Aptevo Therapeutics Research Articles

Risk and Severity of Cytokine Release Syndrome in Patients with Relapsed/Refractory (R/R) AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Risk and Severity of Cytokine Release Syndrome in Patients with Relapsed/Refractory (R/R) AML or MDS Treated with CD3xCD123 Bispecific Antibody APVO436

Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

Tolerability and Single Agent Anti-Neoplastic Activity of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory AML or MDS

Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial

Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial

Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial

Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial

Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial

Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

Updated Survival and Response Analyses from a Phase 1 Study of Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation

Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with High-Risk and Relapsed/Refractory Acute Myeloid Leukemia (AML)

Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with High-Risk and Relapsed/Refractory Acute Myeloid Leukemia (AML)

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

Direct Intravital Imaging of the Bone Marrow and Splenic Hematopoietic Niches in Individual Mice to Define the Early Engraftment Kinetics Following HSC-Transplant

Hematopoietic stem cells (HSCs) give rise to and maintain the entire hematopoietic system for the life of an organism. This remarkable feat has established HSC transplant as an indispensable tool for treating a variety of hematological disorders. Yet the initial steps of homing, engraftment, and clonal expansion, which lead to eventual long-term hematopoietic recovery after HSC transplant, remain incompletely characterized. Given the determinative effect that early HSC activity has on transplant outcomes, a more complete understanding of initial engraftment dynamics is imperative for bettering HSC therapies.Preliminary studies aimed at functional characterization of classic HSC and hematopoietic stem and progenitor cell (HSPC) populations-namely the CD150 +CD48 -Sca-1 +c-Kit +Lin - (SLAM SKL) and Sca-1 +c-Kit +Lin - (SKL) populations, respectively-revealed that these populations exhibit disparate early engraftment dynamics. Using previously developed intravital imaging techniques, we were able to partially characterize early HSC and HSPC engraftment dynamics in mice competitively transplanted with GFP + SLAM SKL and DsRed + SKL cells. The SKL population was found to primarily engraft in the bone marrow, completely recapitulating engraftment behavior of transplanted whole bone marrow. In contrast, the more purified SLAM SKL population engrafted poorly in the marrow space and instead preferentially engrafted in the spleen, where it produced the majority of donor-derived blood at early stages (7 days) after competitive transplant into lethally irradiated mice. However, by 14 days post-transplant, SLAM SKL-derived cells migrated from the spleen to repopulate the majority of bone marrow space. These results reflect the dynamic nature of hematopoietic recovery in a myeloablative model and highlight the need for in vivo imaging techniques to fully understand hematopoietic reconstitution by the SLAM SKL population.In order to further dissect the interactive processes of bone marrow hematopoiesis and splenic extramedullary hematopoiesis, we have developed a novel, multi-organ intravital imaging technique that allows for simultaneous analysis of defined hematopoietic compartments in a single animal. Our multimodal imaging approach combines direct visualization of fluorescently labeled hematopoietic cells in the spleen via our recently developed spleen window, with concomitant observation of hematopoietic cells in tibia marrow environment. Our spleen window is a specially engineered biocompatible ring with an affixed coverslip to allow for direct, non-invasive microscopic visualization of labeled hematopoietic cells in the spleen. The spleen window can be installed with the tibia window in an individual mouse. Multimodal mice can be visualized repeatedly over a minimum of 7 days post-HSC transplant to follow individual cell behaviors within the living recipient. Preliminary results from competitive repopulation assays utilizing our multimodal imaging approach suggest that the SLAM SKL population is an active one that confers rapid hematopoietic recovery in lethally irradiated recipients primarily from extramedullary hematopoiesis in the spleen (CFU-S). The results of ongoing work characterizing the active use of the splenic and marrow niches will be presented. DisclosuresCogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis

IntroductionPhiladelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1.MethodsFollowing the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for “ Philadelphia chromosome ”, “hematopoietic stem cell transplantation” and “ protein kinase inhibitors ” from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTSA total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). ConclusionHematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

Phase 1b Study of Lower-Dose CPX-351 Plus Venetoclax As First-Line Treatment for Patients with AML Who Are Unfit for Intensive Chemotherapy: Preliminary Safety and Efficacy Results

Phase 1b Study of Lower-Dose CPX-351 Plus Venetoclax As First-Line Treatment for Patients with AML Who Are Unfit for Intensive Chemotherapy: Preliminary Safety and Efficacy Results

Co-Expression of an shRNA Targeting MICA/Micb Improves the Clinical Activity of a NKG2D-Based CAR T in Patients with Relapsed / Refractory AML/MDS

While CAR T cell therapy has delivered impressive clinical efficacy in B cell malignancies, similar levels of clinical activity have not been demonstrated in acute myeloid leukemia (AML). One underlying reason for this lack of translation is the relative paucity of validated CAR T targets. Major Histocompatibility Complex Class 1 related proteins MICA and MICB along with the UL16 binding proteins 1-6 (ULBP1-6) are frequently over-expressed on AML and myelodysplastic syndrome (MDS) blasts. The Natural Killer Group 2D (NKG2D) is a single receptor able to bind MICA, MICB and ULBP1-6, thus providing a potentially powerful approach that could be exploited to target this family of targets thereby providing a novel CAR T approach for AML/MDS.Expressing the NKG2D receptor fused to the human CD3z cytoplasmic domain generates a CAR that, when expressed in primary T cells, generates a CAR T product (termed CYAD-01) that showed good anti-tumor activity in preclinical models. In clinical trials, CYAD-01 showed a good tolerability profile but with a disappointing level of clinical activity when combined with cyclophosphamide / fludarabine preconditioning (DEPLETHINK trial, NCT03466320).We hypothesised that the transient expression of MICA/MICB on the CAR T itself may inhibit the activity of the NKG2D CAR through self-targeting and consequent fratricide. We developed a single shRNA able to knockdown both MICA and MICB. Co-expression of this shRNA with the NKG2D CAR generated a second generation CAR T product termed CYAD-02 which was examined in a highly similar AML/MDS patient population and preconditioning regimen as employed in the DEPLETHINK trial.CYAD-02 was evaluated in the the first-in-human CYCLE-1 trial (NCT04167696) in patients with r/r AML/MDS. The dose-escalation phase evaluated three dose-levels (DL) (1x10 8, 3x10 8 and 1x10 9 total cells per infusion), administered as a single infusion after standard preconditioning chemotherapy (cyclophosphamide 300 mg/m²/day and fludarabine 30 mg/m²/day, daily for 3 days) according to a classic 3+3 design.As of July 2021, 11 patients have been treated with CYAD-02 at the different dose-levels (3 at each DL1 and 2 and 5 at DL3). In terms of safety and tolerability, there was no evidence of a differential safety profile of CYAD-02 within the CYCLE-1 trial as compared to that observed in the CYAD-01 clinical trial. Of note, five patients enrolled in all 3 DLs experienced Grade ≥ 3 adverse events (AE) at least possibly related to CYAD-02 (cytokine release syndrome, febrile neutropenia, white blood cell count decreased, infusion related reaction).With respect to clinical activity, seven patients in total achieved stable disease (2 at DL1, 3 at DL2 and 2 at DL3) with 4 demonstrating evidence of transient blast reduction or anti-leukemic activity (decrease of at least 50% of the bone marrow blasts). In addition, two MDS patients at DL3 achieved a marrow complete response. Overall, this suggests dose dependent response to CYAD-02. Furthermore, patients receiving CYAD-02 cells seem to display a greater duration of response and stronger blast reduction as compared to patients who received CYAD-01 in DEPLETHINK.Interestingly, peak engraftment levels were higher for CYAD-02 compared to CYAD-01 at the same dose (DEPLETHINK trial). At DL3, CYAD-02 cells could be readily detected in peripheral blood of 4/5 patients through month 2. In addition, and unlike what is reported in B cell CAR T-cells trials, there was very limited evidence of elevated homeostatic cytokines (IL-7/IL-15) following CyFlu administration with IL-15 not detected in any of the patients and IL-7 showing only a minor increase in 2 patients.The knockdown of MICA/MICB appears to have a positive contribution to the initial clinical activity of CYAD-02 as compared to that achieved with the first generation CYAD-01 CAR T, together with good safety and tolerability. The lack of homeostatic cytokines after preconditioning, likely limiting the engraftment and activity of CAR T cells, may be related to the biology of myeloid malignancies. One approach to further drive the potency of NKG2D-based CAR T cells would likely be armoring the CAR T through using the T cell as a vehicle to secrete cytokines alongside the CAR. Overall, shRNA knockdown technology provides a means to modify CAR T function and here shows that single shRNA can target two independent genes to enhance the phenotype of the CAR Ts. DisclosuresDeeren: Alexion: Consultancy; BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Sanofi: Consultancy, Research Funding; Sobi: Consultancy; Takeda: Consultancy. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Alcantar-Orozco: Celyad Oncology: Current Employment. Dheur: Celyad Oncology: Current Employment. Breman: Celyad Oncology: Current Employment. Braun: Celyad Oncology: Current Employment. Lonez: Celyad Oncology: Current Employment. Gilham: Celyad Oncology: Current Employment. Flament: Celyad Oncology: Current Employment. Lehmann: Celyad Oncology: Current Employment.

Incidence and Characteristics of Central Nervous System Involvement in Adult Acute Myeloid Leukemia Patients

Features of central nervous system (CNS) involvement in acute myeloid leukemia (AML) are not well-defined. Unlike acute lymphoblastic leukemia, there are limited guidelines for the use of intrathecal chemotherapy with induction for AML, and institutional practices vary. Unfortunately, AML patients with CNS involvement often have worse outcomes compared to those without CNS involvement (Del Principe et al., 2018; Rozovski et al., 2015). It is important to better understand the incidence and predictive clinical and features of CNS involvement in AML to identify patients for diagnostic testing and intrathecal chemotherapy. This retrospective analysis evaluated the incidence and characteristics of CNS involvement in adult AML patients at our institution.CNS screening is recommended for AML patients with specific characteristics, including CNS symptoms, monocytic phenotype, FLT3-internal tandem duplication gene mutation, and hyperleukocytosis (>100,000 white blood cells per microliter). Treatment recommendations for CNS involvement include intrathecal methotrexate, intrathecal cytarabine, or a combination of both.In this IRB-approved retrospective study, medical records were analyzed from the University of Kansas Medical Center from years 2015-2020. Patients were selected by searching the electronic medical record for adult AML patients who received a diagnostic lumbar puncture. Characteristics of interest included presence of CNS symptoms, monocytic phenotype, FLT3 mutation, and hyperleukocytosis. Characteristics that prompted CNS screening were recorded for each patient. Additional data collection included next-generation sequencing (NGS), cytogenetic results, and whether CNS screening occurred during an initial diagnosis or during an AML relapse. Lastly, the number of intrathecal chemotherapy doses was recorded for each patient.The incidence of CNS involvement was determined by dividing the number of newly diagnosed AML CNS-positive patients by the total number of newly diagnosed AML patients. Screening detection rates were determined by dividing the number of CNS-positive patients with each characteristic by the total number that received a lumbar puncture. The percentage of CNS-positive patients with each characteristic was determined by dividing the number with each specific characteristic by the total number of CNS-positive patients. The number of intrathecal chemotherapy doses required for CNS clearance was determined using data only from patients that achieved CNS clearance.Forty-eight patients met current guidelines for CNS screening; 25 were CNS-positive and 23 were CNS-negative (overall screening detection rate of 52%). The incidence of CNS involvement among all newly diagnosed adult AML patients was 3.24%. Screening detection rates were 58% for patients with 3 characteristics, 60% for 2 characteristics, 45% for CNS symptoms, and 30% for monocytic phenotype. Not enough patients presented with the FLT3 mutation or hyperleukocytosis in isolation to calculate accurate detection rates. The CNS-positive group consisted of 28% with 3 characteristics, 24% with 2 characteristics, 20% with CNS symptoms, 12% with monocytic phenotype, 4% with FLT3 mutation, 4% with hyperleukocytosis, and 36% were screened during a relapse rather than at initial diagnosis. Two patients were CNS-positive without any of our characteristics of interest (screened due to extramedullary involvement at presentation and the other was screened as part of pre-transplant evaluation). Seventeen patients achieved CNS clearance with 41% requiring 1 dose of intrathecal chemotherapy, 35% requiring 2 doses, and 24% requiring more than 2 doses. NGS and cytogenetic results did not reveal any additional associations.This data indicates that current AML CNS screening guidelines appear to properly identify a patient population at risk for CNS involvement. At our institution, 52% of screened patients were CNS-positive. This analysis also revealed a diverse distribution of characteristics among AML patients with CNS involvement, and patients commonly presented with multiple risk factors. These results emphasize the need for ongoing research to further delineate CNS involvement risk factors in AML. This data will be used for current policy analysis at our institution and potentially prospective studies to better evaluate outcomes for AML patients with CNS involvement. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding.

Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Relapsed or Refractory Acute Myeloid Leukemia: A Systematic Review and Meta-Analysis

Background:Acute myeloid leukemia (AML) is a clonal hematologic malignancy that generally affects older adults. Despite achieving complete remission (CR) in over two-third of patients with initial induction therapy and subsequent allogeneic hematopoietic stem cell transplantation in intermediate-high risk patients, more than half of AML patients experience disease relapse. The prognosis of patients with relapsed/refractory AML (RR-AML) is often poor and treatment modalities are limited. Chimeric antigen receptor T cell (CAR-T) therapy has shown promising results in lymphoid malignancies and myeloma, and these are now being explored for the management of RR-AML. In this systematic review and meta-analysis, we aimed to investigate the outcomes of CAR-T therapy in RR-AML patients.Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane Register of Controlled Trials, and Clinical trials.gov) using MeSH terms and keywords for “Leukemia, Myeloid, Acute” AND “Receptors, Chimeric Antigen” OR “adoptive immunotherapy” from the date of inception to April 2021. A total of 673 articles were screened and original studies reporting patients with RR-AML having CAR-T therapy as the only intervention were included while reviews, duplicate, and non-relevant articles were excluded. A total of 10 studies (8 clinical trials and 2 case reports) were included. The data for following outcomes were extracted: complete response (CR), partial response (PR), overall response rate (ORR), overall survival (OS), progression-free survival (PFS), stable disease (SD), progressive disease (PD), cytokine release syndrome (CRS) and neurotoxicity (NT). Quality evaluation was done using the NIH quality assessment tool. Inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% confidence Interval (CI) were extracted to compute pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.16-2).Results:We identified 39 patients in 10 studies who received CAR-T therapy for RR-AML. Median age of patients was 35 (7.3-80) years and 59% (n=23) were male. The median follow-up time was 5 (0.7-23) months. (Table 1) Four patients had history of allogeneic hematopoietic stem cell transplant (HCT) prior to CAR-T therapy while subsequent HCT was performed in 5 patients. The pooled analysis showed a CR and ORR of 38.5% (95% CI 0.03-0.81, I 2 =66%, n=29) and 56% (CI 0.18-0.91, I 2=58%, n=29), respectively. Median duration of response was 5.5 (1-23) months. OS was reported from 1.9 months to 23 months. The pooled incidence of CRS and NT were 42.7% (95%CI 0.06-0.87, I 2=66%, n=28) and 1.3% (95% CI 0.00-0.16, I 2= 0%, n=21) respectively. Graft-versus-host disease (GVHD) was reported in 2 patients who had prior and subsequent HCT after CAR-T therapy; first patient developed grade IV GVHD in the setting of salvage therapy with donor lymphocyte infusions for relapsed disease 6 months' post CAR-T and 4 months post second allo-HCT while second patient received CAR-T as part of conditioning therapy and developed grade IV GVHD on day 32.Conclusion:CAR-T therapy has shown favorable results comparable to current salvage therapies for relapsed or refractory AML with an acceptable toxicity profile. However, there are several challenges including the heterogeneous biology of AML, lack of a targetable antigen expression on malignant cells, and immune escape and exhaustion. Future prospective studies with improved CAR-T constructs will hopefully improve the outcomes in this therapeutically challenging patient population. [Display omitted] DisclosuresLin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Astelllas Pharma: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Novartis: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding.

Preliminary Results By Age Group of Treatment with CPX-351 Plus Venetoclax in Adults with Newly Diagnosed AML: Subgroup Analysis of the V-FAST Phase 1b Master Trial

Preliminary Results By Age Group of Treatment with CPX-351 Plus Venetoclax in Adults with Newly Diagnosed AML: Subgroup Analysis of the V-FAST Phase 1b Master Trial

Use of Endpoints in Phase III Randomized Controlled Trials for Acute Myeloid Leukemia over the Last 15 Years: A Systematic Review

Background:The use of objective endpoints is critical for the generalization and clinical implications of a study. Overall survival (OS) has traditionally been used as the gold standard for demonstrating the true clinical benefit of therapy or intervention. We systematically evaluated the proportion of different primary and secondary endpoints used in phase III randomized controlled trials (RCTs) for acute myeloid leukemia (AML), and their trends over time.Methods:Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on three databases (PubMed, Cochrane, and Clinical trials.gov) using MeSH terms and keywords for “Leukemia, Myeloid, Acute” AND “Randomized Controlled Trials as Topic” from January 2006 to March 2021. We screened 3290 articles. After excluding duplicates, reviews, and irrelevant articles, 241 articles reporting only phase III RCTs with primary and secondary endpoints on AML or its subtypes were included for our systematic review. Primary and secondary endpoints data were extracted from the included studies, and the frequency of various endpoints as well as their yearly frequencies were calculated. Disease-free survival (DFS) was used to represent similar outcomes including event-free survival (EFS), progression-free survival (PFS), leukemia-free survival (LFS), and relapse-free survival (RFS).Results:Our study included 241 phase III RCTs on AML. OS was the primary endpoint in 114 (47%) studies, while DFS and complete remission (CR) were reported as primary endpoints in 67 (28%) and 41 (17%) studies, respectively. Safety/adverse events, relapse rate (RR), graft versus host disease (GvHD) free survival, hematological improvement (HI), minimal residual disease (MRD), and non-relapse mortality (NRM) were used as primary endpoints in 10 (4%), 8 (3%), 5 (2%), 4 (2%), 3 (1%), and 2 (1%) studies respectively. Incidence of hospitalization, fungal disease, lung infiltrates, chronic GvHD, and allogeneic stem cell transplant each were used as primary endpoints in 1 (0.4%) study. (Table 1) Secondary endpoints followed a similar pattern as detailed in Table 2. OS (n=74, 31%), DFS (n=77, 32%) and CR (n=73, 30%) were commonly reported secondary endpoints. Safety/adverse effects, RR, mortality, quality of life (QoL), HI, MRD, incidence/length of hospitalization, and acute/chronic GvHD were used as secondary endpoints in 35 (14.5%), 15 (6%), 13 (5%), 9 (4%), 9 (4%), 7 (3%), 7 (3%), 5 (2%), and 4 (2%) studies, respectively. After 2013, increase in the use of OS (31% to 52%) and CR (15% to 17%) as a primary endpoint was noted, while the use of DFS as a primary endpoint decreased from 52% to 21%. (Table 1) For secondary endpoints, a higher trend in the use of DFS (19% to 35%) and OS (31% to 45%) and a lower trend in the use of CR (35% to 29%) was observed after 2013. (Table 2)Conclusion:Overall survival and disease-free survival were the most used primary and secondary endpoints in phase III randomized controlled trials for AML. There has been an increase in the use of clinically meaningful and objective endpoint of OS over the past 15 years in AML phase III RCTs. [Display omitted] DisclosuresYacoub: Cara: Current equity holder in publicly-traded company; Dynavex: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. McGuirk: Pluristem Therapeutics: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; EcoR1 Capital: Consultancy; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astelllas Pharma: Research Funding.

Bispecific Anti-CD123 x Anti-CD3 Adaptir™ Molecules APVO436 and APVO437 Have Broad Activity Against Primary Human AML Cells In Vitro

Background: The IL-3 receptor CD123 is an attractive target for antibody-based therapies in acute myeloid leukemia (AML) because of its frequent expression on AML blasts and its reported overexpression on leukemic stem cells (LSCs) as compared to normal hematopoietic tissues. Previously, two CD123 x CD3 bispecific targeting ADAPTIR constructs (APVO436 and APVO437) have been shown to bind CD123 with high affinity, engage T-cells and, in the presence of effector T-cells, cause cytotoxicity in CD123-expressing cell lines as well as in an in vivo xenograft model. Here, we further investigated the determinants of anti-tumor efficacy of these constructs in human AML.Materials and Methods: Frozen aliquots of Ficoll-isolated mononuclear cells from peripheral blood or bone marrow specimens were obtained from adults with AML. CD123 expression on myeloblasts and cells lines and the percentage of endogenous CD3+ T-cells in AML specimens were quantified by flow cytometry. To determine specific cytotoxicity, cell lines or primary AML cells were incubated in culture medium containing various concentrations of ADAPTIR constructs APVO436 and APVO437. Exogenous T-cells isolated from healthy volunteers were labeled with CellVue membrane dye and added at different effector:target (E:T) cell ratios. After 48 hours, cell numbers and drug-induced cytotoxicity, using DAPI to detect non-viable cells, were determined by flow cytometry; target AML cells were identified by forward/side scatter properties and negativity for CellVue dye. Specific cytotoxicity was calculated as: 100 x (%DAPItreated - %DAPIcontrol)/(100-%DAPIcontrol) and are presented as mean±SEM of all samples tested. T-cell activation, proliferation and depletion of CD123+ cell populations in normal and AML specimens were assessed using multi-color flow cytometry.Results: We examined the ability of APVO436 and APVO437 to induce cytotoxicity in primary human AML specimens. Of 20 samples tested, 10 had both >60% viability on thaw and >40% viability after 48 hours in cultures and were included for further analysis. The median percentage of myeloid blasts and CD3+ T-cells in the analyzed specimens was 78.5% (range 52-91.7%) and 2.95% (range 0.3-8.8%). With no exogenous T-cells, APVO436 and APVO437 induced modest cytotoxicity; at 1000 pM, APVO436 and APVO437 induced specific cytotoxicity of 6.8±3.8% and 3.9±3.6%, respectively. There was no statistically significant correlation between the percentage of endogenous T-cells present in the sample and the amount of cytotoxicity in the absence of exogenous T-cells. The addition of healthy donor T-cells increased cytotoxicity in a E:T-dependent manner (p <0.0001 for both APVO436 and APVO437) and increasing drug concentrations also increased cytotoxicity in a statistically-significant fashion (p <0.0001 for both APVO436 and APVO437). There was no consistent linear relationship between MFICD123 of blasts (MFICD123, arbitrary units) and cytotoxicity. Significant cytotoxicity was achieved even at the lowest levels of blast CD123 expression (MFICD123 range among patient samples: 349-3423). Inclusion of all 20 samples in cytotoxicity analysis did not qualitatively change results. APVO436 induced T-cell activation in both normal and AML samples at 24 hours as assessed by quantification of CD25 and CD69 expressing T-cells. T-cell activation was accompanied by proliferation of T-cells in normal and AML specimens at 96 hours in the presence of APVO436. APVO436 induced dose dependent depletion of CD123+ cells which was evident at 24 hours in both normal and AML samples.Conclusion: APVO436 and APVO437 cause target cell cytolysis in a dose-dependent, target-antigen-dependent, and E:T-dependent manner. Broad activity was seen in primary human AML samples and both constructs were effective in inducing cytotoxicity across a range of blast CD123 expression levels, including specimens with very limited CD123 expression. Endogenous T-cell activation and proliferation accompanied by CD123+ cell depletion demonstrate similar activity of anti-CD123 x anti-CD3 ADAPTIRs in both normal and AML subject samples. These data are supportive of further investigation of anti-CD123 x anti-CD3 ADAPTIR molecules as a potential treatment option for AML. DisclosuresGottschalk:Aptevo Therapeutics: Employment, Equity Ownership. Comeau:Aptevo Therapeutics: Employment, Equity Ownership. Hoyos:Aptevo Therapeutics: Employment, Equity Ownership. Walter:ADC Therapeutics: Research Funding; Aptevo Therapeutics: Research Funding.

Patient-Reported Outcomes in Hemophilia B Patients Treated with IB1001 [Coagulation Factor IX (recombinant)

INTRODUCTION. Hemophilia B is a rare bleeding disorder caused by missing or defective factor IX, a clotting protein in the coagulation cascade. Patients with hemophilia B are treated with infusion of concentrated factor IX to replace the deficiency. As a chronic disease, patient quality of life and treatment satisfaction is a fundamental component of overall patient care in hemophilia B. Anecdotal evidence has suggested that some patients experience improved clinical outcomes and increased satisfaction when treated with IB1001, approved in the US as IXINITY®, [coagulation factor IX (recombinant)] (current factor treatment) as compared to their previous treatment. The objective of this study was to undertake a systematic assessment of IB1001 patient responses to measures of clinical care and quality of life that are relevant in hemophilia B in order to provide a more comprehensive description. METHODS. This was a cross-sectional study of hemophilia B patients in the United States currently being treated with IB1001. The study protocol was reviewed and approved by a central IRB. A survey was developed to capture patient-reported responses to clinical and quality of life questions of interest, including demographic characteristics, disease status, bleeding events, treatment, quality of life, and patient satisfaction. Where possible, patients were asked to compare responses on current factor treatment to those while on previous treatment with other available products. Patients were invited to complete the survey online. This was a pilot study to generate a descriptive analysis of patient experience. RESULTS. A total of 17 patients completed the survey. Most patients were male (76.5%) with a mean age of 43.8 years (range 16-73), and had been taking IB1001 for a mean 18 months at the time of this study. The elements most important for patient treatment choice were a high recovery rate, 24-hour half-life, no inhibitor development, and few side effects. Fewer annualized bleeding events were reported with the current factor treatment (mean 3.3 vs 6.7). Joint bleeds were most commonly reported, and most patients stated their bleed frequency was less (41%) or about the same (35%) on their current factor treatment compared to their previous treatment. Most patients reported their activity level as either ‘very active’ (23%), or ‘somewhat active’ (53%), and 47% of patients indicated they are more active now than on prior treatment. Overall, patients were either ‘very satisfied’ (76%) or ‘somewhat satisfied’ (12%) with their current factor treatment, compared with 12% and 23%, respectively, on prior treatment. Patients reported more mobility (29%), less pain (41%), and less anxiety or depression (18%) now than on prior treatment. CONCLUSIONS. In this study, we showed the utility of an online, survey-based instrument in characterizing patient experience with factor replacement products in hemophilia B. This study quantified the details of the patient experience that may have been driving the anecdotes of improved patient satisfaction and quality of life with IB1001. Overall, patients reported increased satisfaction, and improved clinical outcomes on their current factor treatment compared to products they had used in the past. While the data from this pilot study are encouraging, further study is warranted such as linking patient-reported outcomes to medical chart data to validate the clinical response and to better understand the variables that most influence patient satisfaction and quality of life. DisclosuresSchaaf:Aptevo Therapeutics: Employment, Equity Ownership. Lockhart:Aptevo Therapeutics: Consultancy. Fritz:Aptevo Therapeutics: Employment, Equity Ownership. Stromatt:Aptevo Therapeutics: Employment, Equity Ownership.

Developing Models to Predict Intensive Care Unit Admission and Mortality for Adults with Acute Myeloid Leukemia (AML)

Introduction: The survival expectations for adults with acute myeloid leukemia (AML) have improved over the last 40 years, partly due to supportive care advances enabling the delivery of increasingly intensive treatment modalities. However, with increasing therapy intensity comes potential for increased use of hospital resources. Indeed, our recent work with a large national database - the University HealthSystem Consortium (UHC)– demonstrated that intensive care unit (ICU) admissions remained frequent in AML patients over the last decade and were associated with significant mortality and steeply climbing costs. As the next step, we now used this database to develop models to predict ICU admission (“ICU Admission Risk Score”) and mortality (“ICU Mortality Risk Score”) for hospitalized AML patients.Methods: A longitudinal discharge database derived from 239 U.S. UHC participating hospitals was used to retrospectively evaluate AML patients hospitalized from 2004-2012. Clinical data from each hospital's discharge summaries were extracted by certified coders and merged to create the central UHC database. Included were patients with a diagnosis of active AML based on ICD-9 CM coding. Patients were excluded if they had undergone a hematopoietic stem cell transplant. Generalized estimating equations were used to control for patients with >1 admission in the study period . Primary outcomes were ICU admission and in-hospital death after ICU admission. Independent variables included age, gender, geographic location, AML volume of the admitting hospital based on quartiles of unique patients, number of prior ICU admissions, and types of comorbidities and infections present. We then applied multivariate logistic regression to create the models in which each covariate and the multicomponent model's predictive ability was evaluated by testing the area under the receiver operating characteristic curve (AUC). We made 2 models for each outcome: a full model using all relevant covariates tested and a simplified model for facilitating use in clinical practice. Models' internal validity was evaluated with 10-fold cross-validation.Results: 73,955 AML patient admissions were identified for inclusion. Patients had a median age of 58 (range 18-102) years, were 54% male, and were hospitalized in the Northeast (33%), Central (31%), Western (18%), and Southern (17%) U.S. One percent of admissions were at very-low AML volume hospitals, 5% at low, 21% at medium, and 74% at high. Overall, 22% of patients were admitted to the ICU during their hospitalization with a median ICU length of stay of 5 (1st-3rd quartile: 4-25) days. In-hospital mortality was 28% for those requiring ICU care. Factors with the greatest risk for ICU admission and subsequent in-hospital mortality by odds ratio in multivariate analysis included younger age, treatment at a small volume center, baseline lung disease, renal disease, vascular disease, gram negative/positive sepsis, pneumonia, and increasing number of comorbidities. The AUC for the full model for ICU admission was 0.73 (95% confidence interval [CI]: 0.728-0.732) and for the simplified model (composed of number of prior admissions, thrombosis, lung disease, renal disease, vascular disease, fungal infection, and number of comorbidities; Table 1A) was 0.70 (95% CI: 0.690-0.695). The AUC for the full model for in-hospital mortality was 0.70 (95% CI: 0.701-0.705) and for the simplified model (composed of lung disease, renal disease, and number of comorbidities; Table 1B) was 0.86 (95% CI: 0.853-0.859). The AUC was actually higher for the simplified mortality model due to a small number of risk factors with high univariate AUCs; thus including the covariates with low predictive ability decreased the AUC of the large model.Conclusions: These simplified models composed of readily available clinical variables have good performance characteristics in their ability to predict hospital death, and to a lesser extent, ICU admission, for hospitalized AML patients. The inferior performance of the ICU model may be related to heterogeneity in ICU admission criteria between hospitals. As a next step, these models will be externally validated and refined with our large institutional AML dataset to improve their predictive ability. If validated, we plan to use them to risk stratify patients upon hospital admission to allow for testing of primary prevention and intervention strategies. [Display omitted] DisclosuresWalter:Aptevo Therapeutics: Research Funding; ADC Therapeutics: Research Funding.

G-CSF, Cladribine, Cytarabine, and Dose-Escalated Mitoxantrone (GCLAM) in Adults with Relapsed/Refractory Acute Myeloid Leukemia (AML) or High-Grade Myeloid Neoplasms: Final Results from a Phase 1/2 Trial

▪Background: Outcomes with standard chemotherapies for relapsed/refractory myeloid neoplasms are poor, with complete remission (CR) rates often not exceeding 15-20%. Results from a previous 2 study in poor-risk relapsed/refractory acute myeloid leukemia (AML) suggested encouraging activity of a combination of G-CSF, cladribine, cytarabine, and mitoxantrone (GCLAM). Given data suggesting benefit of escalated doses of anthracyclines in AML, we conducted a phase 1/2 study (NCT02044796) of GCLAM using escalated doses of mitoxantrone for patients with relapsed/refractory AML or high-risk myeloid neoplasms (≥10% blasts).Patients and Methods: Patients≥18 years were eligible if they had a treatment-related mortality (TRM) score of ≤6.9 (corresponding to a predicted 28 day mortality of ≤6.9% with standard induction chemotherapy) and adequate organ function (LVEF ≥45%, creatinine ≤2.0 mg/dL, bilirubin ≤3.25 mg/dL). Excluded were patients with uncontrolled infection or concomitant illness with expected survival <1 year. In phase 1, cohorts of 6-12 patients were assigned to 1 of 4 dose levels of mitoxantrone (12, 14, 16, or 18 mg/m2/day, days 1-3, compared to 10 mg/m2/day used in previous trials). Other drugs doses were G-CSF (days 0-5), cladribine 5 mg/m2/day (days 1-5), and cytarabine 2 g/m2/day (days 1-5). In phase 2, patients were treated at the maximum tolerated dose (MTD) of mitoxantrone. A second course of GCLAM was given if CR was not achieved in cycle 1. Up to 4 cycles of consolidation with GCLA (mitoxantrone omitted) were allowed if CR or CR with incomplete blood count recovery (CRi) was achieved with 1-2 cycles of induction therapy. Dose-limiting toxicities (DLTs) were: 1) grade 3 non-hematologic toxicity lasting >48 hours that resulted in >7 day delay of the next treatment cycle; 2) grade ≥4 non-hematologic toxicity if recovery to grade ≤2 within 14 days, both excluding infection or constitutional symptoms.Results: Among 26 patients treated in phase 1, 2 DLTs occurred at dose level 4 (encephalopathy and cardiogenic shock), establishing GCLAM with mitoxantrone at 16 mg/m2/day as the MTD. Forty patients, median age 63 [range: 33-77] years, median TRM score 2.0 [0.2-6.39], with AML (n=34) or high-grade myelodysplastic syndrome (n=6) received GCLAM at MTD; 28% had secondary disease. Nineteen were primary refractory and 21 had relapsed disease (median duration of CR1: 12 months). Cytogenetics were favorable in 1, intermediate in 21, and adverse in 18; 6 patients had NPM1 and 1 had FLT3 mutations. Ten patients achieved CR (25%, 95% confidence interval [CI]: 13-41%) and 13 a CRi (32%, 95% CI: 19-49%) with 1-2 induction cycles, for an overall response rate (ORR) of 58% (95% CI: 40-73%). Nine of the 10 CR patients (90%) were negative for minimal residual disease by flow cytometry. One further patient had a morphologic leukemia free state, 11 had resistant disease, 2 were not evaluable, and 2 died in aplasia within 28 days of therapy for a TRM rate of 5%. The median overall survival (OS) was 11.5 months. Besides infections/fever, the most common grade ≥3 adverse events were rash and hypoxia (fluid overload/infection-related). Median times to an absolute neutrophil count ≥500/μL and platelet count ≥50,000/μL were 29 days each. In multivariable analysis controlling for baseline prognostic features, compared to 41 patients treated with GCLAM outside this study with mitoxantrone at 10mg/m2/day, GCLAM with mitoxantrone at 16mg/m2 was associated with better OS (hazard ratio [HR]=0.45, 95% CI: 0.24-0.85, p=.01) and a nonsignificantly higher ORR (odds ratio [OR]=1.87; 95% CI: 0.69-5.10, p=.22). Further, compared to patient treated with other salvage regimens used at our institution (GCLAC [G-CSF, clofarabine and high-dose cytarabine], n=61; d/MEC [decitabine priming, mitoxantrone, etoposide, and cytarabine], n=52), GCLAM with mitoxantrone at 16mg/m2 was associated with better ORR and OS than d/MEC (OR=3.33, p=.012; HR for death= 0.50, p=.01) and a similar ORR compared to GCLAC (OR=1.69, p=.25) after multivariable adjustment with a HR for death of 0.68 (95% CI: 0.39-1.18, p=.17).Conclusion GCLAM with mitoxantrone at 16 mg/m2/day is well tolerated with a low TRM rate, and has potent anti-leukemia activity in relapsed/refractory myeloid neoplasms. Survival for this regimen appears better than when the regimen is used with mitoxantrone at 10 mg/m2/day and compared to other salvage regimens such as d/MEC. DisclosuresScott:Alexion: Consultancy, Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Acceleron: Other: Data and Safety Monitoring Board; Agios Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Becker:GlycoMimetics, Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding; ADC Therapeutics: Research Funding.