Safah, Hana

Abstract Background: Clonotypic peptide detection by mass spectrometry (MS) leverages monoclonal protein (M-protein) de novo sequencing and peptide quantification to enable ultra-sensitive blood-based monitoring of multiple myeloma (MM) patient M-protein kinetics. Etentamig is a 2nd generation BCMA x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pre-treated patients with relapsed or refractory (RR) MM (Journal of Clinical Oncology, 43;16:suppl.7527). In the current study, we explored the depth and kinetics of MS M-protein response to etentamig monotherapy in serum samples from Phase 1 M22-466 (NCT03933735) study patients. The correlation between blood-based MS M-protein levels and bone marrow minimal residual disease (MRD) negativity as determined by next generation sequencing (NGS) was also evaluated. Method: Clonotypic peptide MS using M-Insight (Sebia/Corgenix) was performed on serum samples from a subset of MRD evaluable patients enrolled into the Phase 1 (NCT03933735) clinical trial of etentamig monotherapy in patients with RRMM. Bone marrow MRD negativity (<10-5 and 10-6) analysis was determined by NGS (clonoSEQ, Adaptive Biotechnologies). Patient pre-treatment (Cycle [C] 1 Day [D] 1) serum samples were digested with proteolytic enzymes to permit sequencing of the M-protein heavy and light chain. Clonotypic peptides specific to the patient's complementarity-determining regions were selected for quantification by MS. Clonotypic peptide quantification by MS was performed on available tracking peripheral blood samples at C2D1, C3D1, C4D1, and C5D1 time points post etentamig monotherapy treatment. Results: Twenty patients who were MRD evaluable and treated with 40 mg and 60 mg doses of etentamig with available serum samples collected from C1D1–C5D1 time points were selected for M-Insight evaluation. Of the 20 patients, 16 (80%) had at least one clonotypic peptide identified prior to etentamig treatment that was utilized for tracking at subsequent time points. Rapid decline in MS M-protein levels was observed in patients treated with etentamig, which strongly correlated with the patients' best International Myeloma Working Group (IMWG) response. At C3D1 post etentamig treatment, patients with complete response (CR)/stringent CR (n=9) demonstrated a significant decline from MS M-protein levels (median: 1.8±0.9 g/dL at C1D1 to 0.03±0.2 g/dL at C3D1) (P<0.001). All evaluable subjects (n=16) had detectable MS M-protein at all time points (n=80). The lowest detectable M-protein level observed in the current dataset was 44 mg/dL (lower limit of quantitation of assay: 10 mg/dL). Subsequent analysis of differences in kinetics between MRD-negative (<10-5) (n=8) and MRD-positive (n=8) patients revealed a deeper reduction in M-protein levels for MRD-negative patients (median 0.02±0.2 g/dL at C3D1 compared with 0.4±0.3 g/dL at C3D1 for MRD-positive patients). Among the 8 patients who achieved MRD negativity at 10-5 threshold, 5 patients also achieved <10-6 threshold, and serum MS M-protein levels remained detectable in these patients (0.07±0.2 g/dL). Conclusions: Using MS-based clonotypic peptide detection, rapid and deep decline in serum M-protein levels was observed in RRMM patients treated with etentamig. Strong concordance was observed between MS M-protein levels and IMWG response, including in patients achieving MRD-negative CR at <10-5 and 10-6thresholds. Non-invasive and ultra-sensitive M-protein detection is feasible in MM and may serve as a key biomarker for enhancing the detection of residual disease in the future.

Abstract Background Etentamig is a second-generation B-cell maturation antigen (BCMA) x CD3 bispecific antibody that has shown promising efficacy and a favorable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). Etentamig possesses a unique combination of 2 high-affinity BCMA binding domains, coupled to a low-affinity CD3 binding domain that have been shown to reduce the negative impact of soluble BCMA (sBCMA), decrease risk for cytokine release syndrome (CRS), and drive sustained T-cell activation with reduced immune exhaustion in preclinical models of MM (Blood 2023;142 [suppl 1]:4666). Here, we describe correlative biomarker analyses from Phase 1 (NCT03933735) and Phase 1b (NCT05650632) clinical trials of etentamig in RRMM designed to assess the impact of sBCMA on clinical response and pharmacodynamic changes in proinflammatory cytokines, and T-cell redistribution, activation, proliferation, and exhaustion. Methods Peripheral blood and serum samples from patients with RRMM enrolled in Phase 1 and Phase 1b open-label studies who received etentamig monotherapy were collected at baseline, on treatment, and at disease progression. The Phase 1b study consisted of dose-optimization (DO) and dose-expansion (DE) phases. During DO, patients received a single step-up dose (SUD) of intravenous etentamig (2 or 4 mg) on Cycle (C) 1 Day (D) 1, followed by the target dose of 60 mg on D4. In DE, based on DO findings, patients received the recommended etentamig SUD (2 mg) on C1D1, followed by 60 mg on D4 with modified dexamethasone predosing. Samples were analyzed by flow cytometry for immune cell populations, Luminex® for cytokines, and electrochemiluminescence for sBCMA. Peripheral blood mononuclear cells and bone marrow mononuclear cells (BMMC) at baseline and on-treatment were subjected to single-cell Cellular Indexing of Transcriptomes and Epitopes sequencing (scCITEseq) and single-cell T-cell receptors (scTCR) / B-cell receptors clonality analyses. Results While baseline serum sBCMA levels did not correlate with clinical response to etentamig at the selected dose level of 60 mg every 4 weeks (Q4W) with 2 mg SUD, a reduction in sBCMA levels over time was associated with best International Myeloma Working Group response. Etentamig treatment led to a rapid and transient increase of proinflammatory cytokines and promoted T-cell redistribution, activation, and proliferation. Maximum reduction in peak levels of CRS-related cytokines, including (interleukin [IL]-6, IL-8, IL-10, tumor necrosis factor–a), were observed in DE compared with DO and 60 mg Q4W without SUD. Peak induction levels of proinflammatory cytokines during C1 correlated with occurrence of CRS (≥Grade [G] 1) as well as clinical response across dose levels. A modified dexamethasone premedication schedule of 2 mg/60 mg Q4W cohort for C1 resulted in significantly reduced baseline levels of IL-6 and key macrophage-associated cytokine/chemokines (eg, monocyte chemoattractant protein-1 and macrophage inflammatory protein-3 beta). Incidence of CRS was lowest in the 2 mg/60 mg Q4W cohort (26% G1, 4% G2, 0% ≥G3). Higher T-cell to myeloma cell ratio in BMMCs at baseline correlated with better response to etentamig. scCITEseq and scTCR analysis revealed that at baseline, responders also had greater CD8+ T-cell cytotoxic activities, increased TCR clonality, and elevated inflammatory signatures in T-cells from both peripheral blood and bone marrow. Etentamig at a dosage of 60 mg Q4W resulted in significant clonal expansion of CD8+ effector T-cells and enhanced gene expression signatures related to activation and cytotoxicity in both CD8+ T effector and natural killer cells. Along treatment cycles, responders maintained their T-cell fitness, high clonality, and low T-cell exhaustion levels. Frequency of baseline CD4+ or CD8+ T-cell exhaustion (programmed cell death receptor 1+/ T cell immunoglobulin and mucin-domain containing-3 +) did not impact clinical response at optimal dose level of 2 mg/60 mg Q4W etentamig. Conclusions Responses to etentamig were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation indicating that the optimal dose of etentamig (2 mg/60 mg Q4W) maximizes its clinical potential as a convenient, safe, and effective therapy for MM.

7527 Background: Etentamig (etenta) is a differentiated BCMA x CD3 bispecific T-cell engager composed of high avidity bivalent BCMA-binding domains, low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS), and silenced Fc tail for extended half-life enabling convenient dosing. We present long term results from 2 ongoing Ph 1 studies evaluating efficacy and safety of etenta in patients (pts) with RRMM. Methods: Data were from a Ph 1 multicenter, open-label, dose escalation/expansion (NCT03933735) trial and Arm A of a Ph 1b, open label (NCT05650632) trial of etenta; both enrolled pts ≥18 years with RRMM, ≥3 prior lines of therapy (LoT), and triple-class exposed. Pts received 60 mg Q4W or 40 mg Q3W, both regimens with similar dose intensity, in the Ph 1 trial; pts from Arm A of the Ph 1b trial received a step-up dose (SUD) on day 1 and full dose of 60 mg Q4W on day 4. This pooled analysis assessed long-term efficacy, safety, and tolerability. Tumor response was assessed per IMWG 2016 criteria. Results: Of 146 pts with RRMM who received etenta, 87 (60%) were male, median age (range) was 68 (40–87) years, median prior LoT were 4 (3–23), and median duration of follow-up was 13 (1–48) months (mo). ORR was achieved in 96 (66%) pts and ≥VGPR in 79 (54%) pts. Response rates across subgroups are reported in the Table. Median duration of response was not reached (NR) (NR–NR) among responders; Kaplan-Meier (KM) estimate at 12 mo was 71% (58.5%–80.5%). Median PFS (mPFS) was NR (8.7–NR) mo; KM estimate at 12 mo was 55% (44.9%–63.1%). Any grade and G3/4 treatment emergent adverse events (TEAEs) occurred in 145 (99%) pts and 116 (79%) pts. Most common G3/4 TEAEs (≥15%) were neutropenia (38%), anemia (23%), lymphopenia (25%), and thrombocytopenia (16%). Infections G3/G4 were reported in 32 (22%) pts; most common infections G3/G4 (≥5%) were pneumonia (12%) and sepsis (5%). TEAEs leading to etenta discontinuation were reported in 13 (9%) pts. Deaths from TEAEs were reported in 13 (9%) pts; 10 were not attributed to etenta treatment. In Arm A of Ph 1 study where 60mg Q4W was administered with SUD and modified dex as premedication, CRS incidence was 30% (4% G2; No ≥G3 events) with median time to CRS onset of 22.3 (5.5–29.6) hours; and median time to CRS resolution of 20.7 (1.8–131.7) hours. Conclusions: Etenta with SUD demonstrated a low CRS incidence, durable response, and tolerability in pts with heavily pretreated RRMM. Efficacy across all subgroups was comparable and maintained, suggesting therapeutic benefits among a broad population and supporting further exploration in the ongoing Ph 3 Cervino study. Subgroup ORR, n (%) ≥VGPR, n (%) mPFS, months (range) Age ≥75years 26 (72) 23 (63.9) NR (7.5–NR) Race: Black 15 (63) 13 (54.2) 13.7 (5.0–NR) High cytogenetic risk 21 (55) 18 (47.4) 7.4 (2.8–NR) 3 prior LoT 29 (64.4) 23 (51.1) 13.5 (5.6–NR) ≥4 prior LoT 67 (67) 56 (56) NR (8.3–NR)

Introduction Patients (pts) with multiple myeloma (MM) eventually become refractory to current treatments. There is an unmet need for new therapies with durable efficacy, favorable safety, and simplified dosing schedules. ABBV-383 is a unique BCMA x CD3 bispecific antibody T-cell engager comprising bivalent high-avidity BCMA binding domains, a low-affinity CD3-binding domain designed to minimize cytokine release and the risk for cytokine release syndrome (CRS), and a silenced Fc tail for extended half-life enabling dosing convenience. In an ongoing first-in-human (FIH) study (NCT03933735) in heavily pretreated pts with relapsed or refractory (RR) MM, ABBV-383 monotherapy (60 mg Q4W) resulted in deep and durable responses. Introduction of a modified dexamethasone (Dex) premedication (premed) schedule in cycle (C) 1 lowered incidence and severity of CRS (43% overall; 5% grade ≥2) vs pts treated with low Dex (71% overall; 20% grade ≥2) (JCO 2024;42[suppl 16]:7531). We now report results of Arm A of the open-label, phase 1b study (NCT05650632) evaluating 1 step-up dose (SUD) of ABBV-383 as a strategy to mitigate the risk of severe CRS and further assess ABBV-383 activity in pts with RRMM. Methods This study is enrolling pts with RRMM, ECOG performance status ≤2, and documented evidence of progression during or after the last treatment. Pts must have received ≥3 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Arm A consists of a dose-optimization (DO) and a dose-expansion (DE) part. During DO, pts received a single SUD of intravenous ABBV-383 (2/4 mg) on C1 day (D) 1, followed by the target dose of 60 mg on D4. In the DE, based on DO findings, pts received the recommended ABBV-383 SUD on C1D1, followed by 60 mg on D4. The modified premed schedule that lowered incidence and severity of CRS in the FIH study was also introduced prior to target dose on C1D4. After C1, pts received 60 mg ABBV-383 Q4W on D1 of each cycle for DO and DE until disease progression, withdrawal, or discontinuation. Primary endpoint was grade ≥2 CRS events during C1. Other endpoints included any grade CRS events, treatment-emergent adverse events (TEAEs), immune pharmacodynamics, and clinical activity. Results As of April 2024, 70 pts were enrolled in Arm A: 47 in DO (2 mg SUD, n=26; 4 mg SUD, n=21) and 23 in DE. Median age was 69 years (range: 40-84), 59% were male, and 76% were triple-class refractory. Median prior lines of therapy was 4 (range: 3-10). Median follow-up time (months [mo]) was 6.5, 7.5, and 2.8 for 2 mg DO, 4 mg DO, and DE, respectively. Any grade CRS was reported in 10 (39%) and 11 (52%) pts during DO at 2 and 4 mg SUD; CRS grade ≥2 occurred in 3 (12%) pts in the 2 mg SUD and in 6 (29%) pts in the 4 mg SUD, leading to selection of 2 mg SUD for DE. In the DE, 7 (30%) pts experienced CRS; 1 (4%) pt experienced grade 2 CRS, there were no grade ≥3 events, and only 2 (9%) pts received tocilizumab to treat CRS. Overall, median time to CRS onset and resolution was 14.7 and 9 hours, respectively; no pts had CRS after C1. Immune effector cell-associated neurotoxicity syndrome occurred in 7 (10%) pts (grade 1: 4%; grade 2: 6%; grade 3: 4%). Most common TEAEs were CRS (40%), neutropenia (37%), diarrhea (29%), anemia (24%), and fatigue (20%); most common grade 3/4 TEAEs were neutropenia (31%), anemia (19%), thrombocytopenia (13%), and leukopenia (11%). Grade 5 TEAEs occurred in 5 pts; 1 event was deemed possibly related to ABBV-383 (COVID-19 pneumonia). In the efficacy-evaluable population (n=68), the objective response rate was 62% (95% CI: 49.2, 73.3); 35 (52%) pts had a VGPR or better. Median time to response was 1.1 mo (range: 1-4) and median duration of follow-up was 5.8 mo (range: 1-12). Response rates are expected to improve with longer follow-up. Maximum reduction in peak levels of CRS-related cytokines, including IL-6, were observed in DE compared with DO and 60 mg Q4W without SUD (FIH study). Peak activation and proliferation of CD8 T cells was comparable with ABBV-383 in DO, DE, and 60 mg Q4W-treated pts. Conclusions Introduction of 1 SUD of 2 mg on D1 followed by full dose of 60 mg on D4 in C1 combined with modification to the Dex premed schedule reduced the incidence and severity of CRS in pts with RRMM, further optimizing the safety profile of ABBV-383. Preliminary efficacy data show early and high response rates, consistent with outcomes from other ABBV-383 studies.

7532 Background: ABBV-383 is a BCMA x CD3 bispecific antibody with 2 high-affinity BCMA-binding domains and a low-affinity CD3 engaging arm that has been shown to decrease the negative impact of soluble BCMA (sBCMA) and drive sustained T-cell activation with reduced cytokine release in preclinical models of MM. Here, we describe correlative biomarker results of baseline and longitudinal sBCMA levels and immune profiles in the ongoing first-in-human trial that supports 60 mg Q4W as the optimal therapeutic dose of ABBV-383 monotherapy. Methods: Peripheral blood and serum samples from patients with RRMM enrolled in the phase 1 open-label, dose-expansion study (NCT03933735) who received ABBV-383 at 20, 40, or 60 mg Q3W or 60 mg Q4W were collected at baseline (post-dexamethasone, pre–ABBV-383), on treatment, and at disease progression. Samples were analyzed by flow cytometry for immune cell populations, Luminex for cytokines, and electrochemiluminescence ligand binding for sBCMA. Results: Median sBCMA levels at baseline were highly variable among patients, but did not associate with clinical response (≥ partial response [PR]) to ABBV-383 at the selected optimal dose level of 60 mg Q4W (<PR: 244.7 ng/mL; ≥PR: 52.2 ng/mL; P=0.13). Reduction in sBCMA levels over time associated with clinical response (Cmin at cycle 5: <PR, 244.7 ng/mL; ≥PR, 4.7 ng/mL; P=0.04). ABBV-383 treatment led to a rapid and transient increase of proinflammatory cytokines, including IL-6, IL-8, IL-10, TNF-α (Cmax within cycle 1: 29, 349.5, 1375, 456.5 pg/mL, respectively), and promoted T-cell redistribution (89% reduction of CD8+ T cells from periphery), activation (1.9-fold increase in CD69+CD8+ T cells), and proliferation (2-fold increase in Ki67+CD8+ T cells) within cycle 1 in 60-mg Q4W-treated patients. The frequency of baseline CD8+ T-cell exhaustion (PD-1/TIM3) did not impact clinical response at the optimal dose level of 60 mg Q4W ABBV-383 (<PR: 3.5%; ≥PR: 3.9%; P=0.9). Peak induction levels of proinflammatory cytokines during cycle 1 correlated with occurrence of cytokine release syndrome (≥G1) as well as clinical response across dose levels. Conclusions: High-avidity BCMA binding coupled to low-affinity T-cell engagement distinguishes the resulting mechanism of action for ABBV-383. Responses to 60 mg Q4W ABBV-383 were independent of baseline sBCMA levels and resulted in rapid and transient proinflammatory cytokine production that promoted robust T-cell redistribution, activation, and proliferation, indicating that the optimal dose of ABBV-383 maximizes its clinical potential as a convenient, safe, and effective therapy for MM. Clinical trial information: NCT03933735 .

7531 Background: MM eventually becomes refractory to current treatments, and new therapeutic options with convenient dosing and improved safety are needed to enhance patient (pt) adherence, access, and outcomes. ABBV-383 is a distinctive next-generation BCMA x CD3 bispecific antibody composed of 2 high-affinity BCMA-binding domains, a low-affinity CD3-binding domain designed to reduce cytokine release syndrome (CRS) risk, and a silenced Fc tail for an extended half-life allowing convenient dosing. ABBV-383 monotherapy has shown promising activity in the ongoing first-in-human phase 1 trial in RRMM (Vij et al. Blood 2023;142[suppl 1]:3378). Here, safety and efficacy results are reported that support the RP2D of 60mg Q4W as the optimal therapeutic ABBV-383 monotherapy dose. Methods: This phase 1 open-label, dose-escalation/expansion trial (NCT03933735) enrolled pts with RRMM who received ≥3 prior lines of therapy with exposure to PI, IMiD, and anti-CD38 mAb. ABBV-383 regimens explored in the expansion phase included 60mg Q4W and 40 or 60mg Q3W. A modified dexamethasone premedication schedule and shortened CRS monitoring period were implemented in the 60mg Q4W cohort for cycle 1. IV ABBV-383 was administered as a flat dose with no step-up schedule. Treatment was continued until disease progression/unacceptable toxicity. Primary objectives were to assess safety, tolerability, PK, PD, and determine the RP2D. Efficacy evaluation was a secondary objective. TEAEs were assessed per CTCAE v5.0 and tumor response per IMWG 2016 criteria. Results: As of May 2023, 220 pts received ABBV-383 (median age: 68 yr [35–92]; median prior therapy lines: 5 [3‒23]). Median FU was 4.1 mo (0.8–5.2) at 60mg Q4W (n=21), 12.2 mo (1.3–34.4) at 40mg Q3W (n=55), and 24.2 mo (0.6–33.4) at 60mg Q3W (n=61). At 60mg Q4W, with the modified premedication regimen, CRS was reported in 43% of pts (38% G1, 5% G2), and ICANS in 5% of pts (G2). In Q3W cohorts, CRS was reported in 71% (40mg; 45% G1, 25% G2) and 70% (60mg; 51% G1, 18% G2, 2% G3) of pts. The incidence of G3/4 neutropenia, anemia, and thrombocytopenia was 14/24/10% at 60mg Q4W, 31/31/16% at 40mg Q3W, and 34/13/13% at 60mg Q3W. G3/4 infections occurred in 10/24/34% of pts at 60mg Q4W, 40mg and 60mg Q3W, respectively. ORR and ≥VGPR were 65/50% at 60mg Q4W, 64/53% at 40mg Q3W, and 60/52% at 60mg Q3W. Corresponding exposure-response (ER) analyses and correlative analyses further supported RP2D determination (separate abstract submissions). Conclusions: The optimal therapeutic dose of 60mg Q4W ABBV-383 monotherapy was selected on the basis of safety, efficacy, and ER analyses. The extended interval of Q4W, with a shortened CRS monitoring period in cycle 1 and no step-up dosing, will improve convenience and reduce the treatment burden for pts. ABBV-383 at 60mg Q4W will be investigated in the registrational phase 3 trial (NCT06158841) in RRMM. Clinical trial information: NCT03933735 .

Abstract Background: Chronic GVHD contributes to morbidity and mortality after allogeneic transplantation. Several phase 2 and 3 open label studies suggested that ATLG (formerly referred to as ATG-F) reduces cGVHD without impacting relapse or survival. This report describes the first prospective randomized double blind phase 3 trial to assess the effect of ATLG (Neovii) when added to tacrolimus / methotrexate prophylaxis on cGVHD free survival. Patients and Methods: This study was conducted at 27 sites in the United States and Australia. 260 patients were randomized (132 placebo, 128 ATLG). 6 patients who were randomized never received ATLG/placebo (4 placebo and 2 ATLG). Data presented include the 128 placebo and 126 ATLG patients who underwent treatment and transplant. Patients were ages 18-65 years with a diagnosis of acute myeloid (AML, 64%) or lymphoblastic (ALL, 21%) leukemia in first or subsequent complete remission or myelodysplastic syndrome (MDS, 15%) with less than 10% marrow blasts. Median age was 48 years (18-65) with 55% males. All patients received 8/8 HLA (A, B, C, DR) allele matched unrelated products (80% mobilized peripheral blood, 20% bone marrow). Myeloablative conditioning was with cyclophosphamide and total body irradiation (Cy/TBI, 27%), busulfan and cyclophosphamide (Bu/Cy, 33%), or busulfan and fludarabine (Bu/Flu, 40%). All patients received tacrolimus starting on Day -1 and standard mtx on days 1, 3, 6, and 11 for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). The primary endpoint of the study was moderate/severe chronic GVHD free survival. cGVHD was scored by the investigator and then confirmed or overturned by an independent adjudication committee. Secondary endpoints included engraftment, acute GVHD , moderate/severe cGVHD, non-relapse mortality, GVHD and relapse free survival (GRFS), progression free (PFS) and overall survival (OS). The impact of ATLG on immune reconstitution was assessed in 91 patients. Results: Treatment arms were balanced with respect to age, diagnosis, remission status, cytogenetics, graft source (PB or BM), CMV serostatus and conditioning regimen. Median follow up of survivors was 745 days (61, 1425). Regarding the primary endpoint, there was no difference in 2 year moderate/severe cGVHD free survival between ATLG and placebo (48 vs 44%, p = 0.57), nor was there a difference in GRFS (Table 1). Neutrophil engraftment at Day 30 was less in the ATLG arm (85% vs 95%, p=0.00001). Grade 2 or higher infusion reactions were higher in the ATLG arm (16% vs 2.3%, p=0.0001). Reactivation of CMV was similar (27% vs 31%, p=0.58). The Day 180 cumulative incidence of grades 2-4 acute GVHD was lower in the ATLG arm (23 vs 40%, p = 0.003) as was the 2-year cumulative incidence of moderate/severe cGVHD (12 vs 33%, p = 0.000006). However, both 2-year OS and PFS were lower in ATLG treated patients (58 v 76% and 47 vs 67%, respectively) due in part to a higher incidence of relapse (32 vs 19%, p=0.068). Multivariable models confirmed that ATLG was associated with inferior OS, HR 1.85 (1.1-2.9, p=.0075) and PFS, HR 1.63 (1.1-2.41, p=0.015). We then conducted an unplanned post-hoc analysis and discovered a striking influence of conditioning regimen on outcomes. There were no differences in OS or PFS between ATLG and placebo arms in patients receiving Bu/Cy or Bu/Flu but a dramatic difference in patients receiving Cy/TBI conditioning (OS, 88% vs 48% p =0.006 and PFS, 75 vs 29%, p=0.007 in placebo and ATLG arms, respectively). 91 patients (44 ATLG, 47 placebo) participated in the immune reconstitution study. ATLG treatment was associated with lower CD3, CD4, and CD8 counts at Days 30, 100, and 360, respectively. In turn lower CD3, CD4, and CD8 counts assessed as time dependent variables were all associated with inferior OS and PFS as well as higher NRM (data not shown). Conclusion: In this first ever prospective, randomized, double blind trial of ATLG added to tacrolimus /methotrexate in recipients of matched unrelated donor grafts after myeloablative conditioning, there was no significant difference in 2 year moderate/severe cGVHD free survival or GRFS. ATLG did significantly reduce grades 2-4 acute and moderate/severe chronic GVHD. However, overall survival was higher in the placebo arm, driven mainly by patients who received Cy/TBI conditioning. Further analyses are needed to understand the proper role for ATLG in HCT. Disclosures Soiffer: Juno: Membership on an entity's Board of Directors or advisory committees; Kiadis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Porter:Genentech: Employment; Novartis: Patents & Royalties, Research Funding. Jagasia:Therakos: Consultancy. Szer:Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ritz:Kiadis: Membership on an entity's Board of Directors or advisory committees. Glavin:Neovii Biotech: Employment. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.