Giralt, Sergio

AbstractTo develop a prognostic model for patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) for myelofibrosis (MF), we examined the data of 623 patients undergoing allo-HCT between 2000 and 2016 in the United States (the Center for International Blood and Marrow Transplant Research [CIBMTR] cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients who received transplantation in Europe (the European Bone Marrow Transplant [EBMT] cohort; n = 623). Patient age >50 years (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98-1.96), and HLA-matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with an increased hazard of death and were assigned 1 point. Hemoglobin levels <100 g/L at time of transplantation (HR, 1.63; 95% CI, 1.2-2.19) and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25-2.52) were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points), and high score (5 points) were 69% (95% CI, 61-76), 51% (95% CI, 46-56.4), and 34% (95% CI, 21-49), respectively (P < .001). Increasing score was predictive of increased transplant-related mortality (TRM; P = .0017) but not of relapse (P = .12). The derived score was predictive of OS (P < .001) and TRM (P = .002) but not of relapse (P = .17) in the EBMT cohort as well. The proposed system was prognostic of survival in 2 large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF about the transplantation outcomes.

PURPOSE Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD). METHODS This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS). RESULTS Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15; P = .24), 48.1% for PTCy (HR, 0.86; 0.61 to 1.23; P = .41), and 41.0% for control. Corresponding rates of overall survival were 60.1% (HR, 1.74; 1.09 to 2.80; P = .02), 76.2% (HR, 1.02; 0.60 to 1.72; P = .95), and 76.1%. CD34 selection was associated with lower moderate to severe cGVHD (HR, 0.25; 0.12 to 0.52; P = .02) but higher transplant-related mortality (HR, 2.76; 1.26 to 6.06; P = .01). PTCy was associated with comparable cGVHD and survival outcomes to control, and a trend toward lower disease relapse (HR, 0.52; 0.28 to 0.96; P = .037). CONCLUSION CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

Abstract Background: Several targeted therapies have been recently approved as treatment options for acute myeloid leukemia (AML), however, complete remissions (CR) in relapsed/refractory (R/R) patients remain low. Due to suboptimal responses to standard therapies, most of these patients do not receive an allogeneic hematopoietic cell transplant (HCT). In addition, AML patients ≥55 years have poor tolerance and high morbidity from a myeloablative HCT. The SIERRA trial (Study of Iomab-B in Elderly Relapsed or Refractory AML) has been investigating the use of Iomab-B, an 131I-labeled anti-CD45 monoclonal antibody, to reduce relapse in patients with active, R/R AML who receive HCT as compared to Conventional Care (CC) therapies. With the recent approval of various targeted therapies like BCL-2 inhibitors (e.g., venetoclax), FLT-3 inhibitors (e.g., midostaurin and gilteritinib) and IDH inhibitors (e.g., ivosidenib), the protocol was amended to include patients refractory to these therapies. We are reporting on the success rate of engraftment and tolerability of Iomab-B among the CC patients who cross-over to receive Iomab-B and HCT after failing these agents. Methods: Approximately 150 older patients with R/R AML are to be randomized (1:1) to receive Iomab-B followed by fludarabine, total body irradiation (2 Gy) and allogeneic HCT, or to conventional care (CC). CC patients receive physician's choice of therapy, including targeted therapies, and may proceed to standard of care allogeneic HCT if they achieve CR. CC patients not achieving CR may cross over to Iomab-B-based HCT. Results: Available data for 136 patients (>90% of target enrollment; median age 65) demonstrated they had a median of 3 (range: 1-7) prior lines of AML therapies. Median marrow blast at time of study entry was 25%. Prior to enrollment, 85 (63%) patients received targeted therapies, including BCL-2 inhibitors (62%), FLT-3 inhibitors (18%), IDH inhibitors (7%) and others (13%; e.g., gemtuzumab ozogamicin). Among the 50 evaluable patients in the Iomab-B group that received HCT, all successfully engrafted after a median radiation dose delivered to marrow of 14.7 Gy (range: 4.6 - 44.6) with a median time to neutrophil and platelet engraftment of 14.5 (range: 9-28) and 18 (range: 4-58) days, respectively. Of 63 patients randomized to the CC arm and with data available, 11 (17%) achieved CR and proceeded to standard of care HCT without Iomab-B while 52 (83%) did not respond to CC therapy. Twenty-seven of 63 (43%) CC patients received targeted therapy, of whom 21 received venetoclax with hypomethylating agents (HMA) or low-dose Cytarabine (LDAC). Seven of the 27 (26%) CC patients remission after targeted therapy and received standard of care HCT. Of the 20 patients who did not respond to targeted therapies, 11 (55%) crossed-over and received Iomab-B/HCT with a median radiation dose delivered to marrow of 18 Gy (range: 12.6 - 22.6). Median time to neutrophil and platelet engraftment was 12 (range: 10-27) and 20 (range: 15-38) days, respectively. Safety data are available for 103 transplanted patients in both groups and are presented in table. The incidence of Grade ≥3 febrile neutropenia (FN) was 37% vs 55%, sepsis 5% vs 30%, and mucositis 10% vs 20% in the Iomab-B group compared to all transplanted patients in the CC group. In patients who received targeted therapy and HCT (crossover or standard HCT), incidences of FN, sepsis and mucositis were 39%, 28% and 22%, respectively. Conclusion: SIERRA trial patients not achieving CR with recently approved targeted therapies who then crossed-over to receive HCT with Iomab-B successfully engrafted. Time to engraftment was similar to those who were randomized to receive Iomab-B and HCT. Available data suggest incidences of sepsis and mucositis are lower in the Iomab-B group. (www.sierratrial.com or clinicaltrials.gov NCT02665065) Figure 1 Figure 1. Disclosures Gyurkocza: Actinium Pharmaceutical Inc.: Research Funding. Nath: Actinium: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Litzow: Amgen: Research Funding; Biosight: Other: Data monitoring committee; Jazz: Other: Advisory Board; Pluristem: Research Funding; Astellas: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; AbbVie: Research Funding. Koshy: Astellas; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Speakers Bureau. Stiff: Seagen: Research Funding; Incyte: Research Funding; Gamida Cell: Research Funding; Janssen: Research Funding; CRISPR Therapeutics: Consultancy, Honoraria; Kite, a Gilead Company: Research Funding; Macrogenics: Research Funding; Bristol Myers Squibb: Research Funding; Cellectar: Research Funding; BioLineRX: Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Cellectar: Research Funding; Actinium: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. Hari: Karyopharm: Consultancy; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau. Chen: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Sabloff: Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jaxx: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Orozco: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Foran: abbvie: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; actinium: Research Funding; OncLive: Honoraria; aptose: Research Funding; trillium: Research Funding; gamida: Honoraria; takeda: Research Funding; boehringer ingelheim: Research Funding; bms: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; pfizer: Honoraria; servier: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Jamieson: Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium. Magalhaes-Silverman: Actinium Pharmaceuticals; Incyte; Marker Therapeutics: Other: Principal Investigator, SIERRA Trial, Actinium, Research Funding. Schuster: Takeda: Consultancy, Speakers Bureau; MorphoSys Ag: Consultancy, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Intellisphere: Consultancy, Speakers Bureau; AbbVie Incorporated: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Epizyme: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Actinium Pharmaceuticals: Other: Principal Investigator, SIERRA Trial, Actinium Pharmaceuticals, Research Funding; Rafael Pharmaceuticals: Research Funding; GSK: Research Funding; AlloVir: Research Funding; Incyte: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau; Celgene: Consultancy, Current equity holder in publicly-traded company, Speakers Bureau. Law: Actinium Pharmaceuticals: Research Funding; Novartis: Consultancy. Levy: Takeda, Celgene, Seattle Genetics, AbbVie, Jazz Pharmaceuticals, Gilead Sciences, Bristol-Myers Squibb, Amgen, Spectrum Pharmaceuticals,Janssen.: Consultancy. Lazarus: Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Berger: Actinium Pharmaceuticals, Inc: Current Employment. Spross: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Desai: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Reddy: Actinium Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Pagel: AstraZeneca: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; BeiGene: Consultancy; Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Incyte/MorphoSys: Consultancy.

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

Introduction: VRD (bortezomib, lenalidomide, dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone) are the two most commonly used triplet induction regimens in transplant eligible patients with multiple myeloma (MM). VCD is commonly used in patients with renal dysfunction at diagnosis. Given the variable results seen in head to head comparison of these (or similar) regimens to date, no definitive conclusion can be made on whether they are equivalent. This large CIBMTR registry study compares the outcomes with VRD vs. VCD induction therapy in patients undergoing upfront autologous stem cell transplant (ASCT). Methods: Patients were included if they underwent upfront ASCT for MM from January 2013 to December 2018 within 6 months of diagnosis, received VRD or VCD induction therapy and achieved at least a partial response pre-transplant. Of 1,135 patients, 914 patients received VRD and 221 received VCD therapy. Cox proportional hazards models were created for progression-free survival (PFS) and overall survival (OS). The following covariates were adjusted in the models: induction regimen (main effect), age, sex, race, performance score, hematopoietic cell transplant-comorbidity index (HCT-CI), estimated glomerular filtration rate (eGFR) at diagnosis, immunoglobulin subtype, cytogenetics, ISS stage, response status at transplant, melphalan dose, and maintenance therapy. Results: As shown in Table 1, patients in the VRD and VCD cohorts had similar age at transplant, adjusted HCT-CI scores, and distribution of high-risk cytogenetics. Patients in the VCD group were more likely to have renal impairment and ISS stage III disease. An eGFR (mL/min/1.73m2) at diagnosis < 60 was seen in 26% of VRD patients vs. 48% of VCD patients. ISS stage III was seen in 17% vs. 34% of patients, respectively. Treatment and Response: Pre-transplant response in the VRD cohort was: complete response (CR)- 17%, very good partial response (VGPR)- 48% and partial response (PR)- 35%. Response in the VCD cohort was: CR- 17%, VGPR- 42% and PR- 41%. Conditioning dose was melphalan 200 mg/m2 in 80% of patients receiving VRD vs. 69% in the VCD group. Post-transplant response was at least VGPR in 74% vs. 75% of patients, respectively. Maintenance in the VRD group was: lenalidomide based (+/- bortezomib)- 80%, bortezomib based- 5%, other-3% and none- 12% of patients. In the VCD group, maintenance was: lenalidomide based- 63%, bortezomib based- 11%, other- 1% and none- 24%. Survival: Patients receiving VRD induction had superior outcomes compared to VCD induction with median PFS from transplant of 44.6 (38.0-55.8) months vs 34.1 (25.8-44.7) months, p 0.004 respectively. Median OS was not reached for either group, with 5-year OS 79 (74-83)% for VRD and 60 (50-69)% for VCD, p <0.001. Univariate PFS and OS outcomes by induction regimen and eGFR at diagnosis are shown in Table 2 and Figure 1. Multivariate analysis is shown in Table 3. After adjusting for prognostic factors, there was no statistically significant difference between the two induction regimens, with hazard ratio (HR) for PFS in the VCD vs VRD group being 1.22 (95% CI: 0.96-1.55, p=0.10). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for PFS. Similarly, on multivariate analysis for OS, there was no statistically significant difference in the two groups, with HR for OS in VCD vs VRD group being 1.33 (95% CI: 0.93-1.92, p=0.12). ISS stage, cytogenetics, disease status prior to transplant, and maintenance were independent prognostic factors for OS. Conclusions: In patients with MM undergoing upfront transplant after VRD or VCD induction, no difference in outcomes was seen based on the induction therapy received after adjusting for other prognostic factors. As several MM patients with renal dysfunction are started on VCD, it is reassuring to see that VCD was not associated with inferior PFS, likely due to the eventual transition to maintenance therapy in the majority due to subsequent improvement of renal function. The use of maintenance treatment was uniformly associated with superior outcomes. Disclosures Sidana: Janssen: Consultancy. Kumar:Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Karyopharm: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Genecentrix: Consultancy; Carsgen: Other, Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy. Giralt:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinuum: Other: Advisory board, Research Funding; Amgen: Other: Advisory Board, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; OMEROS: Research Funding; SPECTRUM Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees, Research Funding; PFIZER: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jensenn: Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Membership on an entity's Board of Directors or advisory committees, Research Funding; MILTENYI: Research Funding; JAZZ Pharmaceutical: Membership on an entity's Board of Directors or advisory committees. Qazilbash:Janssen: Research Funding; Bioclinica: Consultancy; Amgen: Research Funding; Angiocrine: Research Funding; Bioline: Research Funding. Shah:GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy; BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding. D'Souza:Janssen: Consultancy; Akcea: Consultancy; Imbrium: Consultancy; Merck: Research Funding; Pfizer: Consultancy; Teneobio: Research Funding; Amgen: Research Funding.

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.

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient’s own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

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.