Refractory Relapsed Acute Myeloid Leukemia Research Articles

Phase 2 Study of CPX-351 in Combination with Venetoclax in Patients with Newly Diagnosed, High Risk Acute Myeloid Leukemia

Background CPX-351 is a nanoscale liposome of a fixed 5:1 molar ratio of cytarabine and daunorubicin which has improved survival of secondary acute myeloid leukemia (AML) 1. Venetoclax (ven) is a BCL2 inhibitor which, in combination with azacitidine or cytarabine, has become the standard of care for elderly AML. Ven has shown synergism with chemotherapy, with high complete remission (CR) rates in newly diagnosed (ND) and relapsed / refractory (RR) AML 2. In this study, we aim to assess the efficacy and safety of CPX-351 and ven (CPX-ven) in RR and ND AML. Methods This was a phase 2 study with a lead-in safety phase. Enrolment was allowed if the blasts were ≥10%. Patients (pts) age ≥18 with RR AML were eligible for the safety lead-in phase (LIP) or arm A. Arm B enrolled pts age 18 - 69 with ND AML. Other inclusion criteria included adequate liver, renal and cardiac function, and ECOG performance status ≤2. Pts with CNS involvement or prior CPX-351 were excluded. The recommend phase 2 dose was CPX-351 (daunorubicin 44 mg/m 2 and cytarabine 100 mg/m 2 IV on D1, 3 and 5 of induction, and daunorubicin 22 mg/m2 IV on D1 and 3 during consolidation) combined with ven on D2-8 of each cycle. Ven was dosed at 300mg daily and reduced to 150mg or 50mg daily for pts on a moderate or strong CYP3A inhibitors, respectively. The primary outcome measure was complete remission (CR) or CR with incomplete count recovery (CRi). Here, we report the outcomes of arm B including pts with ND AML. Results 14 pts were enrolled on arm B. One pt withdrew and one was too early in treatment, therefore 12 were evaluable. Baseline characteristics are shown in Table 1. The median age was 59.5 years (range, 44 - 69); Four (33.3%) were female. All 12 (100%) pts were classified as adverse risk per the 2017 European Leukemia Net Guidelines. Two (16.7%) pts had treatment for a prior non-myeloid malignancy (therapy-related AML). Eight (66.7%) had an antecedent haematological disorder (secondary AML), of whom seven had treatment (median 1 line, range 1 - 2). Four (33.3%) pts had a complex karyotype, of whom three harbored a TP53 mutation. Nine (75.0%) pts achieved a response, including four CR (33.3%), five CRi (41.6%), and one induction mortality (8.3%) prior to disease assessment. 3/4 (75.0%) pts with complex cytogenetics (including 2/3 (66.7%) with a TP53 mutation) achieved a CR/CRi. Of the secondary AML pts with an evaluable response, 5/7 (71.4%) achieved a CR/CRi. Of the nine pts achieving CR/CRi, five (55.5%) were negative for minimal residual disease (MRD) by flow cytometry. The median number of cycles to CR/CRi was one (range 1 - 2). The median overall survival (OS) was 12.9 months (95% CI, 3.1 - not reached, NR, Figure 1). The median relapse-free survival (RFS) was 8.7 months (95% CI, 3.1 -NR). 7/9 (77.8%) of responding pts underwent an allogeneic stem cell transplant (SCT) after attaining CR/CRi. There were 90 adverse events (AE) in 10 (83.3%) pts. 80 (88.9%) were grade 1 or 2, 10 (11.1%) were grade ≥3. The most common AE was gastrointestinal with seven (7.8%) occurrences. Four (33.3%) pts developed grade ≥3 infections; of these, one (8.3%) died. The cause of death was neutropenic septic shock due to pneumonia. Conclusion CPX-ven is a feasible option for remission induction in pts with high-risk, newly diagnosed AML. The combination produced high rates of response and MRD negativity in a cohort of pts with adverse risk features, including pts with adverse karyotype and AML following prior HMA-based treatment, allowing them to proceed with SCT. Toxicities are as expected for an intensive chemotherapy regimen. Further studies are needed to confirm the efficacy of this combination.

Homoharringtonine Overcomes the Negative Impact of Genetic Patterns on Venetoclax Plus Azacitidine Regimen in Relapsed/Refractory Acute Myeloid Leukemia: A Multi-Center, Cohort Study

Objective: Whether other agents added to venetoclax (VEN) plus hypomethylating agents (HMA) regimen could overcome the negative impact of genetic patterns on response in patients with relapsed/refractory acute myeloid leukemia (RR-AML) remains unclear. Aim of this study was to evaluate whether homoharringtonine (HHT) added to VEN plus azacitidine (AZA) regimen could improve the response and overcome the negative impact of genetic patterns in patients with RR-AML . Methods: A multi-center, cohort study of the response and the genetic patterns of response of VEN plus AZA and HHT (VAH) versus VEN plus AZA (VA) regimens as salvage treatment in the patients with RR-AML was performed. Patients were enrolled from four studies from October 2018 to December 2022 at nine medical centers in china. Results: A total of 321 patients were analyzed, including 150 females and 171 males, with a median age at 46 (IQR, 35-61) years. There were 172 patients in the VAH and 149 in the VA group. VAH significantly improved CRc rate (66.3% vs. 44.3%, P<0.001) and prolonged OS (median OS, not reach vs. 14.3 months, P=0.004), to compared with VA. Multivariate analysis showed that VAH was the independently protective factor for CRc and survival. In addition, VAH significantly overcame the negative impact of FLT3-ITD/TKD, N/KRAS, TET2, DNMT3A mutations, and t(8;21)/AML1-ETO, as well as non-adverse ELN risk, also apparently in adverse ELN risk or complex karyotype, on the response of VA regimen. Conclusion: The impact of genetic patterns on the response presented diversely in different VEN-based regimens. HHT added to VA regimen might improve the response and overcome the negative impact of part genetic patterns in RR-AML. Key words: homoharringtonine, venetoclax, relapsed/refractory, acute myeloid leukemia, genetic pattern

A Phase 1 Study of CD38-Bispecific Antibody (XmAb18968) for Patients with CD38 Expressing Relapsed/Refractory Acute Myeloid Leukemia

Background: Outcomes of adults with relapsed/refractory acute myeloid leukemia (RR-AML) have remained poor. CD38 is a transmembrane glycoprotein that is highly expressed in AML and is potentially targetable with CD38 blocking agents [Naik J et al. Haematologica 2019, Tembhare et al. J Immunother Cancer 2020]. XmAb18968 is a novel CD38-CD3 bi-specific T-cell engager with Fc domain modified to minimize Fcγ receptor binding and non-selective T-cell activation resulting in reduced cytokine release without compromising target cell killing. We designed a phase I clinical trial to assess the safety and tolerability of XmAb18968 in patients with RR-AML. Methods: We conducted a multicenter, open label, phase I dose escalation study of XmAb18968 (NCT05038644). Patients aged ≥18 years with relapsed/refractory AML, ECOG PS 0-2 and adequate organ function were eligible. Major exclusion criteria are hematopoietic cell transplantation within 6 months of enrollment, active acute graft-versus-host disease, and acute promyelocytic leukemia. Dose escalation was conducted using 3+3 design and 4 separate dose levels were studied [0.8mg, 1mg, 1.3mg, 1.5mg]. XmAb18968 was administered intravenously on days 1, 8, 15, 22 on a 28-day cycle. During cycle 1 alone, day 1 dose was fractionated and administered over 2 days to minimize the risk of significant cytokine release syndrome (CRS). Treatment was continued until progression or unacceptable toxicity. The primary objective was to determine the safety and dose limiting toxicity (DLT) and secondary objective was to determine the preliminary efficacy. Measurable residual disease (MRD) status was assessed using multicolor flow cytometry with 0.01% sensitivity. Correlative studies included pharmacokinetics, characterizing changes in serum cytokines and phenotypic expression of activated T-cells and leukemic cells, correlation of the phenotypic expression with changes in transcriptome at the single-cell level, proteomics evaluation of cytokine secretion at the single-cell level and correlation of response with N-glycan profiling, quantitative site-occupancy, and direct glycopeptide analysis. Results: Thirteen patients with RR-AML were enrolled, 12 of whom were evaluable (1 patient came off study before DLT period). Median age was 63 years (45-77), 77% with adverse risk disease, 38% with secondary AML, and received median two (range 2-7) prior lines of therapy. Twelve of 13 patients (92%) were previously treated with venetoclax based regimen and 31% had prior allogeneic HCT. Adverse risk mutations included TP53 (31%), RUNX1 (23%), and ASXL1 (15%). Grade 3 or higher adverse events included anemia (8%), neutropenia (15%), and thrombocytopenia (23%) (Table 1). CRS grades 1-2 were noted in 62% of patients, no grade ≥3 CRS or neurotoxicity (any grade) was seen. There was no dose limiting toxicity (DLT). Of the 12 evaluable total patients, clinically meaningful response was noted in two patients who were MRD positive by flow cytometry prior to study entry and achieved MRD negative CR (Table 2). These two patients who achieved MRD negative CR subsequently proceeded to allogeneic HCT. Median time to response was 1 cycle. Median OS of the cohort was 6.2 months (1.8-NR). Conclusions: XmAb18968 is safe and well tolerated in patients with RR-AML. Dose escalation yielded MRD negative CR in RR-AML patients who were MRD positive at study entry. Details on correlative studies examining mechanisms of therapeutic efficacy and resistance will be reported in the main meeting.

The Efficacy and Safety of CLAG±Ida/Mito+Ven As Salvage Therapy of Relapsed/Refractory Acute Myeloid Leukemia

Purpose: As known CLAG±Ida/Mito regimen is recommended by different guidelines as a chioce for salvage therapy of relapsed/refractory acute myeloid leukemia (RR-AML). Recent study showed venetoclax (Ven) added to CLAG+Ida as frontline treatment of AML acquired a good response and well toleration. Yet, how CLAG±Ida/Mito+Ven works in the salvage therapy of RR-AML remains unclear. Aim of this study was to analyze the efficacy and safety of CLAG±Ida/Mito+Ven as salvage therapy of RR-AML. Methods: A single center, retrospective study was performed. Patients with RR-AML, who were salvagedly treated with CLAG±Ida/Mito+Ven during July 2021 to June 2023, were included. CLAG±Ida/Mito+Ven: cladribine 5mg/m 2 day 1-5, cytarabine 1-1.5g/m 2 day 1-5, PEG-G-CSF 6mg day 0, idarubicin 6mg/m 2 day 1-3 or mitoxantrone 6mg/m 2 day 1-3 (lipo-Mito 20mg/m 2 day 1), Ven 400mg day 2-8. Results: 33 patients were included, with a median age of 42(15-72) years old, male to female 17/16, de novo/sAML 31/2, refractory/relapsed 17/16, ELN-low /intermediate/high risk 7/10/16. They previously received median 2(1-12) cycles of chemotherapy, including 2 relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 14 with prior hypomethylating agents (HMA). Among the 33 patients with CLAG+Ven, 3 were combined with Mito, 1 with Ida, 15 with FLT3 inhibitors. After one cycle of salvage therapy, 24(72.7%) acquired response, including 22(66.7%) with CR/CRi, 15(45.5%) with MRD-negative (accounting for 68.2% of the patients with CR/CRi). Multivariate analysis showed that prior HMA, FLT3 mutation and ELN-high risk were the independently poor factors for CR/CRi. With a median follow-up of 3(1-23) months, 15(45.5%) patients were bridged to allo-HSCT, 3(12.5%) relapsed, 5(15.2%) died, including 3 died of leukemia progression and 2 with transplant-related motality. Patients obtaining CR/CRi had significantly longer overall survival (mOS, 19.8(15.8-23.8) months) than those without (mOS, 5.1(2.7-7.5) months, P=0.013). Patients being bridged to allo-HSCT also had significantly better OS than those without. During the salvage therapy, the median duration of agranulocytosis was 19(11-40) days. 25(75.6%) patients underwent manageable infection. The motality of the 30 and 60 day were 0. Conclusion: CLAG±Ida/Mito+Ven might be a chioce for salvage therapy of RR-AML, with the CR/CRi rate of 66.7%, MRD-negative rate of 68.2% and well toleration. Key words: CLAG, venetoclax, salvage therapy, relapsed/refractory, acute myeloid leukemia

Venetoclax + Cladribine + Low-Dose Cytarabine in Acute Myeloid Leukemia Relapsed or Refractory to Venetoclax + Hypomethylating Agent

Background Venetoclax (Ven) in combination with hypomethylating agent (HMA) is the standard treatment for newly diagnosed elderly/unfit patients with acute myeloid leukemia (AML). Treatment options for patients with relapsed/refractory (RR) disease following Ven-HMA are limited in the absence of targetable mutations. In a recent phase 2 study, the addition of Ven to cladribine (CDA) plus low-dose cytarabine (LDAC), in newly-diagnosed elderly/unfit AML, resulted in complete remission with (CR) or without (CRi) count recovery rate of 93% ( J Clin Oncol 20;40(33)). In the current study, we share our experience with this regimen in patients relapsed or refractory to Ven-HMA, treated outside of clinical trials. Methods Under an institutional review board approved minimum risk protocol, the Mayo Clinic (MN, AZ, FL) database was searched to identify patients with AML who failed treatment with Ven-HMA and subsequently received at least one cycle of salvage therapy with Ven-CDA-LDAC: Ven 100-400 mg, dose adjusted, d1-21, CDA 5 mg/m 2 d1-5, LDAC 20 mg twice daily d1-10, outside of clinical trials. Cytogenetic and molecular studies were performed at the time of Ven-CDA-LDAC initiation in most cases, by conventional karyotype and next-generation sequencing, respectively. The 2022 European LeukemiaNet (ELN) criteria were applied to define risk and response. Survival was calculated from the time of Ven-CDA-LDAC treatment start to last follow-up or death. Results Patient characteristics A total of 39 RR AML patients (median age 65 years, 67% male, 64% de novo), with prior exposure to Ven-HMA, received Ven-CDA-LDAC (median 1 cycle; range 1-5). Study patients had received one ( n=16), two ( n=14), three ( n=5), four ( n=2), five ( n=1) or nine ( n=1) prior therapies, including Ven-HMA. Nine (23%) patients had relapsed following allogeneic hematopoietic stem cell transplant (AHSCT). ELN cytogenetic risk included intermediate (46%, n=18), and adverse (54%, n=21). Mutations involved TP53 in 9 patients (23%), K/ NRAS in 8 (21%), RUNX1 in 7 (18%), TET2 in 6 (15%), ASXL1 in 5 (13%), and STAG2 in 5 (13%). Response and toxicity Eleven (28%) patients achieved CR ( n=2; 5%) or CRi ( n=9; 23%); median time to response was 1 month and median response duration 3.4 months. In addition, 2 (5%) patients each experienced partial remission (PR) and bone marrow aplasia without fulfilling criteria for morphologic leukemia free state. Measurable residual disease (MRD) was negative by multiparametric flow cytometry in 2 of 7 (29%) informative CR/CRi cases. CR/CRi rates were higher in females (54% vs 15%; p=0.01), de novo vssecondary AML (40% vs 7%; p=0.02), and absence of adverse karyotype (50% vs 9%; p<0.01), K/NRAS (35% vs 0%, p=0.01), ASXL1 (32% vs 0%, p=0.05), or STAG2 mutations (32% vs 0%, p=0.05) (Table 1). Multivariable analysis confirmed superior response in de novo AML (p<0.01), absence of adverse karyotype, (p<0.01), and absence of K/NRAS mutations (p=0.02). CR/CRi rates were not significantly affected by relapsed vs refractory setting ( p=0.95), number of prior therapies ( p=0.51), prior AHSCT ( p=0.64), or TP53 mutations ( p=0.64) (Table 1). Treatment-emergent toxicities included infections (49%, n=19), comprising bacteremia ( n=11), pneumonia ( n=10), peri-rectal abscess ( n=6), and laboratory evidence of tumor lysis syndrome (3%, n=1). Survival At a median follow-up of 3.9 months, from initiation of Ven-CDA-LDAC, 31 deaths (79%), 6 relapses (15%), and 7 AHSCT (18%; including 5 in CR/CRi, 1 in aplasia) were documented. Median survival following Ven-CDA-LDAC was 4.6 months, and superior in the presence vs absence of CR/CRi (8.1 vs 2.9 months; p=0.01), and in patients receiving AHSCT (10.5 vs 3.4 months; p=0.02). Absence of adverse karyotype was also associated with superior survival (6 vs 3.4 months; p=0.05). Multivariable analysis confirmed the favorable survival impact of CR/CRi ( p=0.03) and AHSCT ( p=0.05); survival impact was not apparent for secondary AML ( p=0.29) or K/NRAS ( p=0.70) or TP53 ( p=0.10) mutations. Conclusions The current study suggests transplant bridging value for Ven-CDA-LDAC in AML patients relapsed or refractory to Ven-HMA, especially in the absence of adverse karyotype or K/NRAS mutation. AHSCT and achievement of CR/CRi appear to be indispensable for favorable post-Ven-CDA-LDAC survival.

Aberrant expression of T cell activation markers and upregulation of Tregs in bone marrow and peripheral blood in acute myeloid leukemia patients

ABSTRACTBackground:T cells’ function and activation and the immunosuppressive effect of regulatory T cells (Tregs) play a pivotal role in the occurrence and progression of acute myeloid leukemia (AML). In this study, we investigate the expression of T cell activation markers and quantity of Tregs in bone marrow (BM) and peripheral blood (PB) from AML patients and further characterized their correlation with BM leukemic blasts.Methods:Expression of CD25, CD38, CD69, and HLA-DR on the surfaces of CD4+ and CD8+ T cells and the quantity of Tregs in BM and PB from new diagnosed (ND), relapsed-refractory (RR), complete remission (CR) AML patients were measured via flow cytometry.Results:Compared to normal controls (NC), we found higher proportion of CD4+ CD69+ T cells, CD8+ CD69+ T cells and Tregs in PB. CD8+ CD38+ T cells and CD8+ HLA-DR+ T cells in RR were significantly higher than ND, CR and NC). Tregs were normalized when AML patients achieved CR. Moreover, there was a minor positive correlation between AML blasts and CD8+ CD25+ T cells or Tregs, while AML blasts had a minor negative correlation with CD4+ CD69+ T cells.Conclusion:Abnormal activation markers of T cells and Tregs may be involved in the pathological mechanism of ND and RR AML. Our results indicated that CD8+ CD38+ T cells and CD8+ HLA-DR+ T cells might be RR markers of AML patients. Furthermore, Tregs could be used as clinical indicators to evaluate prognosis for AML patients.

Outcomes with chimeric antigen receptor t-cell therapy in relapsed or refractory acute myeloid leukemia: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML). We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer etal. Proportions with 95% confidence intervals (CI) were computed. We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I2=65%) and 65.2% (95% CI 0.36-0.91, I2=57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I2=77%), 3.9% (95% CI 0.00-0.19, I2=22%), and 1.6% (95%CI 0.00-0.21, I2=33%), respectively. CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.

Abstract ND14: Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers

Abstract Pharmacological profile and anti-tumor properties of FHD-286, a novel BAF inhibitor for the treatment of transcription factor-driven cancersMartin Hentemann, Rishi G. Vaswani, Lan Xu, Richard C. Centore, Luis M. M. Soares, Kana Ichikawa, Zhifang Li, Hong Fan, Jeremy Setser, David L. Lahr, Laura Zawadzke, Xueying Chen, Kimberly D. Barnash, Jordana Muwanguzi, Sarah Reilly, Neville Anthony, Gabriel J. Sandoval, Katharine Feldman, Ammar Adam, David Huang, Shawn Schiller, Kevin Wilson, Liyue Huang, Jessica Piel, Johannes Voigt, David S. Millan, Ho Man Chan, Ryan G. Kruger, Carl P. Decicco, Samuel Agresta, Steven F. BellonFoghorn Therapeutics, 500 Technology Square, Suite 700, Cambridge, MA 02139The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its ATP-dependent chromatin remodeling activity, BAF regulates the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. We have discovered and developed a compound that potently and selectively inhibits the ATPase components of the BAF complex, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). Mutational, structural, and biochemical studies demonstrated that this SMARCA4/SMARCA2 inhibitor acts through a unique allosteric mechanism. Pharmacologic inhibition of the BAF complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines from diverse origins. Phenotypic screening of cancer cell lines showed that uveal melanoma and hematological cancer cell lines were exquisitely sensitive to BAF inhibition. FHD-286 is orally bioavailable and demonstrates robust efficacy in multiple cell line and primary human tumor derived xenograft models at well-tolerated doses. In preclinical efficacy and toxicology studies, this first in class molecule demonstrates an acceptable therapeutic index which should allow for flexibility in clinical designs. FHD-286 is currently in two Phase I trials for both relapsed refractory AML and MDS, and metastatic uveal melanoma. Citation Format: Murphy Hentemann. Pharmacological profile and anti-tumor properties of FHD-286: A novel BAF inhibitor for the treatment of transcription factor-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND14.

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.

A Phase I Study of Pevonedistat, Azacitidine and Venetoclax for Patients with Relapsed/Refractory Acute Myelogenous Leukemia (AML)

Background:Outcomes of patients with relapsed/refractory AML (RR-AML) have remained poor. Therapy with venetoclax based combinations in this setting leads to CR/CRi rates of 21-49% (DiNardo CD et al. Am J Hematol 2018, Aldoss I et al. Haematologica 2018, Stahl M et al. Blood Adv 2020). Preclinical studies with BCL-2 inhibitors indicate potential mechanisms of drug resistance including overexpression of the anti-apoptotic protein MCL-1 (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that induces the pro-apoptotic protein NOXA leading to neutralization of MCL-1 and apoptosis. Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated a synergistic effect (Knorr KL et al. Cell Death Differ. 2015). Hence, we designed a phase I study to assess the safety and tolerability of adding pevonedistat to the combination of azacitidine and venetoclax in patients with RR-AML.Study design and methods:We conducted a phase I study with the combination of pevonedistat, venetoclax and azacitidine in patients with RR-AML. Patients aged 18 years or above with morphologically documented RR-AML, ECOG performance status 0-2 and adequate organ function were eligible. Major exclusion criteria were isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, and active acute GVHD. Previous therapy with hypomethylating agents (HMA) or venetoclax was not an exclusion criterion. The dose escalation phase was conducted using 3+3 design. Treatment included azacitidine (75 mg/m 2 daily x 7 days), venetoclax (400 mg daily x 28 days), and pevonedistat in escalating doses (10-20 mg/m 2 IV days 1,3,5 of each cycle) with a cycle length of 28 days. Pevonedistat was given at 10 mg/m 2 dose in cohort 1, 15 mg/m 2 dose in cohort 2 and 20 mg/m 2 dose in cohort 3.The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. Other endpoints included determination of response rates, duration of response, survival, pharmacokinetics, correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo.Results:Thirteen patients participated in the dose escalation phase, 12 of whom were evaluable. Median age was 69 years (61-91), 30.8% had secondary/therapy related AML, 69.2% with adverse risk disease, 53.8% previously received venetoclax/HMA and 23.1% had relapse after prior allogeneic hematopoietic cell transplantation (HCT) (Table 1). Seven patients were enrolled into cohort 1 (pevonedistat 10 mg/m 2 dose) of which one was not evaluable, three patients enrolled into cohort 2 (pevonedistat 15 mg/m 2 dose), and three patients enrolled into cohort 3 (pevonedistat 20 mg/m 2 dose). Grade 3 or higher AEs included febrile neutropenia (23%), infection (15%), anemia (38%), neutropenia (54%), thrombocytopenia (38%). There was 1 dose limiting toxicity (DLT) in cohort 1 (atrial fibrillation) that triggered cohort expansion. However, subsequent patients did not experience DLT despite planned dose escalation. Of the 12 evaluable total patients, CR/CRi was observed in 5 (41.6%) patients. Notably, patients with RR-AML who were venetoclax/HMA naïve had a CR/CRi 83.3% (5/6 patients). The response rates for each cohort are summarized in Table 2. Three of the five patients with CR/CRi (60%) achieved MRD negativity by flow cytometry. Four patients who achieved CR/CRi proceeded to allogeneic HCT after therapy. Median OS of the cohort was 5.4 months (1.8-14) and median OS was not reached in patients with CR/CRi.Conclusions:The addition of pevonedistat to venetoclax and azacitidine backbone is safe and well tolerated in patients with RR-AML. Dose escalation yielded encouraging efficacy in venetoclax/HMA naïve RR-AML patients. The study is currently in the dose expansion phase. Details on correlative studies examining mechanisms of therapeutic efficacy and resistance will be reported in the main meeting. [Display omitted] DisclosuresGuru Murthy: Cardinal health: Honoraria; TG Therapeutics: Other: Advisory board meeting; DAVA Oncology: Honoraria; CancerExpertNow: Honoraria; Qessential: Honoraria; Techspert: Consultancy; Curio Sciences: Honoraria; Guidepoint: Consultancy. Abedin: AltruBio: Research Funding; Helsinn: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Agios: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy.

Haploidentical Natural Killer Cell Therapy As an Adjunct to Stem Cell Transplantation for Refractory Acute Myeloid Leukemia

Refractory acute myeloid leukemia (AML), defined as failure of 2 cycles of induction therapy at diagnosis or of 1 cycle at relapse, represents a subgroup with poor clinical outcomes. In our transplant cohort, the 5-year overall survival in this subgroup was 16% (Ganapule at al. JGO 2017). Haploidentical natural killer cell (NK) therapy is a strategy that is being explored in refractory malignancies. Our in-vitro and animal model data suggest that exposure to arsenic trioxide (ATO) results in enhanced NK cytotoxicity (Alex AA et al. Front. Immunol 2018). Historically, at our center, patients with refractory AML have been treated with cytoreductive therapy (FLAG ± idarubicin or mitoxantrone + etoposide for 3 to 5 days) followed by 1-week rest and then a reduced-intensity transplant with fludarabine + melphalan conditioning while in peak cytopenia. From February 2019, we initiated a phase II single arm clinical trial (CTRI/2019/02/017505) enrolling patients with refractory AML planned for a stem cell transplant in peak cytopenia. Patients received CD56-positive cells from an HLA haploidentical related family donor (other than the stem cell donor, wherever feasible) following cytoreductive chemotherapy. The NK cell donor preference strategy included presence of KIR ligand mismatch, greater number of KIR B motifs (or the B score), lower donor age, and negative donor specific antibodies tested using flowcytometry crossmatch (Figure 1a). CD56-positive selection was done using CliniMACS prodigy system. This was followed by overnight incubation of the CD56 positive cells in autologous plasma with 2 micromolar ATO and 500 U/mL of interleukin-2. The CD56 positive cells were then infused to the patient 1-day after the completion of cytoreductive chemotherapy. This was followed by a reduced intensity stem cell transplant (Figure 1b). The primary outcome variable was 1-year relapse free survival. From February 2019, 14 patients with median age 28 years (IQR: 15.75-31.5) were enrolled in this trial. Six were females. Six had primary-refractory AML while 8 had relapsed-refractory AML. The cytoreductive chemotherapy was FLAG ± idarubicin (n=7), Mitoxantrone + Etoposide (n=6) and GCLAC (n=1). The median blast percentage on flowcytometry MRD testing prior to NK infusion was 15.9% (IQR: 9.1%-54.5%) (n=11). The median B score for the NK cell donors was 2 (IQR: 1-3). The median age of the NK cell donor was 43 years (IQR: 36-49.5). KIR ligand mismatch with the patient was noted in 2 donors. The median CD56-cell dose infused was 46.16 x 10 6/kg (IQR: 25.06-70.36) (Figure 1c). Pre-defined release criteria, including sterile cultures, and endotoxin negativity were met in all cases. There was no infusion related toxicity. The median blast percentage on flowcytometry MRD testing done following NK cell infusion was 11.9% (IQR: 4.9%-47.6%) (n=8). One patient withdrew consent after NK cell infusion and did not undergo transplant. For the remaining 13 patients, the stem cell donor was HLA matched (n=4), HLA 9/10 matched (n=1) or HLA haplomatched (n=8). The median CD34 cell dose infused was 10 x 10 6/kg (IQR:7.51-11.6). Five (38.5%) patients died of immediate post-transplant complications (sepsis (n=3) on days 1, 2 and 28, cerebral venous sinus thrombosis (n=1) on day 1 in a patient treated with hormonal contraceptives for menorrhagia, and veno-occlusive disease (n=1) on day 15 in a patient undergoing a second transplant) while 2 (15.4%) did not engraft (both subsequently died of infective complications following engraftment post-second transplant). Of the remaining 6 (46.2%) patients who engrafted and survived beyond 1 month of the transplant, the day 28 post-transplant MRD was negative for 5 patients while it was positive in 1 patient (0.13%). On follow up, 2 (15.4%) patients developed disease relapse (on days 54 and 218 respectively) and died. The remaining 4 (30.8%) patients are alive and relapse free at last follow up (mean follow up of surviving patients is 16 months). One patient received a CD34 cell boost on day 96 (cell dose - 8.55 x 10 6/kg) for poor graft function. For the entire cohort, the estimated 1-year event free survival is 28.8% ± 13.1%(Figure 1d). Whereas, acute GVHD was noted in 3 patients (50%; out of 6 evaluable patients) and chronic GVHD was noted in 3 patients (50%; out of the 6 evaluable patients). Thus, haploidentical NK cell therapy as an adjunct to transplant is safe and merits further evaluation in patients with AML. [Display omitted] DisclosuresMathews: Christian Medical College: Patents & Royalties: US 2020/0345770 A1 - Pub.Date Nov.5, 2020; AML: Other: Co-Inventor.

Lintuzumab-Ac225 in Combination with CLAG-M Yields High MRD (-) Responses in R/R AML with Adverse Features: Interim Results of a Phase I Study

Background:Lintuzumab-Ac225 (Actimab-A) is a humanized CD33 antibody, lintuzumab, conjugated to an alpha emitting isotope, actinium (Ac225), with potent single agent activity against AML. We hypothesized that a low dose infusion of lintuzumab-Ac225, after salvage chemotherapy, would effectively eliminate residual leukemia and improve remission rates, and depth of remission.Patients and Methods:Adult patients with relapsed/refractory AML (RR-AML), and with adequate organ function and performance status were eligible for screening. On screening, we assessed CD33 expression, greater than 25% of leukemic blasts must have expressed CD33 antigen by flow cytometry for inclusion. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab-Ac225 was administered as a single dose on either day 7, 8, or 9. This trial enrolled to 4 cohorts, administering lintuzumab-ac225 at a dose of 0.25uCi/kg, 0.50uCi/kg, 0.75uCi/kg, and 1.0uCi/kg. Treatment consisted of one induction cycle. Disease assessment, including MRD assessment by flow, was performed between Days 29-42.Results:Sixteen patients with a median age of 64 yrs were evaluable for toxicity and response. Three pts were treated in cohort 1 (0.25uCi/kg), nine pts were treated in cohort 2 (0.5uCi/kg), three pts were treated in cohort 3 (0.75uCi/kg), and one pt was treated in cohort 4 (1.0uCi/kg). Patient characteristics include 63% (n=10) pts with adverse cytogenetics, mutations involving TP53 in 44% (n=7) pts, and secondary/therapy-related AML in 50% (n=8) of patients. Patients received a median 2 lines of therapy, and 50% (n=8) received a venetoclax combination regimen prior to enrollment. Table 1 summarizes patient characteristics.No undue non-hematologic toxicities were observed in this trial. Commonest AEs were neutropenic fever and infection. Among responders, an ANC>1000 was achieved in 9/10 patients, at a median of 33 days, and a platelet count >50k was achieved in 6/10 patients at a median of 37 days. Of note, two patients proceeded to HCT prior to platelet recovery.Overall, among patients enrolled in cohorts 1-3, CR/CRi was observed in 67% (n=10) pts. One patient enrolled in cohort 4 achieved an aplastic marrow by D+42, with subsequent stem cell boost and neutrophil recovery. Of responders, 70% (7/10) had no measurable disease (MRD(-)) by flow cytometry. Among patients receiving <4 lines of prior therapy, 71% (n=5) pts with adverse cytogenetics, 80% (n=4) pts with TP53 mutation, and 80% (n=4) pts receiving a prior venetoclax combination achieved a remission. Estimated 6-month OS was 60%.Conclusions:Lintuzumab-Ac225 at a low dose appears to be safe in combination with the salvage chemotherapy regimen CLAG-M. Furthermore, this combination has demonstrated promising efficacy results among high risk RR-AML patients, namely patients with adverse molecular/cytogenetic features and patients previously receiving venetoclax. Updated Cohort 4 results will be presented at ASH.Upon determination of MTD, we plan to explore the combination of lintuzumab-Ac225 with other salvage regimens (e.g. FLAG, FLAG-Ida, MEC) to determine whether adding this novel agent can generally improve salvage outcomes in hard to treat patients. [Display omitted] DisclosuresAbedin: Helsinn: Research Funding; Agios: Honoraria; AltruBio: Research Funding; Pfizer: Research Funding; Amgen: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Guru Murthy: Guidepoint: Consultancy; Cancerexpertnow: Honoraria; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy. Atallah: Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Honoraria, Research Funding.

Early Clinical Evaluation of Potential Synergy of Targeted Radiotherapy with Lintuzumab-Ac225 and Venetoclax in Relapsed/Refractory AML

Early Clinical Evaluation of Potential Synergy of Targeted Radiotherapy with Lintuzumab-Ac225 and Venetoclax in Relapsed/Refractory AML

Sequential High-Dose Chemotherapy Reinduction Followed By Haploidentical Transplantation in Acute Leukemias

Introduction: Outcomes after T-cell replete haploidentical stem cell transplantation (Haplo HSCT) with post- transplant Cyclophosphamide have been encouraging. As previously published (Schmid C. et al, JCO 2005; Ringdén O. et al, Br J Haematol. 2017), the sequential use of intensive chemotherapy and allogeneic transplantation represents a possible approach for the treatment of high-risk / relapsed-refractory Acute Myeloid Leukemia (AML).Patients and Methods: At our Center, 22 high-risk patients were transplanted during chemo-induced neutropenia after high-dose salvage chemotherapy. Median age at transplant was 49 years (range 21-62); 6/22 (27%) had received a previous allograft. All patients but 2, who presented with blast crisis of chronic myeloid leukemia, suffered from refractory (no. 12) or secondary AML (no. 8). All patients had active disease at the time of Sequential Therapy and median marrow blast count before reinduction was 25% (range 6-88%). All patients received high-dose Cytarabine (≥1g/sqm) containing regimens as reinduction therapy. Conditioning, myeloablative, in 14/22 (64%) and non-myeloablative in 8/22 (36%), was started at a median of 9 days (range 4-15) after the last day of chemotherapy. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cyclophosphamide with calcineurine inhibitors and mycophenolic acid. Bone marrow was used as stem cell source in 18/22 (82%) patients.Results: One/22 patient (4%) experienced primary graft failure and was successfully rescued with a second haploidentical transplant from the same donor. Median day of neutrophil recovery was day +18 (range 14-24). Median follow-up of survivors was 4.1 years (range 5-69 months); 1-year Overall and Event-Free Survivals were 34.5% and 30.3%, while 1-year Relapse Incidence and Non Relapse Mortality were 41.9% and 28%, respectively. Overall cumulative incidences of acute and chronic GVHD were 41% and 33.6% at day +100 and + 400. Among patients who developed GVHD, 3 grade III-IV acute GVHD and 2 moderate-severe chronic GVHD were observed. At 4.1 years post Haplo-HSCT, 5/22 (23%) patients are alive and disease free.Conclusions: To our knowledge, we report the first experience of a sequential approach including Haplo HSCT. Though small the patient cohort, which also includes second transplants, our findings suggest that transplant-related toxicity was acceptable and early relapse was the major treatment-failure. However, long-term survival and disease-free rates in these very poor prognosis patients are rather encouraging. Only the prompt availability of a haploidentical donor allowed to implement this treatment modality. DisclosuresBoccadoro:Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Vitolo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Takeda: Honoraria; Mundipharma: Honoraria.

Efficacy of Adding Bortezomib to Salvage Chemotherapy in Relapsed/refractory Acute Myeloid Leukemia a Prospective Non-Interventional Study.

Relapsed/refractory acute myeloid leukemia (RR-AML) are important types of hematological malignancy for which no effective salvage chemotherapy has been approved. The main purpose of this study was to determine the effectiveness of adding Bortezomib to salvage chemotherapy protocol in RR-AML patients. In this prospective non-interventional study, 40 consecutive patients with RR-AML attending Taleghani Hospital who underwent salvage therapy, were enrolled and subdivided into salvage chemotherapy plus Bortezomib and salvage chemotherapy without Bortezomib and the therapeutic response, adverse effects, and survival among them were determined. The results in this study demonstrated that complete response was present in 30% and 25% in Bortezomib group and the other group, respectively and the partial response was seen in 35% and 50% and no response was present in 35% and 25%, respectively (P = 0.621). Furthermore, in each group, 15% had a side effect (P = 1.000). Mean survival was 8.2 and 7.1 in Bortezomib and the other group, respectively (P = 0.275). Based on the obtained results, it may be concluded that adding Bortezomib to salvage chemotherapy is feasible in RR-AML patients. For evaluation of efficacy further study is recommended.

A Phase I Study of Lintuzumab Ac225 in Combination with CLAG-M Chemotherapy in Relapsed/Refractory AML

Background: Lintuzumab Ac225 is a radiolabeled anti-CD33 antibody, composed of an alpha emitting isotope, Ac225, conjugated with the humanized anti-CD33 monoclonal antibody lintuzumab. As monotherapy, lintuzumab Ac225 was studied as upfront therapy for unfit AML, and nearly 70% of pts achieved a CR/CRi at the highest dose level (2uCi/kg) without significant non-hematologic toxicity. Therefore, we hypothesized that lintuzumab Ac225, when added to the salvage chemotherapy regimen CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone), would be tolerable and would improve remission rates in the treatment of relapsed/refractory AML (RR-AML). This investigator-initiated phase I study is the first study to combine radioimmunotherapy with salvage chemotherapy in pts with RR-AML. Patients and Methods: Medically fit pts with RR-AML, aged 18 years and older were eligible. Eligibility also required that more than 25% of leukemic blasts must have been CD33 positive by flow cytometry. Induction consisted of G-CSF, 300mcg/d, given D1-6, cladribine 5mg/m2, given D2-6, cytarabine 2g/m2, given D2-6, and mitoxantrone 10mg/m2, given D2-4. Lintuzumab Ac225 was administered as a single dose on either day 7, 8, or 9. This trial had three cohorts, administering lintuzumab Ac225 at a dose of 0.25uCi/kg, 0.50uCi/kg, or 0.75uCi/kg. Treatment consisted of one induction cycle, with subsequent therapy up to physician discretion. Results: Fifteen pts were evaluable, with a median age of 61 yrs (Figure 1). Slightly less than half of the pts had previously received venetoclax/HMA and slightly more than half had previously had allogeneic HCT. Three pts enrolled into cohort 1 (0.25uCi/kg), nine pts enrolled into cohort 2 (0.5uCi/kg), and three pts enrolled into cohort 3 (0.75uCi/kg). Grade 3 or greater AEs irrespective of causality included febrile neutropenia (n=12), infection (n=8), maculopapular rash (n=2), nausea (n=2), and one patient each with QTc prolongation and tumor lysis syndrome. Of 15 pts, CR/CRi was observed in 10 (67%) pts. Excluding pts receiving &amp;gt;3 prior lines of therapy, 10/12 (83%) achieved CR/CRi. In cohort 1, 1 patient (33%) achieved remission (1 CR). In cohort 2, 6 pts (67%) achieved remission (3 CR, 2 CRp, 1 CRi). In cohort 3, 3 pts (100%) achieved remission (1 CR, 2 CRp). 7 pts of the 10 with CR/CRi (70%) achieved MRD negativity by flow (Table 2). Two of the 3 patients in cohort 3 were MRD- after therapy and the third had a small number of AML cells detected (0.2%). All pts who were independent for platelet transfusions pre-treatment recovered platelets. Overall, median time to ANC recovery ≥500 was 33 days, and median time to platelet recovery ≥50k was 35 days. 6 pts proceeded to allogeneic HCT after therapy. Conclusion: We conclude that lintuzumab Ac225 in combination with CLAG-M chemotherapy has a clinically acceptable safety profile. Dose escalation yielded highly encouraging efficacy results for RR-AML. With acceptable safety at 0.75uCi/kg, we have amended this protocol to study a 4th dose level at 1.0uCi/kg. Overall, this regimen represents a safe and potentially effective therapy for medically fit RR-AML pts, particularly as a bridge to allogeneic HCT. Disclosures Abedin: Helsinn Healthcare: Honoraria; Actinium Pharmaceuticals: Research Funding; Helsinn Healthcare: Research Funding; Pfizer: Research Funding; Jazz Pharmaceuticals: Honoraria; Agios: Honoraria. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen R&amp;D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy; Sanofi Genzyme, AstraZeneca: Speakers Bureau. Michaelis:Jazz Pharmaceuticals: Research Funding. Atallah:Abbvie: Consultancy; Genentech: Consultancy; Jazz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy, Research Funding; Novartis Pharmaceutical Corporation: Consultancy.

IDH2 Inhibitor Therapy in Relapsed and Refractory Acute Myeloid Leukemia: A Single Institution Experience

Introduction: Mutations in the gene isocitrate dehydrogenase 2 (IDH2) occur in ~12-15% of patients with acute myeloid leukemia (AML). Enasidenib, an oral small molecule selective targeted inhibitor of IDH2 enzymes, was approved forIDH2mutated relapsed/refractory AML (RR-AML) in 2017 (Stein et. al., 2017). There is limited data regarding its efficacy and toxicity outside the context of clinical trials. Using Mayo Clinic's cohort of AML patients, we provide a real-world look at outcomes forIDH2mutated RR-AML patients treated with enasidenib. Methods: A total of 13 patients treated with enasidenib for RR-AML were identified, all of which experienced at least one relapse following induction chemotherapy. Response assessment was based on European Leukemia Net (ELN) 2017 response criteria.Complete blood counts including blast percentage and transfusion dependency were obtained at AML diagnosis, initiation of enasidenib, 2 months and 6 months following initiation of therapy. Transfusion dependency was defined by the need for either a red cell or platelet transfusion within 4 weeks of the designated time frame. We compared the clinical characteristics of patients who achieved complete response (CR) (n=4) to those not achieving CR (n=9), using the Mann-Whitney U test for numerical variables and the Fischer's Exact test for quantitative data. Results: The median age at diagnosis of our 13 patients was 68 years (range 60-82), with a male predilection (n=11) (Table 1). Cytogenetic and molecular genetic findings are provided in Table 2. Complete response (CR) was achieved in 4 (30.7%) patients by cycle 2 and 2 of those patients (50%) proceeded to an allogeneic hematopoietic stem cell transplant (AHSCT). The median time from diagnosis to initiation of treatment for patients in CR was 3.5 months (range 1-7), and for patients not achieving CR was 13 months (range 6-53; p=0.048), with median time of follow up after treatment initiation of 23.5 months (range, 5-36) and 7 months (range, 1-14), respectively. Among 8 patients who were transfusion dependent at baseline, all the CR patients (2/2) achieved red blood cell and platelet transfusion independence 6 months after treatment, instead only (3/6) 50% of those not in CR achieved transfusion independence (p=0.028). An initial trajectory of improvement in counts is noted from the time of diagnosis to the 2 month mark post treatment with 75% of the responder cohort showing improvement in counts which was durable through the 6 month mark, whereas 55% of those that did not respond had worsening counts at month 2 and died prior to 6 month follow up. At the time of data cut-off, the median duration of CR was 14 months (range, 2-33), with 3 of 4 (75%) of responders maintaining CR. Figure 1 details overall responses and outcomes in all 13 patients. None of the patients in our study experienced differentiation syndrome. Five patients were hospitalized in the course of treatment for infectious complications. Two patients were noted to have hyperbilirubinemia however there was no clear indication that this was secondary to enasidenib Median overall survival for all 13 patients was 21 months (range, 6-53 months) with leukemia free survival of 7 months (range, 5-19 months). Furthermore, median overall survival for patients in CR was 27 months (range, 6-42), and those not in CR was 16 months (range, 6-53) (p=0.20). In addition, we observed that 75% of patients who attained CR are alive compared to 11.1% of those not in CR (p = 0.052). Conclusion: We demonstrate a superior CR rate of 30.7% with enasidenib amongstIDH2mutated RR-AML patients compared with clinical trial data showing CR rate of 19.6% (Stein et. al., 2019) despite our patients being heavily pre-treated with median number of two prior therapies (range; 1-5) including prior AHSCT in 2 patients. Moreover, a subset of patients (2 of 4 in CR) were able to undergo ASCHT. Finally, the achievement of CR at 2 months after initiation of therapy serves as an appropriate time point for response assessment. Disclosures No relevant conflicts of interest to declare.

Lintuzumab-225Ac in Combination with Venetoclax in Relapsed/Refractory AML: Early Results of a Phase I/II Study

Background: Overexpression of anti-apoptotic proteins such as MCL-1 has been implicated in resistance to the BCL2 inhibitor venetoclax in relapsed/refractory AML (R/R-AML). Therapeutic agents that reduce resistance to venetoclax as well as exhibiting intrinsic anti-tumor activity may synergize with venetoclax to increase response rates in this difficult to treat patient population. One approach to enhance the potency of venetoclax is through combination with targeted radiotherapy. Studies have shown that radiation-induced DNA damage reduces the level of MCL1 in tumor cells. The monoclonal antibody radioconjugate lintuzumab-225Ac is a highly cytotoxic alpha-radiation emitter that selectively targets CD33, a cell surface antigen expressed on the majority of AML cells but not on non-hematopoietic tissues. Prior clinical studies with lintuzumab-225Ac have demonstrated potent single agent anti-leukemic activity (ASH 2017, 2018). The short range, high-energy alpha-particle emissions from lintuzumab-225Ac elicit single and double-strand DNA breaks in targeted tumor cells. In venetoclax-resistant cell lines in vitro, lintuzumab-225Ac promotes MCL1 degradation resulting in increased cell sensitivity to venetoclax. In vivo mouse xenograft models with venetoclax-resistant AML tumor lines demonstrated enhanced tumor regression and increased survival in mice receiving both venetoclax and lintuzumab-225Ac. This study is the first study to combine radioimmunotherapy with venetoclax in patients with R/R-AML. Study Design: The Phase I portion of the study will use a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of lintuzumab-225Ac when given in combination with venetoclax. The planned dose levels for lintuzumab-225Ac are 0.5, 1.0, and 1.5 µCi/kg. As an exploratory endpoint, BH3 profiling will be performed on patient marrow samples to assess for MCL1 activity. Eligible patients include R/R-AML patients aged 18 years and older with adequate organ function, ECOG Performance Status 0-2, and more than 25% of leukemic blasts CD33 positive by flow cytometry. Patients with antecedent MDS, MPNs, or therapy-related AML are eligible. Other than the cycle 1 dose ramp up to reduce the risk of tumor lysis syndrome, patients receive venetoclax at 400 mg/day PO on Days 1 to 21 of each cycle with dose modification for the use of CYP3A inhibitors. The Lintuzumab-225Ac is administered as a single dose on Day 1 of each cycle (see Study Schema). Results: Three R/R AML patients with a median age of 54 years (range 49-75) have been enrolled to date (see Table 1). The enrolled patients had a median of 2 therapies (2-3) and a median bone marrow blast percentage of 30% (range 20 - &amp;gt;60). All 3 patients had poor risk with adverse cytogenetics, and each patient has an additional high-risk marker (FLT3-ITD+, antecedent JAK2+ myelofibrosis, or TP53 mutation). There have been no lintuzumab-225Ac related dose limiting toxicities (DLT) or non-hematologic Grade 3 or greater related AEs. Patient 1 obtained a partial response with a decrease in BM leukemic blasts from &amp;gt;60% to 30-40% after cycle 1. Efficacy in the other 2 patients at this dose level is too early to evaluate. Conclusion: Combining lintuzumab Ac225 with venetoclax in patients with R/R-AML has an acceptable initial clinical safety profile at the level of 0.5 µCi/kg of lintuzumab-225Ac. Results in the first lintuzumab-225Ac dose cohort are encouraging, and the trial will continue to enroll to evaluate the hypothesis that there will be clinical synergy consistent with pre-clinical studies. Disclosures Hegazi: Tempus: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy. Harpel:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Miao:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ludwig:Actinium Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Berger:Actinium Pharmaceuticals Inc.: Current Employment, Current equity holder in publicly-traded company. Schiller:Abbvie: Research Funding; Kaiser Permanente: Consultancy; Geron: Research Funding; Johnson &amp; Johnson: Current equity holder in publicly-traded company; Kite Pharma: Research Funding; Karyopharm: Research Funding; DeltaFly: Research Funding; Gamida: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Jazz Pharmaceuticals: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Mateon: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Ariad: Research Funding; Stemline: Speakers Bureau; Actinium: Research Funding; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau; Astellas Pharma: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Deciphera: Research Funding; Genentech-Roche: Research Funding. OffLabel Disclosure: Venetoclax use in relapsed-refractory AML.

Biomarker-Driven Phase Ib Clinical Trial of OPB-111077 in Acute Myeloid Leukemia Increases Overall Response Rates

Background: Phase I clinical trial for oncology drugs have the highest clinical failure rate. Drug candidates may be discarded if they don´t show activity. Yet these drugs may have valuable activity in patient subgroups. Biomarkers attempt to identify these sensitive subpopulations, but are normally evaluated and validated in Phase II when good drugs may have been discarded. OPB-111077 is a novel, oral, low-molecular-weight compound that inhibits STAT3 and mitochondrial electron transport. A prior Phase I trial on 145 patients from all tumor types gave only 1 partial response (PR). A strong anti-proliferative activity was identified in Acute Myeloid Leukemia (AML) samples ex vivo. This new biomarker was used for patient selection in this trial. We present a novel design of a Phase Ib trial directly selecting patients with a potential biomarker, that can benefit the patient without increasing toxicity risks, in Relapsed/Refractory (RR) AML patients. Method: This is an open-label, phase Ib dose-escalation clinical trial to evaluate the safety profile, maximum tolerated dose (MTD) and preliminary efficacy of oral OPB-111077 in AML relapsed or refractory to chemotherapy patients. Patients &amp;gt; 18 years old with high risk AML, ECOG ≤2 and adequate organ functions were selected for biomarker screening. Biomarker consisted on a dose response curve for antiproliferative activity of agent in a bone marrow sample of patients incubated 72-96-120h (Figure), quantified as the Area Under the Curve (AUC). Patient samples whose ex vivo biomarker showed low sensitivity (70% worst) we excluded, since they were potentially predicted as resistant to the agent. The remaining 30% with higher sensitivity were included. OPB-111077 was administered orally on a once daily dose schedule in 28-day cycles until intolerable toxicity or disease progression. Two dose schemas were evaluated: 200 (DL1) and 250 mg/day (DL2). Dose limiting toxicities were any Grade ≥ 3 non-hematologic toxicity and any unexpected non-tolerable grade II that requires delay beyond 1 week until recovery and evaluated during the first 28 days of treatment. Adverse events were graded according to NCI-CTCAE vs 4.03 and response criteria was based on those given by Cheson et al. IC50 and area under the curve (AUC) determined by the Vivia ex vivo biomarker were correlated with clinical response. Results: We screened 47 RR AML patients, twelve patients were included and selected by personalized medicine test (5 in DL1 and 7 in DL2), median age 76 years, 92% men, 42% ECOG 0 were included in the study. AML patients were refractory in 41.7% and patients were in median of relapses 2 (range 1-6). No DLT was reported. Adverse events related to study treatment were reported in three patients, all G 1-2: in DL1 one patient had vomiting; in DL2 one patient had extrasystoles and other had anorexia, diarrhoea, epigastric discomfort, nausea and vomiting. Two patients died during study treatment due to disease progression and respiratory infection. Half of the patients discontinued study treatment due to disease progression and 25% due to adverse events (respiratory failure G5, respiratory infection G5 and extrasystoles G2). Over the 6 patients evaluable for efficacy, 3 of them achieved PR and 3 treatment failure as best response. Progression free survival and overall survival were 57 days (95% CI: 37 - 77) and 95 days (95% CI: 27 - 163) respectively. The biomarker AUC and IC50 values stratified patients consistent with their clinical response, although without enough sampling potency for statistical significance. Figure shows the relative position of patients included in the study in the context of the overall population of samples considered to build up the mixed effect population pharmacodynamic model used to analyze samples results and define inclusion criteria. In green those that correspond to patients who showed a positive response; in orange those who failed. Conclusions: OPB-111077 is generally well tolerated and has a manageable toxicity profile. The MTD was not reached. The 50% PR rate achieved by OPB-111077, albeit in a few patients, is substantially higher that the 0.7% (1/145) PR rate achieved in a prior phase I trial on all tumor types1. This innovative Phase Ib design selecting patients using a biomarker may enable to rescue drug failures in the future.

AML-058: First-In-Human Study of a Trail Receptor Agonist Fusion Protein, Eftozanermin Alfa, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Diffuse Large B-Cell Lymphoma

Aims Evaluate pharmacokinetic (PK) profile of Eftozanermin alfa (ABBV-621; eftoza) as monotherapy (eftoza-mono) or eftoza and venetoclax (eftoza-VEN); assess safety and tolerability, preliminary antitumor activity, and exploratory biomarkers. Methods In this phase 1 study, adults with relapsed/refractory (RR) acute myeloid leukemia (AML) or diffuse large B-cell lymphoma (DLBCL) received intravenous eftoza, 1.25, 3.75, or 7.5 mg/kg in AML eftoza-mono and 3.75 or 7.5 mg/kg in AML and DLBCL eftoza-VEN cohorts days 1, 8, and 15 of a 21-day cycle. VEN dose was 400 mg or 800 mg daily (oral). Results As of September 2019, 34 patients enrolled: 4 in AML eftoza-mono(median age 75 yrs; 1.25 [n=1], 3.75 [n=1], or 7.5 [n=2] mg/kg eftoza), 19 in AML eftoza-VEN(median age 72 yrs; 3.75 [n=10] or 7.5 [n=9] mg/kg eftoza), and 11 in DLBCL eftoza-VEN cohorts (median age 64 yrs; 3.75 [n=3] or 7.5 [n=8] mg/kg eftoza). Patients received eftoza for median 1 (AML eftoza-mono), 3 (AML eftoza-VEN), and 2 (DLBCL eftoza-VEN) cycles. Four patients in AML eftoza-VEN cohorts completed ≥5 cycles. Percentage of patients with treatment-emergent adverse events (TEAEs) was 100% for AML eftoza-mono/VEN, and 91% for DLBCL eftoza-VEN. Grade ≥3 TEAEs were in all AML eftoza-mono/VEN patients and 27% in DLBCL eftoza-VEN. Most common grade ≥3 TEAEs were increased alanine (n=4, AML eftoza-VEN) and aspartate (n=4, AML eftoza-VEN; n=1, DLBCL eftoza-VEN) aminotransferase. Serious eftoza-related AEs were in 5 patients (AML eftoza-VEN); none in >1 patient. Eftoza exhibited dose-proportional kinetics at weekly 1.25- to 7.5-mg/kg doses; PK was not affected by VEN. No responses were seen in AML eftoza-mono or DLBCL eftoza-VEN cohorts. Overall response rate in AML eftoza-VEN cohorts was 4/19 (21%), with 3 complete responses (CR; 3.75 mg/kg [n=2], 7.5 mg/kg [n=1]), and 1 CR with incomplete hematologic recovery (7.5 mg/kg); 4 had RD (3.75 mg/kg [n=2], 7.5 mg/kg [n=2]) and 3 PD (3.75 mg/kg [n=3]). Eftoza binding to death receptors on neutrophils was saturated by 2h post-dose in AML and DLBCL cohorts. There was time-dependent desaturation of the receptors for eftoza binding. In 63% of patients with RR AML ≥3, molecular aberrations were observed, with IDH1/2 and RAS being the most frequently mutated genes. Conclusions Eftoza-mono and eftoza-VEN were tolerated in patients with RR AML and DLBCL. Antitumor activity was observed in patients with AML treated with eftoza-VEN at 3.75- or 7.5-mg/kg doses. Abstract was previously published at EHA25.