Abstract: Pharmacologic disruption of the CXCL12/CXCR4 axis induces hematopoietic stem and progenitor cell (HSPC) mobilization. Unfortunately, there is still a significant portion of patients who fail to mobilize an adequate number of HSPCs to proceed to transplantation. For example, one-third of healthy donors mobilized with the CXCR4 antagonist plerixafor (Mozobil, AMD3100) alone require more than one apheresis to obtain the minimal number of CD34+ HSPCs necessary for transplantation (Devine et al. Blood 2008). Therefore, efforts to discover and develop more potent inhibitors of the CXCR4/CXCL12 axis continue. Methods: We tested four nonpeptide CXCR4 antagonists (ALT1188, 1187, 1128, and 1228) with low molecular weights and a novel and simple scaffold: an azacarbazole, linked via a short chain alkyldiamine to a tetrahydroquinoline. This template incorporates the critical features necessary for CXCR4 inhibition, while eliminating the toxic metal-chelating properties of AMD3100. Specificity was tested using CXCR4 monoclonal antibody (mAb) clones 12G5 (binds to first and second extracellular domains) or 1D9 (binds to the N-terminus) and CXCL12-mediated transmigration assays. To evaluate the mobilization of HSPC progenitors, wild-type or splenectomized mice were left untreated (unmobilized) or treated with ALT1188 (0.6 to 20 mg/kg), AMD3100 (5 mg/kg), G-CSF (250 mg/kg/d x 5 d) or combinations. Total WBC, colony forming units (CFU), and peripheral blood cell subsets were determined at different time points. For competitive repopulation cell assays, PBMCs from 1.5, 1 or 0.5 mL of blood from CD45.2+ unmobilized or mobilized C57BL/6 mice were mixed with 2x105 CD45.1+/CD45.2+ C57BL/6 BM cells and injected into lethally irradiated CD45.1+ C57BL/6 recipients. Results: Initial mobilization studies with the four test compounds showed that ALT1188 induced the greatest and most prolonged mobilization of mouse CFUs. Therefore ALT1188 was selected as the lead compound for further testing. Similar to AMD3100, ALT1188 inhibited the binding of CXCR4 mAb clone 12G5 (IC50 = 0.93 nM) but not clone 1D9 and completely blocked CXCL12-induced transwell migration of human CD34+ HSPCs and G2 acute lymphoblastic leukemia cells. Mobilization of mouse CFUs by AMD3100 was maximal within 1 to 3 hours, and circulating HSPCs returned to baseline levels by 6 hours. In contrast, a single injection of an equivalent dose of ALT1188 mobilized 3-fold more CFUs with peak numbers of circulating cells being maintained at 6 hours post-injection. We have completed ALT1188 dose response studies (peak mobilization with 2.5 to 5 mg/kg; maximum tolerated dose is 20 mg/kg) and demonstrated that the prolonged and enhanced mobilization of murine HSPCs by ALT1188 compared to AMD3100 is maintained in three different mouse strains (BALB/C, C57BL/6 and DBA). When combined with G-CSF, ALT1188 mobilized 1.7-fold (P = 0.04) and 4-fold (P = 0.008) more CFU than the combination of G-CSF and AMD3100 at 1 and 3 hours, respectively. Analysis of mobilized peripheral blood subsets showed that, like AMD3100, ALT1188 induced pan mobilization of B and T cells, neutrophils, monocytes and plasmacytoid DCs. Furthermore, analysis of Sca-1+c-kit+lineage- (SKL) cells showed that ALT1188 mobilized 5-fold more SKL cells than AMD3100 at 3 hours after inhibitor administration. Ongoing competitive transplant studies show that ALT1188-mobilized cells produce significantly higher chimerism than cells mobilized by AMD3100 at day 35 after transplant (P = 0.01). In separate studies, we found that the maximum number of circulating CFU is reached after 3 to 4 days when AMD3100 or ALT1188 are administered by continuous infusion via osmotic minipumps in nonsplenectomized mice. Overall, continuous infusion of ALT1188 mobilized 5-fold higher CFU than a single bolus injection of the drug and 2.7-fold greater CFU than continuous AMD3100 administration in normal mice. Surprisingly, AMD3100 and ALT1188 showed remarkably different mobilization kinetics in splenectomized animals. While AMD3100 still required 4 days to reach peak circulating CFU levels, ALT1188 induced maximum CFU mobilization within a single day of pump infusion. Summary: ALT1188 induces increased and prolonged mobilization of murine HSPC compared to AMD3100. The potential of ALT1188 to mobilize human CD34+ HSPCs remains to be determined. Disclosures: Tahirovic: Altiris Therapeutics: Employment. Bridges:Altiris Therapeutics, Inc: Employment. Gooding:Altiris Therapeutics: Employment, Equity Ownership. Dipersio:Altiris Therapeutics: Research Funding.

Abstract: Introduction: The BEAM conditioning regimen (carmustine [BCNU], etoposide, cytarabine, melphalan) is widely used as the high dose chemotherapy given to patients with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) who are undergoing autologous stem cell transplant (ASCT). The lyophilized formulation of melphalan (Alkeran) commonly included in the BEAM regimen has several limitation based on its marginal solubility and the requirement to reconstitute it in propylene glycol (PG), which itself is associated with toxicities. PG-free melphalan (Evomela) overcomes these limitations by using the solubilizing agent Captisol, an inactive excipient used in 6 FDA-approved parenteral drug formulations, to improve the stability of the reconstituted melphalan. PG-free melph alan is stable for 8-10 hours after reconstitution, it can be refrigerated (unlike Alkeran), and it avoids the potential toxicities of PG. PG-free melphalan has demonstrated bioequivalence to Alkeran, and it was safe and effective when used as the conditioning regimen for multiple myeloma patients undergoing ASCT. This Phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the BEAM regimen. Methods: Adult patients with NHL or HL who were eligible for ASCT and gave informed consent were prospectively enrolled after collection of an adequate peripheral blood stem cell product. Carmustine, etoposide, and cytarabine were given at standard doses on Day -6 thru Day -3. PG-free melphalan, 140 mg/m2, was diluted with normal saline to a concentration of ≤ 0.45 mg/ml and infused over 30 minutes on Day -2. Autologous stem cells were infused on Day 0. Supportive care was per institutional standards. The primary endpoint was toxicity, and patients were followed post-transplant for toxicity, engraftment, and disease response. Results: Forty-five patients were enrolled from April 2014 thru June 2015 (mean age 52, range 18-73; 31 males/14 females; 32 NHL [15 diffuse large B-cell, 8 mantle cell, 9 other]/13 HL). Response prior to transplant was complete remission (CR, n=21), partial remission (PR, n=22), or progressive disease (PD, n=2). All patients completed BEAM with PG-free melphalan and stem cell infusion (median 5.1 CD34+ cells/kg), and 40 patients had sufficient follow-up for toxicity and engraftment assessments. The most common Grade 3-4 non-hematologic toxicities were neutropenic fever, (n= 26, 67%), infections (n=16, 41%), and electrolyte abnormalities (hypokalemia and hypophosphatemia in 8 and 23 patients, respectively). Twenty-four patients (60%) had oral mucositis, which was mostly Grade 2 (21 with Grade 2; 3 with Grade 3). Moderate or severe gastrointestinal toxicities were uncommon; 5 patients (12.5%) had Grade 3 diarrhea and 3 (7.5%) had Grade 3 nausea/vomiting. There were no treatment-related deaths. Thirty-nine patients (98%) had neutrophil and platelet engraftment at mean 10 and 21 days, respectively. One patient did not have platelet engraftment by Day +100. Among 36 patients who had response assessment at 60-100 days post-ASCT, 29 (81%) were in CR, 2 in PR, and 6 had PD. There have been three deaths, at 6-12 months post ASCT, all due to progressive disease. Conclusions: PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing ASCT. It was shown to have a safety profile that compares favorably with Alkeran, and it avoids potential PG-associated toxicities. Of note, Grade 3-4 mucositis, diarrhea, and nausea/vomiting each occurred in fewer than 15% of patients, the engraftment rate was high (98%), and response rates were consistent with expectations. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction: Allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) is the standard of care for adult patients with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). The addition of tyrosine kinase inhibitors (TKI) to therapy have resulted in significantly higher rates of complete molecular remissions (CMR) and better overall outcomes. Given the increased toxicity associated with HCT, we aimed to study the benefit of HCT in adult patients with Ph+ ALL in CR1 in CMR. Methods: We performed a multi-institutional, retrospective analysis of 186 patients ≥18 years of age who received induction therapy including TKI for Ph+ ALL from January 2001 through December 2018 and achieved a CMR CR1. Patients achieving CMR within 3 months of diagnosis were included. Sixty-six patients underwent HCT consolidation (HCT group) and 120 patients did not receive HCT in CR1 (no HCT group). Primary outcomes of interest were overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and GVHD free relapse free survival (GRFS). GRFS was defined as being alive without grade III-IV acute GVHD, extensive or systemic chronic GVHD requiring therapy, or relapse. Although GRFS in no HCT group should be exactly as RFS, GRFS comparison was done to compare the composite outcome of quality of life in addition to survival in two groups. Landmark analysis was performed at 3 months to ensure CMR in all subjects at time 0. Survival end points were estimated using Kaplan-Meier method and analyzed with the log-rank test and Cox proportional hazard regression models. Gray's test was used for the comparison of cumulative incidence between cohorts. Results: Patient characteristics at diagnosis are summarized in Table 1. Compared to the non-transplanted patients, HCT patients were younger (median age 45 years vs. 56 years, p & lt;0.001) and had better performance status at diagnosis (Karnofsky score & gt; 90% in 90% of patients vs. 60%, p & lt;0.001). Among patients in the no HCT group, 92.5% were treated with TKI as maintenance therapy with 43% receiving the treatment for more than 3 years. In the HCT group, 86.4% underwent myeloablative conditioning, 81.8 % had a matched related or unrelated transplant, and 47% had TKI as maintenance therapy after transplantation. The rates of patients with transplantation-comorbidity index (HCT-CI) of 0, 1-2, and 3 or more at transplant were 26.7%, 33.3% and 40% respectively. Median follow-up for survivors was 73.2 months (range, 4.3-206 months). Among transplant patients, 65.2% developed acute GVHD with 48.8% of them having a maximum grade of 2. Additionally, 51.6% developed chronic GVHD. In both univariate and multivariate analysis, there was no statistically significant difference in OS or RFS between the two treatment groups (Figure 1A and 1B). Compared to the non-transplanted patients, HCT patients had higher rates of NRM (HR: 3.57; 95% CI: 1.62-7.85), lower rates of CIR (Figure 1C), and a trend toward lower GRFS (Figure 1D). Five-year estimates of the probabilities of OS, RFS, CIR, and GRFS were 65%, 59%, 21%, and 38% for allo-HCT group and 58%, 54%, 28%, and 54% for no allo-HCT group, respectively. Conclusions: Comparing transplant versus chemotherapy only consolidation in CR1, this multicenter retrospective study shows that adult patients with Ph+ ALL in CMR have similar estimates of OS and RFS. Lower CIR in the HCT group was offset by higher NRM, resulting in similar RFS. Results of this study need to be confirmed in a prospective randomized trial. Disclosures Ghobadi: Kite: Consultancy, Research Funding; BMS: Consultancy; Amgen: Consultancy, Research Funding; EUSA: Consultancy; WUGEN: Consultancy. Kantarjian:Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Sanofi: Research Funding; Oxford Biomedical: Honoraria; BMS: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; BioAscend: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Delta Fly: Honoraria. Jabbour:AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Uy:Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Genentech: Consultancy. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; DKMS America: Membership on an entity's Board of Directors or advisory committees; Genzyme: Speakers Bureau; Takeda: Patents & Royalties; Cytonus: Consultancy; Omeros: Consultancy. Ravandi:Macrogenics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding. Kebriaei:Amgen: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support.

Abstract: Introduction: A common initial treatment approach for PTLD includes reduction of immunosuppression (RIS) and single-agent rituximab, followed by sequential chemoimmunotherapy for non-responding patients (pts). However, in relapsed disease, there is less consensus on optimum therapy. Moreover, there are very limited data regarding the use of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory SOT-related PTLD, despite its documented efficacy and tolerability in large B-cell lymphoma (LBCL). Methods: We conducted a multicenter, retrospective, RWE analysis of adults who had SOT-associated PTLD. We obtained baseline clinical features at diagnosis of PTLD including prior organ transplant, immunosuppression usage, international prognostic index (IPI), EBV status, treatment course, response to therapy, and clinical course with CD19 CAR-T. Post-CAR-T survival analyses were performed using Kaplan-Meier with comparison by response using log rank. Results: A total of 20 pts across 8 U.S. academic centers were included in the analysis. Pathology was monomorphic B-cell PTLD in all cases; most pts had diffuse LBCL NOS, with 3 high-grade BCL NOS cases. Prior SOT included 15 kidney transplants (75%), 3 liver (15%), 1 intestinal (5%), and 1 heart transplant (5%). Median time from SOT to PTLD diagnosis was 107 months (mos) (5-379). The median age at time of CART was 55 years (31-75 years) with 4 pts (22.2%) aged & gt;70 years (see Table). The tumor EBV status was negative in 16 pts (80%), positive in 1 (5%), and unavailable in 3 pts (15%). The IPI score upon relapse prior to CAR-T therapy was 3-5 among 14 pts (70%) and 0-2 for the other 6 pts (30%). Most of the pts had stage III-IV disease (95%), and elevated LDH (80%) prior to CAR-T. There were also 5 pts (25%) with & gt;1 site of extranodal involvement, and 1 pt (5%) had secondary central nervous system involvement. For initial therapy of PTLD, 4 pts (20%) received rituximab alone, 12 (60%) had R-CHOP, and 4 (20%) received dose-adjusted R-EPOCH. The median number of prior therapies prior to CAR-T was 2 (1-4); bridging therapy prior to CAR-T are listed in the Table. Immunosuppression was stopped completely prior to CAR-T infusion in 15 (75%) pts, with prednisone alone continued for 3. For CAR-T therapy, 13 pts (65%) received tisagenlecleucel and 7 pts (35%) axicabtagene ciloleucel; 18 received commercial product and 2 were treated on a clinical trial. For tolerability, 16 (80%) pts experienced cytokine release syndrome (CRS): 9 (45%) grade (G) 1, 5 (25%) G2, and 1 (5%) each for G3 and G4. The immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 14 (70%) pts: 2 (10%) G1, 5 (25%) G2, 5 (25%) G3, and 2 (10%) G4. There were 2 (10%) pts with treatment-related mortality (TRM) at 1.5 and 4.5 mos post-CAR-T (1 pneumonia/sepsis and 1 encephalopathy). The overall response rate was 65%, with 50% complete remission (CR) and 20% stable disease. 13 of 15 pts resumed immunosuppression post-CAR-T after a median of 2.2 mos (1-14). Of these pts, 8 were started on steroids; 2 on tacrolimus, 1 both steroid and tacrolimus; 1 everolimus; and 1 on sirolimus. 3 pts (15%) experienced allograft rejection after CAR-T, all of which were kidney SOTs occurring at 1, 4, and 14.6 mos after CAR-T infusion; 1 pt died due to disease progression (1.5 mos) and the 2 other pts required hemodialysis. CRS and ICANS scoring for these 3 pts were 0, 0, 2, and 1, 3, 1, respectively, and all were off immunosuppression at time of rejection. Overall, at a median follow-up of 25 mos (5-112), 13 pts (65%) had progression of disease or TRM, and 7 pts (35%) remained in remission (Figure A/B). Additionally, as highlighted in Figure C/D, all non-relapsing pts had achieved CR with CAR-T therapy (7/10 CR remain in remission), which was strongly associated with outcomes (PFS HR 0.03 (95% CI 0.00-0.29), P=0.002; and OS HR 0.06 (95% CI 0.01-0.57), P=0.014). Conclusions: This RWE provides the largest analysis to date of CD19 CAR-T therapy in relapsed/refractory SOT-related LBCL PTLD. We found that rates of CAR-T-related CRS and neurologic events appeared comparable with previous non-PTLD CAR-T data. Furthermore, 50% of SOT-PTLD pts obtained a CR, with approximately one-third of pts sustaining long-term remission, and achievement of CR was a critical factor associated with survival. Finally, with abrogation of immunosuppression prior to CAR-T, and careful resumption post-therapy, organ preservation was achieved in most pts. Figure 1 Figure 1. Disclosures Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Lazaryan: Kadmon: Consultancy; Avrobio: Membership on an entity's Board of Directors or advisory committees; Humanigen: Membership on an entity's Board of Directors or advisory committees. Jacobson: Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Naik: Sanofi: Other: Virtual Advisory Board Member ; Takeda: Other: Virtual Advisory Board Member ; Kite: Other: Virtual Advisory Board Member. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Nastoupil: TG Therapeutics: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead/Kite: Honoraria, Research Funding; ADC Therapeutics: Honoraria; Denovo Pharma: Other: DSMC; Epizyme: Honoraria, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; IGM Biosciences: Research Funding; Caribou Biosciences: Research Funding; Bayer: Honoraria; MorphoSys: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Ahmed: Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seagen: Research Funding; Merck: Research Funding; Xencor: Research Funding.

Abstract: Background: The use of a clonal master engineered induced pluripotent stem cell (iPSC) line as a renewable source for the mass production of immune effector cells offers distinct advantages over existing patient (pt)- and donor-derived cell-based cancer immunotherapy approaches, including off-the-shelf availability for broad pt access and multi-dose administration. FT596 is an iPSC-derived, off-the-shelf, CD19-directed chimeric antigen receptor (CAR) natural killer (NK) cell therapy capable of multi-antigen targeting in combination with monoclonal antibody (mAb) therapies. FT596 has three anti-tumor modalities: (1) a proprietary CD19-targeting CAR; (2) a novel high-affinity, non-cleavable CD16 Fc receptor that enables tumor targeting and enhanced antibody-dependent cell cytotoxicity in combination with a therapeutic mAb; and (3) IL-15/IL-15 receptor fusion promoting cytokine-autonomous persistence. Preclinical in vivo models of leukemia and lymphoma demonstrate potent CAR-mediated efficacy of FT596 against CD19+ tumor cells and activity against both CD19+ and CD19- tumor cells when combined with the anti-CD20 agent rituximab (Goodridge et al. 2019). Methods: FT596 is being investigated in a multicenter, Phase I clinical trial in pts with relapsed/refractory (R/R) B-cell lymphomas (BCLs) and chronic lymphocytic leukemia (ClinicalTrials.gov: NCT04245722). Conditioning chemotherapy (fludarabine 30 mg/m 2 and cyclophosphamide 500 mg/m 2 on Days -5 to -3) is administered followed by a single dose of FT596 as monotherapy (Regimen A) or combined with rituximab (R) 375 mg/m 2 (Regimen B1) or obinutuzumab 1000 mg/m 2 (Regimen B2) on Day -4. FT596 single-dose levels between 30 and 900 million cells are being tested. Pts experiencing clinical benefit may receive a second cycle of conditioning followed by a single dose of FT596 with FDA approval (Cycle 2). Primary objectives are to determine the recommended Phase II dose of FT596 and safety and tolerability. Additional key objectives include preliminary anti-tumor activity per the Lugano Classification, pharmacokinetics, and anti-product immunogenicity. Results: As of a data cutoff date of 25 June 2021, 20 pts with R/R BCL (12 with aggressive histology, 8 indolent) were treated in dose escalation with FT596, including 10 in Regimen A and 10 in Regimen B1 (3 with 30 million cells, 4 with 90 million cells, and 3 with 300 million cells in each regimen). Pts had received a median of 4 prior therapies, with 7 having received CAR T-cell therapy and 5 with autologous stem cell transplant. Ten of 20 pts were refractory to last prior therapy. No dose-limiting toxicities were reported with either regimen. No graft-versus-host disease (GvHD) or immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. Two cases of cytokine release syndrome (CRS) were reported (one Gr 1 and one Gr 2). The most common treatment-emergent adverse events of any grade were neutrophil count decreased (85%), nausea (75%), anemia (50%), WBC count decreased (45%), fatigue and platelet count decreased (40% each), and peripheral edema (35%). No B- or T-cell mediated anti-product responses were observed. Of 17 efficacy-evaluable pts, 5 of 8 in Regimen A and 4 of 9 in Regimen B achieved an objective response after the first FT596 treatment cycle. At single-dose levels of ≥90 million cells, 8 of 11 efficacy-evaluable pts achieved an objective response, including 7 complete responses (CR). Of 4 pts with prior CAR T-cell therapy treated at ≥90 million cells, 2 achieved CR. The FDA approved all requests for FT596 retreatment. Seven of 9 responders received Cycle 2; 1 pt with CR elected not to receive Cycle 2, and 1 pt with partial response (PR) experienced disease progression prior to initiation of Cycle 2. Five pts (4 with CR, 1 with PR after Cycle 1) completed Cycle 2, and 2 pts initiated Cycle 2 after data cutoff. CR was maintained after Cycle 2 in all 4 pts with CR, while the 1 pt with PR experienced a deepening PR after Cycle 2. No CRS, ICANS, or GvHD were reported with Cycle 2. Conclusions: FT596 monotherapy or in combination with R was well tolerated and demonstrated activity in pts with R/R BCL, including in pts previously treated with CAR T-cell therapy. Administration of a second FT596 treatment cycle was well tolerated with evidence of continuing clinical benefit. Dose escalation of FT596 is ongoing. Updated clinical and translational data will be presented at the conference. Disclosures Bachanova: Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy. Patel: Kite Pharma: Consultancy, Speakers Bureau; Janssen: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy; Morphosys: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Park: Kite Pharma: Consultancy; BMS: Consultancy; Artiva: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Amgen: Consultancy; Affyimmune: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Autolus: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; PrecisionBio: Consultancy; Novartis: Consultancy. Flinn: Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Shah: Fate Therapeutics, Inc.: Current Employment. Wong: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Bickers: Fate Therapeutics, Inc.: Current Employment. Szabo: Fate Therapeutics, Inc: Current Employment. Wong: BMS: Current equity holder in publicly-traded company; Fate Therapeutics, Inc: Current Employment. Valamehr: Fate Therapeutics, Inc.: Current Employment. Atwal: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Chu: Gilead: Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company; Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Elstrom: Fate Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; BeiGene: Current equity holder in publicly-traded company. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy.

Abstract: Introduction: Granulocyte colony-stimulating factor (G-CSF) is the most commonly used drug for stem cell mobilization. Unfortunately, 5-30% of patients fail to collect sufficient hematopoietic stem/progenitor cells (HSPCs) to proceed to transplant. New strategies are needed to increase HSPCs collection in these patients. We previously reported that bortezomib directly and rapidly mobilizes HSPCs in mice by modulating the VLA-4/VCAM-1 axis (Ghobadi A et al. Blood 2014, 124: 2742-2753). Ixazomib (MLN9708) is a next-generation small-molecule proteasome inhibitor that has several potential advantages over bortezomib including oral route of administration. Here we study the effect of ixazomib on stem cell mobilization in mice. Methods: DBA mice were treated with: (1) ixazomib via oral gavage (o.g., 8 mg/kg), (2) a single intravenous (iv) dose of bortezomib (0.8 mg/kg), (3) AMD3100 (5 mg/kg) SC, and (4) control diluent for ixazomib (2-hydroxypropyl-β-cyclodextrin [HPBCD]). Blood was harvested at baseline and 12, 15, and 24 hours (h) after ixazomib and bortezomib administration and at 3 hours and 12 hours after AMD3100 administration. Harvested peripheral blood (PB) was plated on MethoCult media (Stem Cell Technologies) for colony forming unit-cells (CFU-C) enumeration. Results: Compared to vehicle (ixazomib diluent, 2-hydroxypropyl-β-cyclodextrin [HPBCD]), ixazomib mobilized significantly more peripheral blood colony forming unit-cells (CFU-C) at 12 - 15 h after administration (mean peak CFU-C: 105/ml vs. 870/ml respectively, i.e., a 0.6 vs. 5-fold increase in CFU-C , P 〈 0.02; Figure 1A). The majority of CFU-Cs mobilized by ixazomib were CFU-GM (CFU-granulocyte and monocyte, Figure 1B). The magnitude and kinetics of HSPC mobilization in the single ixazomib oral gavage group was identical to a single dose of IV bortezomib (Figure 1C, mean peak of 870/ml vs. 975/ml respectively, P 〉 0.66). There was no statistically significant difference in peak HSPC mobilization between the ixazomib (12 h after ixazomib administration) and AMD3100 groups (3 h after AMD3100 administration) (mean peak of 870/ml vs. 1240/ml respectively, P = 0.36) suggesting that ixazomib is a potent HSPC mobilizing agent (Figure 1D) with intermediate mobilization kinetics compared to AMD3100 (2-3 hours) and G-CSF (5-6 days) and with identical kinetics to IV bortezomib (12-15 hours). Conclusion: Ixazomib is a potent and modestly rapid HSPC mobilizer agent in mice. Kinetics and magnitude of HSPC mobilization by ixazomib is identical to bortezomib. Trials to assess proteasome inhibitors as mobilizing agents are currently underway at Washington University. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction Axi-cel is approved in the US for the treatment of adult patients with relapsed or refractory large B cell lymphoma after 2 or more lines of systemic therapy. A post-marketing study is ongoing in the US utilizing the infrastructure created by the Center for International Blood and Marrow Transplant (CIBMTR) for post-approval safety and efficacy assessment and to follow these patients for 15 years through the established cellular therapy registry. This is the first year analysis of this study. Methods From October 18, 2017 to May 1, 2019, 453 axi-cel recipients were voluntarily reported to the CIBMTR. Of these, 295 patients from 43 US centers that have at least the first follow-up assessment submitted at 3 months were included in this analysis. Median follow-up was 6 months (range, 1-14 months). Results The median age overall was 61 years, 101 (34%) patients were ≥ 65 years, and 197 (67%) patients were male (Table 1). Baseline clinical characteristics included Eastern Cooperative Oncology Group (ECOG) performance score 0-1 (77%), transformed lymphoma (27%), double-hit lymphoma (36%), prior autologous transplant (34%), and chemotherapy-resistant disease (66%) prior to axi-cel. The median time from diagnosis to axi-cel infusion was 18 months (range 2-274 months). Overall response rate (ORR) was 70% (complete response [CR] 52% and partial response [PR] 18%). Patients ≥ 65 years were generally comparable vs younger patients with a slightly better CR rate (62% vs 46%, p=0.03) but similar overall response rate (CR+PR, 75% vs 67%, p=0.26). Cytokine release syndrome (CRS) of any grade was reported in 83% of patients. Incidence of Grades ≥ 3 CRS according to Lee et al 2014 was 11%, and was 14% according to American Society for Transplantation and Cellular Therapy (ASTCT) Consensus Grading (Table 2). Two patients died due to CRS. Median time to any grade CRS was 3 days (range, 1-17 days), and 94% of CRS cases resolved with a median duration of 7 days (range, 1-121 days). Among patients with CRS, tocilizumab, corticosteroids and siltuximab were used in 70%, 26% and 1% of cases, respectively. Neurologic adverse events (AEs) of any grade occurring after axi-cel infusion were reported in 181 (61%) patients. One patient was reported to die from cerebral edema. Additional information on neurologic AE severity will be presented. The median time to onset of any grade neurologic AEs was 6 days (range, 1-82 days), and 88% resolved by time of data submission with a median duration of 8 days (range, 1 to 105 days). Corticosteroids were used in 56% of patients for treatment. Patients ≥ 65 years had comparable CRS (85% vs 82%, p=0.62), grades ≥ 3 CRS (13% vs 9%, p=0.62), and neurologic AEs (68% vs 58%, p=0.13) vs patients & lt; 65 years of age. Prolonged cytopenias (thrombocytopenia and neutropenia), as defined by an inability to recover within 30 days after the administration of axi-cel, occurred in 7% of patients. Preliminary data reveals 6 patients (2%) reported subsequent neoplasms: myelodysplasia (n=3), lung cancer (n=1), neuroendocrine tumor (n=1), and cutaneous squamous cell carcinoma (n=1); additional details, including pre-existing risk factors, will be addressed when the updated analysis is presented. Conclusion Post-approval axi-cel use reported in this registry study in the US, when compared to the registrational ZUMA-1 trial, includes a larger proportion of older patients, patients with transformed or double-hit lymphoma, and patients with a worse performance status. Despite these differences, best responses and toxicities are comparable to those reported for the ZUMA-1 trial. CRS severity assessment varied based on the grading method utilized, with a slightly higher rate of grade 3 CRS based on ASTCT Consensus Grading compared with Lee et al 2014. The safety and efficacy outcomes of patients ≥ 65 years at this early stage are comparable to those of younger patients, although further analysis with more follow-up is warranted. Disclosures Pasquini: Novartis: Research Funding; Kit Pharma: Research Funding; BMS: Research Funding; Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy. Locke:Cellular BioMedicine Group Inc.: Consultancy; Kite: Other: Scientific Advisor; Novartis: Other: Scientific Advisor. Herrera:Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding. Siddiqi:Seattle Genetics: Speakers Bureau; BeiGene: Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Kite: Research Funding; Astra Zeneca: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Juno: Consultancy, Research Funding; Janssen: Speakers Bureau. Ghobadi:Celgene: Consultancy; Wugen: Consultancy; Kite Pharma a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Dong:Gilead Inc: Other: Own Stock; Kite Pharma: Employment. Nikiforow:Kite/Gilead: Honoraria; Novartis: Honoraria; NKarta: Honoraria. Purdum:Kite Pharma: Employment. Horowitz:Sanofi: Other: Unrestricted educational and research grant, Research Funding; Chimerix: Other: Unrestricted educational and research grant; CSL Behring: Other: Unrestricted educational and research grant, Research Funding; Regeneron: Other: Unrestricted educational and research grant; Kite Pharma/Gilead: Other: Unrestricted educational and research grant, Research Funding; Daiichi Sankyo: Other: Unrestricted educational and research grant; GlaxoSmithKline: Other: Unrestricted educational and research grant; Janssen: Other: Unrestricted educational and research grant, Research Funding; Gamida Cell: Other: Unrestricted educational and research grant, Research Funding; Actinium: Other: Unrestricted educational and research grant; Amgen: Other: Unrestricted educational and research grant; Bristol-Myers Squibb: Other: Unrestricted educational and research grant, Research Funding; Magenta: Consultancy, Other: Unrestricted educational and research grant; Mesoblast: Other: Unrestricted educational and research grant, Research Funding; Miltenyi Biotech: Other: Unrestricted educational and research grant, Research Funding; Oncoimmune: Other: Unrestricted educational and research grant; Pharmacyclics: Other: Unrestricted educational and research grant; Seattle Genetics: Other: Unrestricted educational and research grant; Shire: Other: Unrestricted educational and research grant. Hooper:Kite Pharma Inc: Employment, Other: Owner Stock. Kawashima:Kite: Employment. Jacobson:Bayer: Consultancy, Other: Travel Expenses; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Precision Biosciences: Consultancy, Other: Travel Expenses; Pfizer: Consultancy, Research Funding; Humanigen: Consultancy, Other: Travel Expenses; Celgene: Consultancy, Other: Travel Expenses.