acute myeloid leukemia (AML) patients is challenging. Hematopoietic cell transplant comorbidity index (HCT-CI) score was designed for risk assessment of patients undergoing an allogeneic transplant. However, it is often used in clinical practice to assess induction mortality risk in AML patients. We analyzed the predictive power of the score to assess induction mortality risk as well as overall survival in AML patients at our institution. Methods: Between Jan 2009 and March 2013, 101 consecutive newly diagnosed AML patients treated at our institution were included for analysis. All patients received bolus HiDAC (3gm/m2) on day 1-5 and high dose mitoxantrone (80mg/m2) on day 2. The median age was 65 years (range18-90). The total number of patients in the age group 〈 60, 60-69 and ≥70 were 30(29.7%), 35(34.6%) and 36(35.6%) respectively. HCT-CI scores were calculated before induction chemotherapy. Kaplan Meir curve was used to calculate OS and PFS. 4-week induction mortality was calculated from the date of the induction chemotherapy. The patient cohort was divided into those with HCT-CI scores of 〉 or ≤3. Results: The number of patients with the HCT-CI score of 0,1,2 and 3 were 8,13,17 and 13 respectively. 50% of our patients (51 patients) had a score of 4 or more on the HCT-CI index. The 4 and 8-week mortality in our cohort was 3/101 (2.9%) and 7/99 (7%) respectively. 4-week induction mortality in 〈 60, 60-69 and ≥70 years of age groups were 0/30(0%), 1/35(2.8%) and 2/36(5.5%) respectively. Similarly, in above age groups, 8-week induction mortality were 0/29(0%), 2/34(5.8%) and 5/36(13.8%) respectively. The median OS in patients with an HCT-CI score ≤3 was 87 months versus 11.5 months in those with a score 〉 3 (log-rank, p=0.0046, Fig1). 2-yr NRM rate for patients with HCT-CI score ≤3 and 〉 3 was 47% and 71%, respectively (p=0.01, Fig2). Hazard ratio for overall mortality in patients with HCT-CI score 〉 3 is 1.793 with p=0.023, 95% CI = (1.083 - 2.971). HR for 8-week mortality in patients with an HCT-CI score 〉 3 is 2.035 (p=0.412), although not statistically significant due to a low number of events. However, by Cox multivariable regression analysis HCT-CI retained a significant impact on 8-week mortality (HR=1.24, p= 0.03) and overall survival (HR=1.144, p= 0.006). Conclusion: An HCT-CI score is a valuable tool in the assessment of the induction mortality in newly diagnosed AML patients and can be used for risk assessment of overall mortality. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Abstract: Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% 〉 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P 〈 .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P 〈 .0001).

Abstract: Background: Allo-SCT is a curative option for patients with AML and MDS. It is unclear whether there is an upper age limit for Allo-SCT. CIBMTR showed similar outcomes for patients older than 65 years after Allo-SCT (McClune et al J Clin Oncol 28:1878-1887). A single center report of 54 patients (70 - 75 years) established the feasibility of Allo-SCT in patients over age 70 (Brunner et al Biol Blood Marrow Transplant 19:1374-1380). There is no published data on Allo-SCT in patients older than 75 years. Methods: Retrospective analysis was performed on all patients with diagnosis of AML or MDS who underwent an Allo-SCT after their 75th birthday at UMass Memorial Medical Center on an IRB approved protocol. Results: 14 patients were identified from the database. Median age at transplant was 78.4 years (range 75.2 - 83.6). Diagnosis was AML (N=10) and MDS (N=4). Disease status at SCT for AML patients was CR1 (N=6), ≥ CR2 (N=2) and relapse (N=2). Source of stem cell was peripheral blood (PB) (N=11) and cord blood (CB) (N=3). Median time from diagnosis to SCT was 7 months (range 3 - 98). Karnofsky score (KS) at SCT was 90 (N=5) and 80 (N=9). Three patients had prior autologous SCT. Source of stem cells was peripheral blood (PB) (N=11) and cord blood (CB) (N=3). Donors were mostly unrelated (N=13) with one being mismatched related (N=1). For PB recipients the HLA matching was 10/10 in 7 patients and 9-11/12 in 4 patients. CMV serostatus was neg/neg (N=2), pos/pos(N=4) and pos/neg (N=7). ABO mismatch was major (N=1) and minor (N=6). Conditioning regimen was reduced intensity in 13/14 recipients. All three CB recipients received Melphalan (Mel) based conditioning (Thio/Flu/Mel 100-140mg/m2). Conditioning for PB recipients was Busulfan(Bu) based (N=6) and Mel (dose 50 - 140mg/m2)based (N=5). Graft versus Host Disease (gvhd) prophylaxis was Tacrolimus (Tac) with Mycophenolate mofetil (MMF) for all CB-SCT recipients Flu/Bu-2 recipients. All Mel based PB-SCT recipients received post-transplant Cyclophosphamide (days 3, 4) with Sirolimus. HLA mismatched patients also receive Tac. 11/14 patients received ATG. All PB recipients engrafted their neutrophils at a median of 16 days (range 13-21). 10/11 patients engrafted their platelets at a median of 18 days (range 0-32). One CB recipient died on day 10 before engrafting. Other two CB recipients engrafted their neutrophils on day 14 and platelets on days 33 & 37. Day 100, 1- year and 5 - year overall survival for the entire cohort was 70.7% (95% CI 39.4-87.9), 53% (95% CI 23.3-75.9) and 22.1% (95% CI 3.8 -49.9) respectively. Two patients developed grade III and 3 patients developed grade II acute gvhd. Chronic (limited) gvhd was seen in one patient only. 9 patients died at a median of 264 days (range 10 - 802) post SCT. There were no deaths due to disease progression. Three patient are currently surviving beyond 2 years. Two of these patients are immune suppression free, gvhd free and live alone with a KS of 100. 3 out of 4 patients over age 80 years survived more than 2 years. Conclusion: Allo-SCT is feasible in selected patients over the age of 75. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Abstract: Background B cell maturation antigen (BCMA) is a clinically validated target for multiple myeloma (MM) based on its restricted expression profile and potential functional role in promoting MM cell survival. HPN217 is a BCMA-targeting T cell engager derived from the Harpoon Tri-specific T cell Activating Construct (TriTAC ®) platform. It is a recombinant polypeptide of approximately 50 kDa, engineered to be a small globular protein to enable efficient drug diffusion and exposure in tumor tissue and have a prolonged serum half-life at the same time. It contains three humanized antibody-derived binding domains, targeting BCMA for MM cell binding, albumin for half-life extension, and CD3ε for T cell engagement, activation, and cytolytic function differentiation. Methods The ongoing Phase 1 study initially evaluates escalating doses of once weekly IV administrations of HPN217 in patients with relapsed/refractory (R/R) MM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and a CD38-targeted therapy. Prior exposure to BCMA-targeting agent is permitted for this initial part of the trial. Premedication to minimize cytokine release syndrome (CRS) includes dexamethasone, diphenhydramine, acetaminophen, and a proton pump inhibitor. Primary endpoints are safety, tolerability, and determination of maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D). Secondary objectives are pharmacokinetics (PK), pharmacodynamics, immunogenicity, and preliminary anti-myeloma activity. Results As of July 5, 2021, 22 patients have been treated with HPN217 in 8 individual cohorts ranging from 5 to 2150 µg/week. Patients treated received a median of 8 (range of 4 - 16) prior systemic regimens, including 5 patients who received prior BCMA-targeted belantamab mafodotin or orvacabtagene autoleucel. No dose-limiting toxicities (DLTs) have been observed and MTD has not been reached. The most common treatment-emergent adverse events (TEAEs) are hematological changes including anemia, neutropenia, and thrombocytopenia. No CRS was observed in dose cohorts receiving 5 - 270 µg/week (n=7). CRS (Grade 1, 2) was observed in 4 of 15 patients receiving ≥810 µg/week. In one patient treated at 810 µg/week, transient elevated liver transaminases (Grade 4 AST and Grade 3 ALT) was observed. A second patient in the 270 µg/week cohort also showed Grade 1 AST increase. All CRS events and liver enzyme increases resolved, and all patients were successfully re-treated with escalating doses. HPN217 demonstrated a dose proportional increase in Cmax and AUC with a median serum half-life of 74 hours (range of 38 - 197 hours), confirming half-life extension. Half-life, clearance rate, and volume of distribution were dose-independent, suggesting linear PK kinetics. Pharmacodynamic analysis shows a dose-dependent, transient increases in serum cytokines and chemokines (e.g., IL-6, IL-8, IL-10, TNFα). A transient reduction in circulating T lymphocytes accompanied by upregulation of the activation markers CD25 and CD69 were also observed. Patient response to treatment will be reported. Conclusions HPN217 represents a novel half-life extended BCMA-targeting T cell engager that can be safely administered to patients with R/R MM at a dose of up to 2150 µg weekly. TEAEs have been transient and manageable. Transient serum cytokine/chemokine increase, T cell margination and upregulation of T cell activation markers, indicate target engagement of BCMA on plasma cells and CD3 on T cells, respectively, supporting the proposed mechanism of action for HPN217. Dose escalation, including implementation of step dosing, with the goal of establishing an RP2D regimen, is ongoing. NCT04184050 Disclosures Madan: Sanofi: Consultancy, Research Funding; GSK: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Karyopharm: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; BMS: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Cowan: Janssen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Sanofi Aventis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Secura Bio: Consultancy; Cellectar: Consultancy; Nektar: Research Funding; GSK: Consultancy; Harpoon: Research Funding. Bensinger: BMS, Janssen, Poseida, Regeneron, Trillium: Research Funding; Amgen, BMS, Janssen, Sanofi: Speakers Bureau. Hillengass: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Curio Science: Speakers Bureau; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Beijing Medical Award Foundation: Speakers Bureau; Adaptive: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Skyline: Membership on an entity's Board of Directors or advisory committees; Axxess Network: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Beijing Life Oasis Public Service Center: Speakers Bureau. Leleu: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Celgene: Honoraria; Gilead Sciences: Honoraria; AbbVie: Honoraria; Janssen-Cilag: Honoraria; Karyopharm Therapeutics: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Lipe: Seagen Inc.: Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; sanofi: Consultancy; GlaxoSmithKline: Consultancy; amgen: Research Funding; Cellectar: Research Funding; Karyopharm: Research Funding; Harpoon: Research Funding. Nath: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company. Sun: Harpoon Therapeutics: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months.

Abstract: Abstract 3560 Introduction: Acute myeloid leukemia (AML) originates from rare leukemia stem cells (LSCs). LSCs are chemotherapy resistant and responsible for disease recurrence. AML containing a high percentage of LSCs displays aggressive biology in animal models. Using humanized mice Saito et al (Sci Transl Med 2010; 2: 1–11) have recently shown that xenografted CD25+ LSCs initiate AML and are chemotherapy resistant. Confirmation with clinical data from human AML is needed. Methods: In order to determine the prognostic impact of CD25 expression on AML outcome we have retrospectively investigated CD25 expression in 56 patients (pts) diagnosed and treated for AML at our institution between 02/2008 to 05/2011. 46 pts who had non-APL morphology, were treated with induction chemotherapy and had an adequate specimen for CD25 assessment were included in further analysis. CD25 expression was assessed in each specimen by flow cytometry and immunohistochemistry and correlated with clinical outcome. Patients: Median age was 61 years (22–84), 18 (39%) pts were older than 65; F:M ratio was 19:27, 3 (7%) patients had good risk (core binding factor leukemias), 26 intermediate (diploid karyotype and no good or high risk; 57%) and 17 (37%) high risk cytogenetics (complex, anbormality of 3q26, monosomy 7 and 5). 6 (13%) pts had NPM1mut/FLT3-ITDwt, 6 (13%) pts had NPM1wt/FLT3-ITDmut and 9 (13%) pts had NPM1mut/FLT3-ITDmut. As induction high dose cytarabine/anthracycline based regimen was used in 36 (78%) pts, 7 pts received 7+3 (15%) and 3 (7%) pts received hypomethylating agent. 24 (53%) pts received stem cell transplantation (SCT; 16 [35%] allogeneic and 8 [17%] autologous). The median follow up of the surviving pts was 11.2 months (1.1–38.7). Results: CD25 was detected in 17 pts (37%; 16 at diagnosis and 1 at relapse). Six CD25+ pts experienced relapse (3 pts with 3 or more relapses) heralded by increase in the percentage of CD25+ blasts. 65% of pts with CD25+ AML also had FLT3-ITDmut (p=0,0012). When comparing CD25+ and CD25- pts there was no statistical difference in distribution of the following characteristics: sex, age (65+), cytogenetics risk, presence of NPM1mut, type of induction, SCT. Fifteen (88%) of CD25+ pts experienced relapse compared to 8 (28%) of CD25- pts (p= 0.00007), 8 (47%) CD25+ pts died and 9 (31%) CD25- pts died (p=ns). The median relapse free survival (RFS) of all pts was 10.8 months with the median overall survival (OS) 12.2 months. The estimated 6-month RFS was significantly decreased in CD25+ pts compared to CD25- pts (26% vs 79%, p= 0.0003). This did not translate into a difference in OS between both groups (1-year OS: CD25+ 43% vs CD25- 65%, p=ns). In univariate analysis CD25 positivity was a stronger predictor for relapse (HR 5.28 [2.21–12.62], p=0.0002) than FLT3-ITDmut (HR 4.72 [2.04–10.92] ; p= 0.0003). In multivariate analysis CD25 positivity was also a stronger predictor for relapse (HR 6.54 [1.34–9.15], p=0.01) than FLT3-ITDmut (HR 4.72 [2.04–10.92] , p= 0.03). Pts undergoing SCT had significantly longer 1-year OS (66%) compared to pts without SCT (21%; p=0.0004). In multivariate analysis SCT was a predictor for improved OS (HR 0.2 [0.07–0.57], p=0.0002). CD25+ pts who received SCT had also significantly longer 1-year OS (63%) compared to CD25+ pts who did not receive SCT (0%; p=0.0098). SCT did not impact RFS in either group. Conclusion: CD25 represents a novel prognostic factor in AML. The increase in CD25+ blasts at relapse is associated with increased relapsed rate and refractory AML supporting the LSCs hypothesis. The detection of CD25 serves not only as a prognostic marker, but may be valuable for minimal residual disease assessment in patients who lack a molecular marker. In our experience treatment inclusive of stem cell transplantation abrogated the negative impact of CD25 expression on OS. Exploration of CD25 as a therapeutic target in AML is warranted. Disclosures: No relevant conflicts of interest to declare.

Abstract: Abstract 3290 Background: Patients with high risk AML, defined as those with age 〉 60 years or multiple medical co-morbidities determined by Charleston comorbidity index (CCI) carry a poor prognosis and inferior outcomes after 7+3 induction chemotherapy. CR rates tend to range from 6–51% and induction death rates between 9–48%. We present here a single institution experience of high risk AML patients treated with an induction regimen consisting of high dose mitoxantrone and cytarabine (HiDAC/MITO). Methods: We performed a retrospective analysis of all patients with AML who received HiDAC/MITO induction from January 2009- January 2010 at our institution. Patients with age ≥60 or age 〈 60 with high CCI received HiDAC at 3gm/m2 over three hours on days 1 to 5 plus MITO 80mg/m2 once on day 2. Effect of other high risk features including poor risk cytogenetics, therapy related AML (t-AML), AML with prior antecedent hematological disorder (AHD) and relapsed AML on treatment outcome were also evaluated. The primary endpoints of the study were CR (defined as bone marrow blasts 〈 5%) at day 30 and treatment related mortality within 30 days of initiation of treatment. End of follow-up was June 30, 2010. Results: 20 AML had received HiDAC/MITO for remission induction. The median age was 66.5 years (range 47 to 78), those with age ≥ 70 was 8 (40%). CCI was ≥ 5 in 18 (90%) patients. Other high risk features included high risk cytogenetics in 8 (40%) and non-denovo AML (AML with AHD, t-AML or relapsed AML) in 11 (55%). Overall CR rate was 17 (85%, CI: 61%-96%) and 3 (15%) patients had refractory disease. There was no treatment related mortality. Median time to neutrophil recovery ( 〉 1000/ul) was 27 (range 19 to 37) days and median time to platelet recovery ( 〉 100,000/ul) was 28 days (range 23 to 44) days. Patients with non–denovo AML were more likely to be refractory to treatment or relapse after day 30. Median follow up of the entire cohort is 288 (range 29 to 530) days. 3 month and 6 month overall survival (OS) was 94.7% and 73.3% and progression free survival (PFS) 93.8% and 87.5%, respectively. The median OS was 410 days (CI: 243-*); (denovo 410 vs. others 381 days). Median PFS is 524 days (CI: 381-*); (denovo *not reached vs. others 381 days). 11(55%) patients were able to proceed to autologous (4) or allogeneic (7) stem cell transplantation (SCT) after receiving HiDAC/MITO. The time to transplant ranged from 44 to 195 days. Median OS of the patients who underwent SCT is 524 days versus 269 days for the non transplant group (p =0.0038). The HiDAC/MITO induction regimen was well tolerated. Cardiac toxicity defined by symptomatic CHF was noted in 6/20 patients. Of the six patients 2 had prior cardiac history and 1 had prior anthracycline exposure and 1 had both anthracycline exposure and cardiac history. Cardiac toxicity was delayed and identified by echo at a median of 90 range (42 to139) days after induction chemotherapy. None of these patients died from cardiac toxicity. Conclusions: In this high risk AML population, HiDAC/MITO induction was well tolerated and demonstrated an overall response rate of 85% and no induction deaths, allowing a substantial number (55%) of patients to proceed to SCT. Contrary to our expectations advanced age or multiple medical co-morbidities did not affect CR rate or survival, thus high lighting the utility of this regimen for high risk newly diagnosed elderly patients with AML. Disclosures: No relevant conflicts of interest to declare.

Abstract: 2517 Background: Approximately 50% to 60% of pts with r/r LBCL will either not achieve a complete response (CR) or will relapse with current treatments and require additional therapy. Autologous anti-CD19 chimeric antigen receptor T (CAR T) therapies have revolutionized the care of patients whose disease progresses following standard therapies, but patient-specific manufacturing processes and long wait times to treatment present challenges for their broad clinical use. Allogeneic (healthy-donor-derived), off-the-shelf, anti-CD19 (CAR T) treatment promises broader and more rapid access to one-dose treatment with curative intent. Initial phase 1 data for the anti-CD19 AlloCAR T cell product ALLO-501 (NCT03939026) and successor, ALLO-501A (NCT04416984), demonstrated a manageable safety profile with no dose-limiting toxicities (DLTs), and efficacy comparable to autologous CAR T therapy in pts with r/r LBCL who were autologous CAR T-naïve. This update provides additional follow up and a focus on participants who received the conditioning regimen and cells made with an optimized manufacturing process currently under study in the first potentially pivotal trial for an allogeneic CAR T product. Methods: In these two multicenter, single-arm, open-label, phase 1 trials, a cohort of autologous CAR T-naïve pts with r/r LBCL underwent 3-day lymphodepletion (LD) with FCA90, fludarabine (F, 30 mg/m 2 /day), cyclophosphamide (C, 300 mg/m 2 /day), and ALLO-647 (A [anti-CD 52 mAb] 30 mg/day; total dose: 90 mg) followed by a single dose of ALLO-501 or ALLO-501A produ ced by the Alloy manufacturing process. Results: As of Jan 26, 2023, 12 pts received the FCA90 LD regimen and CAR T therapy with 100% receiving product per specifications with a median time from enrollment to LD of 3 days. Median follow-up time (actual) was 7.1 months (range: 1.4, 36.0). No DLTs, severe (Gr3+) cytokine-release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) events occurred. An overall response rate and a CR rate of 66.7% and 58.3%, respectively, were observed. Median DOR was 23.1 months. Among 8 pts with the opportunity to be followed for 6 months, 5 (62.5%) had achieved CR and 4 (50.0%) sustained CR through 6 months. Analyses of vector copy number pharmacokinetics at Days 28 and 56 documented substantial and sustained expansion of CAR T cells. Conclusions: A one-time dose of allogeneic CAR T therapy following LD with FCA90 provided durable responses with a manageable safety profile in patients with r/r/ LBCL comparable to those treated with autologous CAR T cells. This treatment enables rapid access to off-the-shelf treatment with a median time from trial enrollment to treatment of 3 days. These findings support broader evaluation of ALLO-501A in the ongoing, first potentially pivotal phase 2 trial (ALPHA2) of off-the-shelf allogeneic CAR T cells. Clinical trial information: NCT03939026 .