Stiff, Patrick J.

SummaryIn young and fit patients with mantle cell lymphoma (MCL), intensive induction therapy followed by a consolidative autologous haematopoietic cell transplant (autoHCT) is the standard of care in the front‐line setting. Recently, time‐to‐event analysis has emerged as an important risk assessment tool in lymphoma, though its impact in MCL is not well defined. We utilized the Center for International Blood and Marrow Transplant Research database to evaluate the effect of post‐autoHCT time to relapse on overall survival (OS) over time in 461 patients who underwent autoHCT within 12 months of MCL diagnosis. On multivariate analysis, the impact of relapse on OS was greatest at the six‐month [hazard ratio (HR) = 7·68], 12‐month (HR = 6·68), and 18‐month (HR = 5·81) landmark timepoints. Using a dynamic landmark model we demonstrate that adjusted OS at five years following each landmark timepoint improved with time for relapsing and non‐relapsing patients. Furthermore, early relapse (<18 months) following autoHCT defines a high‐risk group with inferior post‐relapse OS. This retrospective analysis highlights the impact of time to relapse on OS in MCL patients undergoing up‐front autoHCT and emphasizes the need to consider novel therapeutic approaches for patients suffering early relapse.

SummaryZUMA‐1 (NCT02348216) examined the safety and efficacy of axicabtagene ciloleucel (axi‐cel), an autologous CD19‐directed chimaeric antigen receptor (CAR)‐T cell therapy, in refractory large B‐cell lymphoma. To reduce treatment‐related toxicity, several exploratory safety management cohorts were added to ZUMA‐1. Specifically, cohort 6 investigated management of cytokine release syndrome (CRS) and neurologic events (NEs) with prophylactic corticosteroids and earlier corticosteroid and tocilizumab intervention. CRS and NE incidence and severity were primary end‐points. Following leukapheresis, patients could receive optional bridging therapy per investigator discretion. All patients received conditioning chemotherapy (days −5 through −3), 2 × 106 CAR‐T cells/kg (day 0) and once‐daily oral dexamethasone [10 mg, day 0 (before axi‐cel) through day 2]. Forty patients received axi‐cel. CRS occurred in 80% of patients (all grade ≤2). Any grade and grade 3 or higher NEs occurred in 58% and 13% of patients respectively. Sixty‐eight per cent of patients did not experience CRS or NEs within 72 h of axi‐cel. With a median follow‐up of 8·9 months, objective and complete response rates were 95% and 80% respectively. Overall, prophylactic corticosteroids and earlier corticosteroid and/or tocilizumab intervention resulted in no grade 3 or higher CRS, a low rate of grade 3 or higher NEs and high response rates in this study population.

PURPOSEStandard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.PATIENTS AND METHODSOne hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.RESULTSMean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.CONCLUSIONSubjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Background: Patients ≥55 years of age with high-risk acute myeloid leukemia (AML) may benefit from an allogeneic hematopoietic cell transplantation (HCT), which is often the only potentially curative therapy available. However, complete remission (CR) is usually a pre-requisite for most centers to perform HCT, as CR predicts an optimal outcome. Many older patients with relapsed/refractory (R/R) AML are not transplanted as they do not achieve the required CR. In addition, due to their advanced age, they are unable to tolerate the myeloablative conditioning required for eradication of disease, while the more tolerable reduced intensity conditioning often exhibits high rates of relapse. The SIERRA trial is a prospective, randomized, phase 3 trial for older patients with R/R AML to address this unmet need. We hypothesized that a targeted delivery of radiation to the marrow, achieved with a limit of 24 Gray (Gy) radiation dose to the liver, via an infusion of a therapeutic dose of Iomab-B enables successful engraftment despite active disease in the marrow. Methods: Eligible patients were ≥55 years with active R/R AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients were randomized (1:1) to the Iomab-B or Conventional Care (CC) arm. Patients randomized to Iomab-B received an outpatient dosimetric dose of Iomab-B followed by nuclear medicine imaging to determine the personalized therapeutic dose that would deliver radiation to the marrow while limiting the delivery of radiation to the liver to 24 Gy. HCT is performed 12-14 days following the infusion of a therapeutic dose of Iomab-B, and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and low-dose Total Body Irradiation (TBI 2 Gy x 1 dose). Patients on the CC arm received investigator's choice of salvage therapy, including newly approved targeted agents, and could proceed to physician's choice of conditioning and HCT if they achieved CR. If CC patients did not achieve CR, the study allowed them to cross-over and receive Iomab-B-based conditioning followed by allogeneic HCT. Results: Preliminary data were available from 106 patients (Table 1). 53 patients (median age 64) were randomized to Iomab-B and received allogeneic transplant. All Iomab-B patients engrafted, despite a pre-therapy median of 26% marrow blasts. After randomization, 83% (44/53) CC patients failed salvage therapy, including 45% (24/53) who received targeted agents. 26 of 44 (60%) CC patients, with a median 33% marrow blasts, crossed over and received Iomab-B followed by allogeneic HCT. Patient age, donor type (MRD, MUD), bone marrow cellularity, blast percentage, type of donor, stem cell dose, administered Iomab-B activity (mCi), and absorbed radiation dose to the marrow (Gy), were analyzed for time to engraftment among each group. Median time to neutrophil and platelet engraftment were 14 days (range 9-22) and 17 days (range 4-39) respectively, with 91% of evaluable patients achieving full donor chimerism (&gt;95% by day 100, Table 1). Neither the radiation dose delivered to the marrow (median 14.7 Gy; range, 4.6-32 Gy; Table 1) nor the total administered activity (median 632 mCi; range, 354-1027 mCi) showed correlation with the time to either neutrophil (p value=0.525) or platelet engraftment (p value=0.952). Regression analyses, considering all of the variables individually, did not indicate a statistically significant correlation (p &gt; 0.1) between days to engraftment and radiation dose delivered to the marrow. These results were consistent for the Iomab-B cross-over group as well. Furthermore, the marrow absorbed dose did not show a significant correlation with % chimerism at day 28 in patients on the Iomab-B arm or in cross-over patients. Conclusion: Dosimetry to determine a patient-specific therapeutic dose of Iomab-B of 24 Gy to the liver provided absorbed marrow radiation doses that allowed for reliable engraftment after allogeneic HCT in older patients with R/R AML, despite a heavy leukemia burden with median bone marrow blasts of 26% prior to HCT (Iomab-B arm). There was no relationship between total administered activity or radiation dose delivered to the marrow with the speed of engraftment. The SIERRA trial is currently enrolling patients (www.sierratrial.com or clinicaltrials.gov NCT02665065). Disclosures Gyurkocza: Actinium: Research Funding. Nath:Daiichi Sankyo: Consultancy, Honoraria; Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Delta-Fly: Research Funding; Amgen: Research Funding. Hari:Takeda: Consultancy; BMS: Consultancy; GSK: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Incyte Corporation: Consultancy. Al-Kadhimi:Actinium Pharmaceuticals Inc.: Research Funding; Genzyme: Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Gilead Science: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Novavax: Current equity holder in publicly-traded company. Abboud:BMS: Current equity holder in publicly-traded company; AbbVie Inc: Current equity holder in publicly-traded company; Forty Seven Inc: Research Funding; Abbott Labs: Current equity holder in publicly-traded company; AlloVir: Research Funding; Ryvu: Research Funding; Actinium Pharmaceuticals Inc.: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; Pfizer: Research Funding. Magalhaes-Silverman:Incyte: Research Funding; Kadmon Holdings: Research Funding; Actinium Pharmaceuticals: Research Funding. Foran:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; Revolution Medicine: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Schuster:Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Amgen: Other: Research Support; Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Levy:Karyopharm: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Research Funding, Speakers Bureau; Baylor University Med Center: Current Employment. Giralt:ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding; OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding. Liang:Actinium Pharmaceuticals: Current Employment. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Reddy:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of patients (pts) with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies. ZUMA-1 is the multicenter, single-arm, registrational Phase 1/2 study of axi-cel in pts with refractory LBCL. In a 2-year analysis of ZUMA-1 (median follow-up, 27.1 months; N=101), axi-cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively (Locke et al. Lancet Oncol. 2019). Here, we present additional survival follow up and recovery of normal, polyclonal B cells from ongoing responders in ZUMA-1. Methods: Eligible pts with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis at enrollment and subsequently received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). The primary endpoint was objective response rate (ORR), and the first response assessment was 4 weeks post infusion. Response assessments were performed per protocol up to 24 months or disease progression, whichever occurred first. For pts in ongoing response beyond Month 24, response assessments continued per institutional standard-of-care (SOC). Blood levels of CAR T cells were quantified using polymerase chain reaction and B cells were characterized using flow cytometry in pts with ongoing responses and evaluable samples. Results: A total of 111 pts were enrolled, and axi-cel was administered to 101 pts. As previously reported in the ZUMA-1 2-year analysis, among pts who received axi-cel, the median time from axi-cel infusion to both objective response and CR was 1.0 month (range, 1 - 12 months; Locke et al. Lancet Oncol 2019). When the entire enrolled population (N = 111) was included on an intent-to-treat basis, the median manufacturing time was 17 days (range, 14 - 51; n = 110 as manufacturing was not feasible for 1 pt). Additionally, among the 111 pts, the median time from enrollment/leukapheresis to objective response and CR was 1.7 months (range, 0.7 - 12.9) and 1.9 months (range, 0.7 - 13.3), respectively. Responses have been durable, and with a minimum of 3 years of follow-up (median, 39.1 months), the median overall survival (OS) was 25.8 months, and the 3-year OS rate was 47%. Importantly, no axi-cel-related secondary malignancies have been reported. As previously reported, pts in ongoing response after 2 years had significantly greater peak CAR T cell expansion in blood 7 - 14 days after axi-cel infusion than did those with relapse (P = 0.014) or no response (P = 0.0003; Locke et al. Lancet Oncol 2019). Blood samples from 22 pts in ongoing response (per institutional SOC) at ≥ 3 years were available for analysis of CAR T cells and evaluation of B cell recovery. All evaluable pts had detectable B cells in blood at 3 years post axi-cel. Notably, 91% of pts in ongoing response at 3-year follow-up demonstrated recovery of polyclonal B cells measured by presence of both kappa and lambda light chains on non-malignant CD19+CD20+ B cells. The median kappa-lambda ratio of 1.6 and relative levels of key B cell subsets, including memory and naive B cell immunophenotypes, suggested reconstitution of B cell repertoire, consistent with published data from healthy individuals (Deneys et al. J Immunol Methods 2001; Scott et al. J Clin Pathol 2018). Additionally, 15/22 (68%) had both minimal levels of detectable CAR gene-marked cells and detectable polyclonal B cells in blood. Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for durable remissions of LBCL. Overall survival and translational findings with ≥ 4 years of follow-up will be presented. Conclusions: Axi-cel produced rapid responses and longterm disease control in pts with refractory LBCL. Most responses occurred by the first assessment, and the brief time elapsed between enrollment and response supports both the speed and success of manufacturing. Furthermore, axi-cel-treated pts with ongoing responses at ≥ 3 years showed evidence of restoration of a normal B cell compartment and clearance of functional CAR T cells, a critical component of the long-term safety of CD19-directed CAR T cell therapies. Disclosures Locke: Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ghobadi:Celegene: Consultancy; Wugen: Consultancy; Atara: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Oluwole:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy. Lin:Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Timmerman:Merck: Research Funding; Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Valor: Research Funding. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Flinn:Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; BeiGene: Consultancy, Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Calithera Biosciences: Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Curis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Goy:COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Fred Hutchinson: Patents & Royalties. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siddiqi:Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support . Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Vezan:Merck: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. Bashir:Kite, a Gilead Company: Current Employment; OmniacPharmConsult Ltd: Current Employment, Current equity holder in private company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Chu:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Kite, a Gilead Company: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Novartis: Other: personal fees; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees.

Background: Despite recently approved novel targeted therapies, most patients with high-risk acute myeloid leukemia (AML) still require allogeneic hematopoietic cell transplantation (HCT) to achieve long-term survival. However, older patients with relapsed/refractory (R/R) AML are often unable to undergo HCT due to the toxicity of myeloablative pre-conditioning. Since higher doses of chemotherapy and radiation are associated with prolonged myelosuppression or infectious complications, targeted radiotherapy with Iomab-B, employed in the SIERRA trial, was designed to minimize toxicities in a patient population unable to tolerate standard high-dose myeloablative HCT pre-conditioning. We hypothesize that Iomab-B, which spares non-hematologic organs such as the GI tract, exhibits a favorable toxicity profile with respect to mucositis, febrile neutropenia (FN), and sepsis. Methods: The SIERRA trial is a prospective trial for patients ≥55 years of age with R/R AML (≥5% blasts) and 8/8 HLA-matched related or unrelated donors. Patients were randomized (1:1) to Iomab-B or Conventional Care (CC). Those in the Iomab-B group received a dosimetric infusion of Iomab-B followed by nuclear imaging to determine the personalized therapeutic dose to be delivered to the bone marrow and to other sites of disease. Therapeutic dose calculations, utilizing the Olinda software (Version 2.1, Hermes Medical) to determine the delivery of a maximum of 24 Gray (Gy) dose to the liver, were performed based on the imaging results. HCT is performed 12-14 days following the infusion of a therapeutic dose of Iomab-B, and a non-myeloablative conditioning backbone of fludarabine (30 mg/m2 x 3) and low-dose Total Body Irradiation (TBI 2 Gy x 1 dose). CC patients received the investigator's choice of salvage therapy. Safety data was evaluated from randomization and up to 100 days after HCT in the patients randomized to the Iomab-B group. We specifically evaluated AE variables of mucositis (Gr 2-4), FN (Gr3,4) and sepsis. An analysis was performed with both total activity of Iomab-B as well as with the radiation dose delivered to the bone marrow, stomach wall, small and large intestinal walls. For each of the 3 AEs of interest, a multivariate analysis was performed, allowing each of the predictor variables to be included in the model. Results: A total of 106 patients were randomized at the time of analysis. For those randomized to Iomab-B, data is available for 45 patients that received a therapeutic dose of Iomab-B and HCT. The median dose of Iomab-B administered was 603 mCi (range 313-1027 mCi) and the median radiation dose delivered to the marrow in the Iomab-B group was 14.7 Gy (range 4.6 - 32 Gy). All patients (median age 64) treated with a therapeutic dose of Iomab-B achieved neutrophil engraftment after a median of 14 days post-HCT (range 9-22), despite presenting with a median 26% marrow blasts prior to initiation of therapy. Rates of mucositis, FN, and sepsis are shown in Table 1. No correlation between AEs (FN, mucositis, sepsis) and administered Iomab-B activity (p=0.08), nor with dose delivered to GI tract (p=0.09) was observed. Furthermore, these AEs were not related to the dose of radiation received by the small intestine (median 2.7 Gy range 1.1-6.8 Gy) large intestine (median 2.6 Gy range 0.9-6.5 Gy), nor an average of all 4 GI sites (median 2.8 Gy range 1.6-6.8 Gy). Conclusions: Unlike cases involving treatment with cytotoxic chemotherapy and external beam radiation where mucositis, infections and sepsis increase along with the administered dose, targeted myeloablative conditioning with Iomab-B resulted in low incidences of severe mucositis, FN, and sepsis. These AEs do not appear to be related to the total dose of Iomab-B administered nor to the specific radiation dose delivered to the bone marrow. Furthermore, a low dose of radiation (2.8 Gy) was received by the GI tract compared to the larger dose of radiation (14.7 Gy) delivered to the marrow. Taken together, these results represent potentially significant improvements in the safe delivery of myeloablative therapy with high-dose targeted radioimmunotherapy, prior to HCT in older patients with R/R AML. This SIERRA trial is currently enrolling patients (www.sierratrial.com or clinicaltrials.gov NCT02665065). Disclosures Gyurkocza: Actinium: Research Funding. Nath:Actinium: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Hari:Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy; BMS: Consultancy; Takeda: Consultancy; Incyte Corporation: Consultancy. Al-Kadhimi:Actinium Pharmaceuticals Inc.: Research Funding; Genzyme: Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Gilead Science: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Novavax: Current equity holder in publicly-traded company. Abboud:Ryvu: Research Funding; Actinium Pharmaceuticals Inc.: Research Funding; Pfizer: Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company; BMS: Current equity holder in publicly-traded company; Abbott Labs: Current equity holder in publicly-traded company; AbbVie Inc: Current equity holder in publicly-traded company; AlloVir: Research Funding; Forty Seven Inc: Research Funding. Magalhaes-Silverman:Kadmon Holdings: Research Funding; Actinium Pharmaceuticals: Research Funding; Incyte: Research Funding. Foran:Xencor: Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; Agios: Honoraria, Research Funding; H3Biosciences: Research Funding. Schuster:Amgen, Abbvie, Gilead, Takeda, Celgene, Pharmacyclics, Astellas, Verastem, Merck, Novartis, Takeda, Genentech,, Seattle Genetics: Other: Personal Fees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board; Amgen: Other: Research Support; Ziopharm: Other: Research Support; Novartis: Other: Served on advisory board; Jazz: Consultancy. Levy:Karyopharm,Takeda, BMS: Consultancy, Honoraria, Speakers Bureau. Giralt:KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Liang:Actinium Pharmaceuticals: Current Employment. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Reddy:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company.

Abstract Introduction: We previously reported that plerixafor + G-CSF was as safe as and more effective than placebo + G-CSF in mobilizing hematopoietic stem cell for autologous transplant in patients with non-Hodgkins lymphoma (NHL) through 100 days follow-up (DiPersio ASH 2007). We report herein the 12 months data. Methods: This was a phase 3, multicenter, randomized, double-blind, placebo-controlled study. NHL patients requiring an autologous hematopoietic stem cell transplant were eligible. Patients received G-CSF (10 μg/kg) subcutaneously daily for up to 8 days. Beginning on evening of Day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 μg/kg) or placebo subcutaneously. Starting on morning of Day 5, patients began daily apheresis for up to 4 days or until ≥ 5 x 106 CD34+cells/kg were collected. We report herein the 12 months graft durability and hematology data. Results: As reported previously, 89/150 (59%) patients in the plerixafor group and 29/148 (20%) patients in the placebo group met the primary endpoint of collecting ≥ 5 x 106 CD34+ cells/kg in ≤ 4 days of apheresis, p &lt; 0.001. 135 patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation. Median time to neutrophil and platelet engraftment was similar in both groups. There were no differences in graft durability through 12 months follow-up between the two groups. Two plerixa for treated patients had graft failure (one had pre-existing MDS and one developed AML). One plerixafor-treated patient had delayed platelet engraftment. The hematology profiles were similar between the two groups through 12 months follow-up, except that patients in the plerixafor group had significantly higher platelet count at 12 months than patients in the placebo group (p=0.026) (Table 1). During the 12 months follow-up, 14/135 (10.4%) patients in plerixafor group and 10/82 (12.2%) patients in the placebo group died. 7/14 in the plerixafor group and 5/10 in the placebo group died of disease progression. Plerixafor + G-CSF Placebo + G-CSF Hematology data presented as mean ± SD and n= number of patients with available data aAll patients who underwent transplantation bAll patients who underwent transplantation and had laboratory data at the study visit cP values were NS for all variables at all time points between groups except for platelet count at 12 months (p=0.026) Graft durability (n, %) 100 daysa 128/135 (94.8%) 78/82 (95.1%) 6 monthsb 120/123 (97.6%) 77/78 (98.7%) 12 monthsb 110/112 (98.2%) 65/65 (100.0%) Platelet (x 109/L) 100 days 183 ± 83 (n= 113) 169 ± 81 (n=63) 6 months 190 ± 78 (n=100) 180 ± 77 (n=64) 12 monthsc 209 ± 81 (n=50) 170 ± 78 (n=37) Neutrophils (x 109/L) 100 days 3.1 ± 1.7 (n=107) 3.2 ± 2.1 (n=61) 6 months 3.3 ± 1.4 (n=98) 3.8 ± 2.6 (n=64) 12 months 3.5 ± 1.4 (n=50) 4.2 ± 2.7 (n=38) Hemogloblin (mg/dL) 100 days 12.3 ± 1.5 (n=112) 12.3 ± 1.5 (n=63) 6 months 12.5 ± 1.5 (n=100) 12.4 ± 1.5 (n=64) 12 months 13.0 ± 1.4 (n=50) 12.7 ± 1.6 (n=37) Conclusions: The addition of plerixafor to G-CSF resulted in higher CD34+ cell collection in fewer days of apheresis and higher proportion of patients proceeding to transplant than G-CSF alone. Importantly, this 12 months report showed that transplants with cells collected with plerixafor resulted in graft durability rates that were similar to cells collected with G-CSF alone.

Abstract Introduction: The impact of transplanted CD34+ cell dose on clinical outcomes remains controversial. The purpose of this study was to examine the relationship between CD34+ cell dose transplanted and platelet, neutrophil, and lymphocyte counts at 100 days, 6, and 12 months following autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Methods: Data were obtained from two phase 3 clinical studies that compared the safety and efficacy of plerixafor and G-CSF with placebo and G-CSF in mobilization of hematopoietic blood stem cells for autologous transplantation in NHL patients and in MM patients. The details of the study designs and preliminary safety and efficacy outcomes have been reported (DiPersio, ASH 2007). The following data were obtained from the two clinical study databases: number of CD34+ cells transplanted (first transplant only) as determined by a central laboratory, absolute neutrophil, platelet, red blood cell, and lymphocyte counts at 100 days, 6, and 12 months post-transplant. The proportions of patients who had platelet ≥150 x 109/L or neutrophil ≥2.5 x 109/L or lymphocyte ≥0.5 x 109/L at 100 days, 6, and 12 months were compared among these transplanted CD34+ cell dose categories regardless of mobilization treatment: 2–4 x 106 cells/kg, &gt;4–6 x 106 cells/ kg, and &gt; 6 x 106 cells/kg. Two separate analyses were performed, one for NHL patients and one for MM patients. Results: For the NHL study, 135/150 (90.0%) patients in the plerixafor group underwent transplantation after initial mobilization compared with 82/148 (55.4%) patients in the placebo group, p&lt;0.001. The mean number of CD34+ cells transplanted was 6.06 ± 2.98 x 106 (median 5.41, range 1.79–17.6) for the plerixafor-treated patients and 4.09 ± 1.56 x 106 (median 3.85, range 1.98–8.7) for the placebo-treated patients, p&lt;0.001. For the MM study, 142/148 (95.9%) patients in the plerixafor group and 136/154 (88.3%) patients in the placebo group underwent transplantation. The mean number of CD34+ cells transplanted was 5.84 ± 2.64 x 106 (median 5.34, range 1.9 to 16.7) for the plerixafor-treated patients and 4.37 ± 2.01 x 106 (median 3.98, range 1.8 to 16.9) CD34+ cells/kg for the placebo- treated patients. A significant linear trend with increasing proportion of patients with platelet count ≥150 x 109/L with increasing transplanted cell dose categories was observed at 100 days, 6, and 12 months for NHL patients and at 100 days for MM patients (Table 1). There were no apparent significant relationships between transplanted cell dose categories and other hematopoietic parameters. Table 1: Analysis of percentage of patients reaching a platelet count of ≥ 150 x 109/L by transplanted cell dose categories Transplant Cell Dose (CD34+ cells/kg) 2–4 x 106 ≥ 4–6 x 106 ≥ 6 x 106 P value* NHL Patients N=76 N=75 N=66 100 days 28 (48.3%) 42 (66.7%) 45 (81.8%) &lt;0.001 6 months 31 (56.4%) 36 (66.7%) 42 (76.4%) 0.026 12 months 18 (56.3%) 21 (80.8%) 24 (82.8%) 0.020 MM Patients N=75 N=82 N=64 100 days 41 (68.3%) 57 (90.5%) 47 (88.7%) 0.004 6 months 48 (78.7%) 61 (89.7%) 51 (87.9%) 0.147 12 months 25 (73.5%) 33 (82.5%) 26 (81.3%) 0.435 For all transplanted cell dose categories, the proportions of patients are based on the number of patients with available data at each time point.*p-value for testing linear trend using Mantel-Haenszel Chi-square test Conclusions: Results from these ad hoc analyses confirm previous reports that transplanted cell dose may be associated with better long-term platelet recovery. Due to the small sample size in each transplanted cell dose category and the nature of ad hoc analyses, further studies are warranted to determine if the introduction of plerixafor will allow the mobilization and transplantation of higher quantity of CD34+ cells, which may positively influence long-term hematopoietic recovery.

Abstract CXCR4, the chemokine receptor for stromal derived factor-1 (SDF-1) plays an important role in the homing and migration of hematopoietic stem cells. Selective inhibition of the binding of the CXCR4 receptor by the molecule AMD3100 leads to the mobilization of hematopoietic progenitors, including CD34+ cells into the circulation, even in the steady state. Preliminary studies have indicated that AMD3100 given 10–11 hours before each apheresis along with standard doses of G-CSF mobilizes more CD34+ cells per kilogram than does G-CSF alone. A Phase II study of this combination in patients with NHL and myeloma is underway. G-CSF at 10μg/kg/day for a duration of up to 9 days is administered with AMD3100 at 240 μg/kg/day starting on the evening of day 4 of G-CSF therapy, (10–11 hours prior to first and subsequent daily aphereses) until 5 x 106 CD34/kg are collected, or for a maximum of 5 days of a standard 3 blood volume apheresis. Both agents are administered subcutaneously. To date 20 patients (myeloma-6, NHL-14) have been enrolled and analyzed. Of these 20, 14 are considered to have been ‘heavily pre-treated’ using standard definitions (≥ 10 cycles of chemotherapy, platinum based salvage chemotherapy and/or radiation therapy to bone marrow sites). Blood CD34 assays (cells/μl) were performed before and after each AMD 3100 dose and on each apheresis product. After the first dose of AMD3100 there was a 2.6 fold increase in CD34/μl in blood (23 → 60 CD34+ cells/μl). The median number of apheresis performed was 2 (range 1–5); the median total CD34 collected for all 20 patients was 5.7 x 106/kg (range 2.32–14.58 x 106/kg). All patients had collections of &gt; 2.0 x106 CD34/kg, and in 12 of 20 the 5 x 106 CD34/kg cell dose goal was collected, including 8 of 14 in the heavily pre-treated group. In fact in 6, the 5 x 106 CD34/kg cell dose was collected in a single apheresis. The median CD34/kg cell dose collected for the 14 heavily pre-treated patients was 5.7 x 106/kg (2.32–6.48 x 106/kg). There were no serious AE’s related to the use of AMD3100. Transient GI toxicity (mostly diarrhea) occurred in 10 of 20 patients shortly after the injections of AMD3100, but only 3 required therapy. Engraftment data is available for the first 12 patients treated. Time to ANC &gt;500/μl and platelets &gt; 20,000/μl was 9 (range 8–10) and 12 (range 9–19) days respectively. This novel combination of AMD3100 and G-CSF appears to be effective in mobilizing large numbers of CD34+ cells, even in patients considered to be heavily pre-treated, and is an effective alternative to chemotherapy/cytokine mobilization. Compared to studies of G-CSF alone, this combination may reduce the number of apheresis procedures needed to collect an adequate graft for rapid hematopoietic engraftment. The study is ongoing with accrual to date of 40 patients.

Background: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the radiosensitivity of MM, fractionated dosing of CLR 131 is being examined in RRMM in a Phase 1 trial (NCT02278315) and a Phase 2 trial, CLOVER-1 (NCT02952508). Methods: Both the Phase 1 and Phase 2 trials of CLR 131 aim to determine efficacy and safety in RRMM. Eligibility criteria include progressive or relapsed MM that is refractory to at least 1 proteasome inhibitor (PI) and 1 immunomodulatory (IMiD) drug with no upper limit to the number of prior lines of therapy. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (&lt; 20% of total marrow irradiated). The Phase 1 trial was a single and fractionated ascending dose escalation safety study and the Phase 2 trial is evaluating 3 doses: a bolus dose and 2 fractionated doses. The fractionated doses of CLR 131 included infusion of either 31.25 mCi/m2 CLR 131 or 37.5 mCi/m2 CLR 131 (administered as 15.625 mCi/m2 or 18.75 mCi/m2, respectively, on day 1 and day 7 (± 1 day)) administered as a 30-minute intravenous infusion is reported here. Adverse events (AEs) are graded by NCI-CTCAE v4.03. Responses were determined using IMWG criteria as assessed by the investigator. Results: As of 30Jul2019, 10 subjects have received fractionated 31.25 mCi/m2 and 6 subjects fractionated 37.5 mCi/m2 CLR 131. In addition, 1 subject was scheduled to receive fractionated 37.5 mCi/m2 CLR 131 but died due to progressive disease prior to administration of the second dose; this subject is not included in the analyses below as they did not receive both fractionated doses. There is no upper age limit for enrollment and the median age for the 16 RRMM patients was 71 (range 51-83), including 6 females and 10 males with a median of 4 prior therapies (range 2 to 13). Seven patients had prior ASCT. CLR 131 demonstrated 100% disease control rate in subjects receiving either fractionated dose of CLR 131. The overall response rate (ORR) in the fractionated 37.5 mCi/m2 cohort is 50%. Three subjects in the cohort experienced a partial responses (PR), median time to response 43 days, and the other three had minimal responses (MR) with an average 39% reduction in m-protein. In this cohort, 80% of the subjects were either quad- or penta-refractory; all 80% were refractory to daratumumab. There were two subjects in the 31.25 mCi/m2 cohort with non-secretory disease and their status was followed by FDG-PET imaging. Both have been excluded from the evaluation of efficacy as their disease does not meet with IMWG criteria for response. No patients in this cohort achieved a PR or better however a majority of the subjects experienced a minimal response. The primary AEs include thrombocytopenia, anemia, neutropenia, and fatigue (Table 2). The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average. 40 days) and subsequent recovery (average 17 days post nadir). Conclusions: CLR 131 is a unique, first in class targeted radiotherapeutic for RRMM. Preliminary data for CLR 131 administered as a fractionated dose shows an acceptable and expected safety profile in this patient population. Fractionated dosing at 37.5 mCi/m2 has shown an efficacy signal and has been adopted as the standard for CLR 131 dosing in ongoing and future trials. Dose escalation to determine the highest tolerated dose is ongoing in the Phase 1 study and is currently examining a fractionated infusion of 40 mCi/m2 administered as 20 mCi/m2 CLR 131 on day 1 and day 7 (± 1 day). Based upon these data enrollment to the fractionated 37.5 mCi/m2 cohort of the Phase 2 trial continues. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Stiff:Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Ibrahim:Cellectar: Honoraria, Research Funding; Incyte: Research Funding; Pfeizer: Research Funding; Puma: Research Funding; Eli Lilly: Research Funding; Hoffman-LaRoche: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Cull:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Green:GSK: Consultancy; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Oliver:Cellectar Biosciences: Employment. Longcor:Cellectar Biosciences: Employment, Equity Ownership.