Antibody Therapies for the Treatment of Acute Myeloid Leukemia: Exploring Current and Emerging Therapeutic Targets

INTRODUCTION: Acute myeloid leukemia (AML) is the most common and deadly type of leukemia affecting adults. It is typically managed with rounds of non-targeted chemotherapy followed by hematopoietic stem cell transplants, but this is only possible in patients who can tolerate these harsh treatments and many are elderly and frail. With the identification of novel tumor-specific cell surface receptors, there is great conviction that targeted antibody therapies will soon become available for these patients. AREAS COVERED: In this review, we describe the current landscape of known target receptors for monospecific and bispecific antibody-based therapeutics for AML. Here, we characterize each of the receptors and targeted antibody-based therapeutics in development, illustrating the rational design behind each therapeutic compound. We then discuss the bispecific antibodies in development and how they improve immune surveillance of AML. For each therapeutic, we also summarize the available pre-clinical and clinical data, including data from discontinued trials. EXPERT OPINION: One antibody-based therapeutic has already been approved for AML treatment, the CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin. Many more are currently in pre-clinical and clinical studies. These antibody-based therapeutics can perform tumor-specific, elaborate cytotoxic functions and there is growing confidence they will soon lead to personalized, safe AML treatment options that induce durable remissions

Effective Menin inhibitor-based combinations against AML with MLL rearrangement or NPM1 mutation (NPM1c)

Treatment with Menin inhibitor (MI) disrupts the interaction between Menin and MLL1 or MLL1-fusion protein (FP), inhibits HOXA9/MEIS1, induces differentiation and loss of survival of AML harboring MLL1 re-arrangement (r) and FP, or expressing mutant (mt)-NPM1. Following MI treatment, although clinical responses are common, the majority of patients with AML with MLL1-r or mt-NPM1 succumb to their disease. Pre-clinical studies presented here demonstrate that genetic knockout or degradation of Menin or treatment with the MI SNDX-50469 reduces MLL1/MLL1-FP targets, associated with MI-induced differentiation and loss of viability. MI treatment also attenuates BCL2 and CDK6 levels. Co-treatment with SNDX-50469 and BCL2 inhibitor (venetoclax), or CDK6 inhibitor (abemaciclib) induces synergistic lethality in cell lines and patient-derived AML cells harboring MLL1-r or mtNPM1. Combined therapy with SNDX-5613 and venetoclax exerts superior in vivo efficacy in a cell line or PD AML cell xenografts harboring MLL1-r or mt-NPM1. Synergy with the MI-based combinations is preserved against MLL1-r AML cells expressing FLT3 mutation, also CRISPR-edited to introduce mtTP53. These findings highlight the promise of clinically testing these MI-based combinations against AML harboring MLL1-r or mtNPM1

Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations

partially_open16Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1-28) and azacitidine (75 mg/m2; days 1-7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.partially_openembargoed_20230131Pollyea, Daniel A; DiNardo, Courtney D; Arellano, Martha L; Pigneux, Arnaud; Fiedler, Walter; Konopleva, Marina; Rizzieri, David A; Smith, B Douglas; Shinagawa, Atsushi; Lemoli, Roberto M; Dail, Monique; Duan, Yinghui; Chyla, Brenda; Potluri, Jalaja; Miller, Catherine L; Kantarjian, Hagop MPollyea, Daniel A; Dinardo, Courtney D; Arellano, Martha L; Pigneux, Arnaud; Fiedler, Walter; Konopleva, Marina; Rizzieri, David A; Smith, B Douglas; Shinagawa, Atsushi; Lemoli, Roberto M; Dail, Monique; Duan, Yinghui; Chyla, Brenda; Potluri, Jalaja; Miller, Catherine L; Kantarjian, Hagop

Bone marrow pathologic abnormalities in familial platelet disorder with propensity for myeloid malignancy and germline RUNX1 mutation

A subset of patients with familial platelet disorder with propensity to myeloid malignancy and germline RUNX1 mutation develops hematological malignancies, often myelodysplastic syndrome/acute myeloid leukemia, currently recognized in the 2016 WHO classification. Patients who develop hematologic malignancies are typically young, respond poorly to conventional therapy, and need allogeneic stem cell transplant from non-familial donors. Understanding the spectrum of bone marrow morphologic and genetic findings in these patients is critical to ensure diagnostic accuracy and develop criteria to recognize the onset of hematologic malignancies, particularly myelodysplastic syndrome. However, bone marrow features remain poorly characterized. To address this knowledge gap, we analyzed the clinicopathologic and genetic findings of 11 patients from 7 pedigrees. Of these, 6 patients did not develop hematologic malignancies over a 22-month follow-up period; 5 patients developed hematologic malignancies (3 acute myeloid leukemia; 2 myelodysplastic syndrome). All patients had thrombocytopenia at initial presentation. All 6 patients who did not develop hematologic malignancies showed baseline bone marrow abnormalities: low-for-age cellularity (n=4), dysmegakaryopoiesis (n=5), megakaryocytic hypoplasia/hyperplasia (n=5), and eosinophilia (n=4). Two patients had multiple immunophenotypic alterations in CD34-positive myeloblasts; 1 patient had clonal hematopoiesis. In contrast, patients who developed hematologic malignancies had additional cytopenia(s) (n=4), abnormal platelet granulation (n=5), bone marrow hypercellularity (n=4), dysplasia in ≥2 lineages including megakaryocytes (n=3) and acquired clonal genetic aberrations (n=5). In conclusion, our study demonstrated that specific bone marrow abnormalities and acquired genetic alterations may be harbingers of progression to hematological malignancies in patients with familial platelet disorder with germline RUNX1 mutation

Targeting of epigenetic co-dependencies enhances anti-AML efficacy of Menin inhibitor in AML with MLL1-r or mutant NPM1

Monotherapy with Menin inhibitor (MI), e.g., SNDX-5613, induces clinical remissions in patients with relapsed/refractory AML harboring MLL1-r or mtNPM1, but most patients either fail to respond or eventually relapse. Utilizing single-cell RNA-Seq, ChiP-Seq, ATAC-Seq, RNA-Seq, RPPA, and mass cytometry (CyTOF) analyses, present pre-clinical studies elucidate gene-expression correlates of MI efficacy in AML cells harboring MLL1-r or mtNPM1. Notably, MI-mediated genome-wide, concordant, log2 fold-perturbations in ATAC-Seq and RNA-Seq peaks were observed at the loci of MLL-FP target genes, with upregulation of mRNAs associated with AML differentiation. MI treatment also reduced the number of AML cells expressing the stem/progenitor cell signature. A protein domain-focused CRISPR-Cas9 screen in MLL1-r AML cells identified targetable co-dependencies with MI treatment, including BRD4, EP300, MOZ and KDM1A. Consistent with this, in vitro co-treatment with MI and BET, MOZ, LSD1 or CBP/p300 inhibitor induced synergistic loss of viability of AML cells with MLL1-r or mtNPM1. Co-treatment with MI and BET or CBP/p300 inhibitor also exerted significantly superior in vivo efficacy in xenograft models of AML with MLL1-r. These findings highlight novel, MI-based combinations that could prevent escape of AML stem/progenitor cells following MI monotherapy, which is responsible for therapy-refractory AML relapse

Hematopoiesis under telomere attrition at the single-cell resolution

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells’ self-renewal capabilities and eventually leads to their exhaustion. Mechanistically, we demonstrate that targeting members of the Ifi20x/IFI16 family of cytosolic DNA sensors using the oligodeoxynucleotide A151, which comprises four repeats of the TTAGGG motif of the telomeric DNA, overcomes interferon signaling activation in telomere-dysfunctional hematopoietic stem cells and these cells’ skewed differentiation towards the megakaryocytic lineage. This study challenges the historical hypothesis that telomere attrition limits the proliferative potential of hematopoietic stem cells by inducing apoptosis, autophagy, or senescence, and suggests that targeting IFI16 signaling axis might prevent hematopoietic stem cell functional decline in conditions affecting telomere maintenance

Bacillus Calmette-Guérin vaccination as defense against SARS-CoV-2 (BADAS):a randomized controlled trial to protect healthcare workers in the USA by enhanced trained immune responses

Background: A large epidemic, such as that observed with SARS-CoV-2, seriously challenges available hospital capacity, and this would be augmented by infection of healthcare workers (HCW). Bacillus Calmette-Guérin (BCG) is a vaccine against tuberculosis, with protective non-specific effects against other respiratory tract infections in vitro and in vivo. Preliminary analyses suggest that regions of the world with existing BCG vaccination programs have lower incidence and mortality from COVID-19. We hypothesize that BCG vaccination can reduce SARS-CoV-2 infection and disease severity. Methods: This will be a placebo-controlled adaptive multi-center randomized controlled trial. A total of 1800 individuals considered to be at high risk, including those with comorbidities (hypertension, diabetes, obesity, reactive airway disease, smokers), racial and ethnic minorities, elderly, teachers, police, restaurant wait-staff, delivery personnel, health care workers who are defined as personnel working in a healthcare setting, at a hospital, medical center or clinic (veterinary, dental, ophthalmology), and first responders (paramedics, firefighters, or law enforcement), will be randomly assigned to two treatment groups. The treatment groups will receive intradermal administration of BCG vaccine or placebo (saline) with groups at a 1:1 ratio. Individuals will be tracked for evidence of SARS-CoV-2 infection and severity as well as obtaining whole blood to track immunological markers, and a sub-study will include cognitive function and brain imaging. The majority of individuals will be followed for 6 months, with an option to extend for another 6 months, and the cognitive sub-study duration is 2 years. We will plot Kaplan-Meier curves that will be plotted comparing groups and hazard ratios and p-values reported using Cox proportional hazard models. Discussion: It is expected this trial will allow evaluation of the effects of BCG vaccination at a population level in high-risk healthcare individuals through a mitigated clinical course of SARS-CoV-2 infection and inform policy making during the ongoing epidemic. Trial registration: ClinicalTrials.gov NCT04348370. Registered on April 16, 2020.</p

AXL/MERTK inhibitor ONO-7475 potently synergizes with venetoclax and overcomes venetoclax resistance to kill <i>FLT3</i>-ITD acute myeloid leukemia

FMS-like Tyrosine Kinase 3 (FLT3) mutation is associated with poor survival in acute myeloid leukemia (AML). The specific Anexelekto/MER Tyrosine Kinase (AXL) inhibitor, ONO-7475, kills FLT3-mutant AML cells with targets including Extracellular- signal Regulated Kinase (ERK) and Myeloid Cell Leukemia 1 (MCL1). ERK and MCL1 are known resistance factors for Venetoclax (ABT-199), a popular drug for AML therapy, prompting the investigation of the efficacy of ONO-7475 in combination with ABT-199 in vitro and in vivo. ONO-7475 synergizes with ABT-199 to potently kill FLT3-mutant acute myeloid leukemia cell lines and primary cells. ONO-7475 is effective against ABT-199-resistant cells including cells that overexpress MCL1. Proteomic analyses revealed that ABT-199-resistant cells expressed elevated levels of pro-growth and anti-apoptotic proteins compared to parental cells, and that ONO-7475 reduced the expression of these proteins in both the parental and ABT-199-resistant cells. ONO-7475 treatment significantly extended survival as a single in vivo agent using acute myeloid leukemia cell lines and PDX models. Compared to ONO-7474 monotherapy, the combination of ONO-7475/ABT-199 was even more potent in reducing leukemic burden and prolonging the survival of mice in both model systems. These results suggest that the ONO-7475/ABT-199 combination may be effective for AML therapy