Abhyankar, Sunil

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 (>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 > 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: 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.

Background: Patients ≥55 years of age with rel/ref AML who have failed to achieve complete remission (CR) after standard induction & salvage therapies do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to inability to receive myeloablative conditioning and lack of efficacy. With the advent of recently approved targeted therapies (e.g. venetoclax, IDH inhibitors) more patients achieve CR, however durable responses in heavily pre-treated patient populations remain unsatisfactory with very few patients being transplanted. The SIERRA (Study of Iomab-B in Elderly Relapsed or Refractory AML) trial is a prospective, randomized, phase 3 trial designed to address this unmet need. We present the preliminary analysis of the first 50% of patients and analyze the proportion of patients who fail standard chemo and targeted therapies that can then successfully undergo HCT with Iomab-B-based conditioning. Study continues to enroll (N=150), primary end-point durable CR of ≥180 days. Methods: Eligible patients are ≥ 55 years with rel/ref AML (≥5% blasts), adequate organ function, and related/unrelated 8/8 HLA-matched donors. Patients are randomized (1:1) to receive Iomab-B followed 12-14 days later by reduced intensity conditioning (fludarabine(FLU)/TBI) and HCT, or to conventional care (CC). CC patients may receive investigator's choice of salvage therapy, including newly approved targeted agents such as venetoclax, IDH Inhibitors and may proceed to standard HCT if they achieve CR. If patients do not achieve CR, the study allows cross-over (CO) to Iomab-B with HCT. Results: Preliminary data are available from the first 75 patients enrolled on the SIERRA trial. Median age of 64 years (range: 55-77). All patients had active measurable disease (Table 1). Patients in this trial were heavily pretreated with 85% failing ≥2 induction therapies and 33% failing targeted therapies. Molecular and cytogenetics was 68% adverse risk. (NCCN, v1.2018) Following therapeutic dose of Iomab-B as a single agent, there was significant reduction of circulating blasts by day 3 (99%, p<0.0001), and peripheral blasts became undetectable by day 8 prior to FLU. All patients transplanted on the Iomab-B arm with data available showed median days to engraftment of ANC at 14 (range: 9-22) and platelets at 16 (range: 4-30) (Table 1). After randomization, 82% (31/38) patients in the CC arm failed salvage therapy and did not proceed to standard HCT. Significantly, 32% (12/38) of these patients received targeted therapy. 73% (8/11) of the patients receiving venetoclax with HMA or cytarabine did not adequately respond and did not proceed to standard HCT, 45% (5/11) crossed over to Iomab-B and received HCT. Following standard chemotherapies, 85% (22/26) were evaluated for CO. In total, 63% (19/30) received Iomab-B and HCT. The most common reason preventing crossover was disease progression. All crossover (Iomab-B) patients showed similar engraftment (Table 1). CC patients showed increased incidence of febrile neutropenia with grade 3 prior to CO evaluation or HCT, compared to Iomab-B patients prior to HCT (CC: 34%, Iomab-B: 8%). Iomab-B administration was generally well-tolerated with no grade 4 and 1 grade 3 infusion reaction. There were no Iomab-B-related deaths or 100 day non-relapse transplant related mortality deaths in patients on the Iomab-B arm (Table 1). Conclusion: 100% of the patients receiving HCT on the Iomab-B arm engrafted, despite a median of 29% BM blasts pre-Iomab-B. 82% of the patients on the CC arm failed to be eligible for standard of care transplant, including a high percentage of those receiving targeted therapies. On the CC arm, 63% of eligible patients crossed over to Iomab-B/HCT with robust engraftment despite a median of 35% BM blasts pre-Iomab-B. The incidence of grade 3 febrile neutropenia was higher in patients treated on the conventional care arm with salvage therapy vs. those treated on the Iomab-B arm prior to HCT. In conclusion, despite advanced age, active disease and heavily pre-treated patients, 68% (50/74) of all patients enrolled in the SIERRA trial were able to undergo HCT after reinduction and targeted conditioning with Iomab-B. These results show significant improvements in the current rates of transplantation in this patient population. This SIERRA trial is currently enrolling. For full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Gyurkocza: Actinium Pharmaceuticals: Research Funding. Nath:Astellas: Consultancy; Actinium: Consultancy; Daiichi Sankyo: Consultancy. Stiff:Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Unum: Research Funding; Cellectar: Research Funding; Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding. Tomlinson:Actinium Pharmaceuticals, Inc: Other: Travel Support. Abhyankar:Incyte: Speakers Bureau; Therakos: Other: Consulting, Speakers Bureau. Hari:AbbVie: Consultancy, Honoraria; Cell Vault: Equity Ownership; Sanofi: Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Amgen: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria. Al-Kadhimi:Seattle Genetics: Other: Stocks; Celldex Biotech: Other: Stocks. Foran:Agios: Honoraria, Research Funding. Orozco:Actinium Pharmaceuticals: Research Funding. Van Besien:Miltenyi Biotec: Research Funding. Sabloff:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding. Kebriaei:Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding; Pfizer: Honoraria; Kite: Honoraria; Jazz: Consultancy; Amgen: Research Funding. Levy:Takeda (Millennium Pharmaceuticals): Consultancy. Lazarus:Adaptive Biotechnologies: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Actinium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva Pharmaceuticals: Speakers Bureau; Biosight: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; AstraZeneca: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Pluristem Therapeutics, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Genentech: Speakers Bureau. Giralt:Novartis: Consultancy; Actinium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Research Funding; Kite: Consultancy; Miltenyi: Research Funding; Takeda: Consultancy, Research Funding; Johnson & Johnson: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy. Berger:Actinium Pharmaceuticals, Inc: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment. Pagel:Pharmacyclics: Consultancy; AstraZeneca: Consultancy; Gilead Sciences: Consultancy.

Abstract Background: Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (R/R AML) who have failed standard induction therapies most often receive salvage therapy with a wide variety of agents, but very few achieve remission. These patients do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to lack of efficacy using a standard HCT approach. The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial designed to address this significant unmet need in R/R AML. This trial compares Iomab-B, an 131I-radiolabeled anti-CD45 antibody as targeted conditioning prior to HCT against standard conventional care therapies with an accrual goal of 150 patients. We have performed a preliminary safety analysis, validating the initial feasibility of this multi-center trial. Methods: Eligible patients are ≥ 55 years of age with active, R/R AML, adequate organ function, and related/unrelated matched donor. Patients are randomized (1:1 ratio) to receive dosimetry directed Iomab-B followed 12 days later by HCT with fludarabine 30 mg/m2 x 3 days and 2 Gy of total body irradiation as transplant conditioning, or to a Conventional Care (CC) arm. Patients randomized to CC, may receive investigator's choice of salvage induction chemotherapy including approved targeted agents as well as Venetoclax (in combination with a hypomethylating agent) and proceed to standard HCT if they achieve complete remission (CR). If patients do not achieve CR, the study allows optional cross-over to the Iomab-B arm, evaluated between days 28-42 after CC therapy. The primary efficacy endpoint for the study is durable complete remission (dCR) of 6 months. The secondary efficacy objective is to evaluate overall survival at 1 year. Results: Forty patients have been enrolled to date and data are available for 38 patients (19 = Iomab-B, 19 = CC) as of July 5th, 2018. The median age was 63 years (range: 55-76). All patients had active disease at the time of enrollment with median bone marrow (BM) blasts of 30% in the Iomab-B arm and 47% in the crossover arm prior to receiving Iomab-B (Table 1). Of the patients in the CC arm, 88% did not achieve a CR and 65% of those crossed-over to receive Iomab-B. The most common reason preventing crossover was declining performance status. Time to HCT was not increased in the crossover patients receiving Iomab-B compared to those that underwent a standard of care transplant after achieving CR (median 65 vs 75 days), while the Iomab-B arm patients were transplanted at a median of 27 days after randomization. Iomab-B therapy was well-tolerated with no grade 3 or 4 infusion-related reactions reported. The median activity of Iomab-B was 626 mCi (range: 397-1027). All patients randomized to Iomab-B (N=13) engrafted, with median days to engraftment of ANC at 13 (range: 9-22) and platelets at 17 (range: 13-26). All patients who received Iomab-B after crossover (N=9) also engrafted with time to engraftment similar to patients initially randomized to the Iomab-B arm (Table 1). Donor chimerism (≥95%), within 100 days after HCT, was found in 9 of 10 patients in the Iomab-B arm and 8 of 9 patients in those that crossed over to receive Iomab-B, with two patient exceptions having mixed donor chimerism at day 28. A preliminary safety analysis for all randomized patients on either study arm showed the most frequent non-hematologic adverse events ≥ grade 3 occurring in >10% patients were febrile neutropenia (34.2%), stomatitis (15.8%), malnutrition (13.2%), epistaxis, sepsis, hypotension, hypobilirubinemia and fatigue (all 10.5%). There were no Iomab-B-related deaths. Interpretation: Preliminary safety analysis demonstrates the feasibility of delivering targeted conditioning with Iomab- B for HCT in R/R AML patients who have active disease and a high BM blast burden (median: ≥ 30%) prior to transplantation. All patients who received Iomab-B, including those crossed over after failing to achieve CR on CC salvage therapy, engrafted ANC within 13 days, despite active disease prior to transplant. In addition, the time to HCT from randomization was not increased in patients receiving Iomab-B after cross-over compared to those who underwent standard of care HCT after achieving CR on the CC arm. This study is currently enrolling and for full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Tomlinson: Foundation Medicine: Consultancy. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Chen:Bellicum Pharmaceuticals: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Lazarus:Pluristem Ltd.: Consultancy. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Abstract Abstract 906 Background: Single-arm Phase 2 trials of DF in the treatment of severe VOD/MOF post-SCT demonstrated a complete response (CR) in 36–46% of patients (pts). A subsequent Phase 3 trial enrolling pts with more severe VOD (28%/24% with ventilator/dialysis dependence at study entry vs 5%/7%) demonstrated a CR of 24% compared to 9% in a matched Historical Control (HC); p=0.0148; Richardson ASH 2009). Given the life-threatening nature of VOD/MOF, DF was made available in the United States through a Treatment IND protocol (T-IND) in December 2007 to gather additional safety and response data. Methods: Pts were required to have a diagnosis of VOD based upon Baltimore criteria (total bilirubin ≥ 2.0 mg/dL with ≥ 2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure). Pts without a Baltimore diagnosis could enroll with biopsy-proven evidence of VOD. Eligibility criteria were expanded to permit patients with late onset VOD (VOD diagnosed after 21 days (d) or VOD/MOF after 28d post-SCT). Key exclusion criteria included clinically significant bleeding or need for >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF. Mortality was assessed at D+100. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d); treatment duration was recommended for at least 21d. Results: This interim analysis is based on 104 pts enrolled between14Dec2007-29Sep2009 and treated at 36 institutions. Most sites (n=23) enrolled only 1–2 pts. Nearly all pts (n=98) had undergone prior SCT; 6 had prior chemotherapy only; and 29 pts had late onset VOD post-SCT. Of the SCT pts, 69 pts enrolled in the T-IND met eligibility criteria for the original Phase 3 trial. Baseline demographics included median age 17 years (range 0.1 – 66); 59% male; and 16% with prior SCT. The most common diagnosis was leukemia (30% AML; 22% ALL; 7% other leukemia). The majority of pts had undergone allogeneic SCT (88%) with conditioning consisting of cyclophosphamide (76%), busulfan (42%) and/or TBI (41%). Mean onset of VOD post-SCT was 17 days. At entry, 20% of pts were dialysis dependent; 28% were ventilator dependent. Mean number of days of DF administration was 20 (range 2–88). Of the 104 pts, 36 (35%) achieved a CR by D+100. For the various sub-populations, the CR by D+100 rate was 24% for pts with late-onset VOD (n=29); 35% for those pts undergoing SCT (n=98); and 39% for the 69 pts who matched the entry criteria for the Phase 3 trial. Comparison of this group of 69 pts to the Phase 3 HC showed a statistically improved outcome (p=0.0007). Similar to the Phase 3 results, the CR rate was higher in pts who were not on dialysis/ventilator at study entry (41% vs 23%). Although children had previously been noted to have a higher CR rate in prior studies, the CR rate in the T-IND was similar in children compared to adults (35% and 34%, respectively). Overall D+100 mortality rate equaled 61% (n=104). Comparing the 69 pts who met Phase 3 entry criteria, D+100 mortality was 58% (p=0.0465 compared to the HC using Kaplan Meier estimates by log-rank analysis). Toxicity proved manageable: 11 pts experienced a total of 13 drug-related AEs including pulmonary hemorrhage (n=5), GI hemorrhage (n=3), hypotension (n=2), rectal hemorrhage, cerebral hemorrhage and pulmonary alveolar hemorrhage (1 pt each). Overall, 10% of pts experienced a drug-related toxicity that led to discontinuation. Similar to the observation of decreased GvHD in pediatric pts undergoing SCT who received prophylactic DF compared to best supportive care, the incidence of all grade GvHD was relatively low (8%). Conclusions: In 104 pts with severe VOD/MOF enrolled at 36 US institutions, use of DF demonstrated a 35% CR by D+100. Comparing those pts who met criteria for the Phase 3 trial to the HC used in that study, D+100 CR and survival were significantly improved in this study population. DF-associated toxicities are consistent with prior studies. Following an amendment in 30Sep2009, entry criteria for the T-IND study were expanded to permit enrollment of pts without SCT (VOD post chemotherapy) as well as pts without MOF to evaluate earlier intervention. Analysis of this group will be performed separately. Enrollment into the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment.