2020 ASH: Anti-tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models

View Poster:
Anti-tumor Activity of ASTX029, a Dual Mechanism Inhibitor of ERK1/2, in Preclinical AML Models

Abstract:

Oncogenic mutations in genes such as the RAS family (KRAS, NRAS or HRAS) or receptor tyrosine kinases (RTKs) drive tumor growth through aberrant activation of the mitogen activated protein kinase (MAPK) signaling pathway. Acute myeloid leukemia (AML) patients frequently exhibit activating mutations in MAPK pathway members, such as NRAS and KRAS, suggesting that these malignancies may be driven by aberrant activation of the MAPK pathway. Targeting of the MAPK pathway has been clinically validated in solid tumors, with agents targeting BRAF and MEK approved for the treatment of BRAF-mutant melanoma. However, there is currently no approved therapy directly targeting activated RAS family members and resistance to MAPK pathway inhibitors is frequently associated with reactivation of MAPK signaling. ERK1/2 (ERK) is a downstream node in the MAPK pathway and therefore represents an attractive therapeutic target for inhibition of MAPK signaling in these settings.

We have recently described in vivo anti-tumor activity in MAPK-activated solid tumor models following treatment with ASTX029, a highly potent ERK inhibitor developed using fragment-based drug design. ASTX029 has a distinctive ERK binding mode which confers dual mechanism inhibition of ERK, inhibiting both the catalytic activity of ERK and its phosphorylation by MEK. Here, we demonstrate that ASTX029 is also active in AML models and potently inhibits in vitro and in vivo MAPK signaling and growth in these models.

Using a panel of 15 AML cell lines, we investigated sensitivity to ASTX029 in vitro. We observed that 8 cell lines bearing mutations leading to increased MAPK pathway signaling were sensitive to treatment with ASTX029 with an average IC50 value of 47 nM, in contrast to an average IC50 value of 1800 nM for cell lines without activating mutations. The phosphorylation of RSK, a direct substrate of ERK, was suppressed for up to 24 h following treatment with ASTX029 in vitro. We have previously demonstrated good oral bioavailability for ASTX029 and once daily dosing resulted in significant tumor growth inhibition in AML cell line xenograft models. To confirm target engagement in vivo, we examined MAPK signaling in xenograft tissue and observed inhibition of the phosphorylation of RSK and of ERK itself, consistent with the dual mechanism of action proposed for ASTX029.

In summary, the ERK inhibitor, ASTX029, has potent activity against MAPK-activated tumor models, including AML models, and is now being tested in a Phase 1/2 clinical trial in advanced solid tumors (NCT03520075). These data highlight its therapeutic potential for the treatment of AML in patients with mutations leading to MAPK pathway activation and support further investigation in these patient populations.

ASH 2020: Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

View Video Poster: Comparative Results of Azacitidine and Decitabine from a Large Prospective Phase 3 Study in Treatment Naive Patients with Acute Myeloid Leukemia Not Eligible for Intensive Chemotherapy

Abstract:

Background:
Background: Prognosis of elderly (≥65 years of age) patients (pts) with acute myeloid leukemia (AML) remains dismal with a substantial proportion being deemed unfit for intensive chemotherapy. Monotherapy with the hypomethylating agents azacitidine (AZA) or decitabine (DEC) has been the de facto standard of  care for the treatment of chemotherapy-ineligible AML pts although both AZA and DEC did not improve median OS compared to low-dose cytarabine (LDAC) or physician choice, respectively, in phase III trials. No clinical trials comparing AZA and DEC head-to-head in AML exist. Here, we present a subgroup analysis of pts enrolled in the phase III ASTRAL-1 trial (NCT02348489) who were randomized to the AZA or DEC control arm.

Methods:
ASTRAL-1 randomized 815 treatment-naïve AML pts ineligible for intensive chemotherapy in a 1:1 ratio to either guadecitabine or treatment-choice (TC) of AZA, DEC, LDAC (NCT02348489). Study protocol and results have been presented previously (Fenaux, EHA 2019). Briefly, adult (≥18 years of age) pts with newly-diagnosed AML ineligible for intensive chemotherapy based on age of 75 years or older, major organ comorbidities, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-3 were eligible for enrollment. Exclusion criteria included prior treatment with AZA or DEC, extramedullary central nervous system AML, inability to tolerate treatment in the TC arm, or refractory congestive heart failure, uncontrolled active infection, or advanced pulmonary disease. Pts were pre-selected to receive either AZA, DEC, or LDAC with subsequent 1:1 randomization to either guadecitabine or TC in the respective arm. Patients treated with standard doses and schedules of AZA or DEC within the TC arm were included in the subgroup analysis presented here. Co-primary outcomes were rates of complete response (CR) and median, 1-year, and 2-year overall survival (OS) as defined by the International Working Group response criteria for AML. Composite CR (CRc) was defined as the composite of CR, CR with incomplete platelet count recovery (CRp), and CR with incomplete cell count recovery (CRi).

Rates of CR among pts treated with AZA and DEC were compared using Fisher’s exact test. Survival outcomes were compared using log-rank tests to compare the hazard ratio for death among the AZA and DEC treated pts. Subgroup analyses for OS stratified by patient and disease characteristics were performed.

Results:

815 patients were enrolled in the ASTRAL-1 trial across 144 sites in 24 countries with 171 and 167 pts being randomized to and treated with AZA and DEC in the TC arm of the trial, respectively. Baseline patient and disease characteristics were well-balanced between the AZA and DEC-treated pts (Table 1). The median number of treatment cycles was 6 (range [R]: 1-31) in the AZA arm and 5 (R: 1-34) in the DEC arm. There was no statistically significant difference in the co-primary endpoint of CR with 30 pts (17.5%) in the AZA and 32 pts (19.2%) in the DEC arm achieving CR (p=0.78). The rate of CRc (CR + CRp + CRi) was comparable among AZA and DEC-treated patients with 22.2% (38 out of 171 pts) and 25.1% (42 out of 167 pts), respectively (Table 2). Median OS between AZA and DEC-treated pts was similar with 8.7 months and 8.2 months in the two arms, respectively (hazard ratio [HR] for death: 0.97; 95% CI: 0.77-1.23; p=0.81). One-year and 2-year OS was comparable in both groups with 39% and 15% in the AZA arm and 32% and 14% in the DEC arm, respectively. Median OS estimates in clinically or genetically-defined patient subgroups were similar between AZA and DEC-treated pts. Serious adverse events leading to death occurred more frequently in the AZA arm compared with DEC (AZA: 38% vs 26% with DEC; p=0.02).

Conclusion:

Outcomes in treatment-naïve AML pts ineligible for intensive chemotherapy treated with AZA or DEC in the randomized phase III ASTRAL-1 trial are comparable with CR rates of 17.5% and 19.2% and median OS of 8.7 months and 8.2 months, respectively. No patient, disease, or molecular characteristics predicted a higher likelihood of response to either AZA or DEC. Safety in this frail patient population was comparable to prior trails of HMAs in AML and no major safety differences between AZA and DEC were detected although fatal serious adverse events tended to be higher in the AZA-treated cohort.

ASH 2020: Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

View Poster:
Clinical Efficacy and Safety of Oral Decitabine/Cedazuridine in 133 Patients with Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML)

Abstract:

Introduction:
Hypomethylating agents (HMAs) or DNA methyltransferase inhibitors (DNMTi) such as decitabine or azacitidine are established standard of care for the treatment of MDS and CMML. The oral bioavailability of these agents has been limited due to rapid degradation by cytidine deaminase (CDA) in the gut and liver, hence requiring intravenous infusion or subcutaneous injections daily for 5-7 days every month (m). This parenteral administration requirement adds significant burden to older cancer patients due to daily time commitment and travel to treatment centers. It also increases exposure to and infection risk with SARS-CoV-2 during the COVID-19 pandemic. Oral decitabine 35 mg/cedazuridine 100 mg (ASTX727) is an oral fixed dose combination drug of decitabine and the CDA inhibitor cedazuridine that have shown 99% (90% CI 93% to 106%) equivalent exposure to standard dose IV decitabine 20 mg/m2 in a randomized cross-over study (Garcia-Manero et al, ASH 2019). Here, we present the clinical efficacy and safety results of oral decitabine/cedazuridine from 133 patient study in MDS and CMML (ASTX727-02 ASCERTAIN study).

 Methods:
We used a randomized cross over design where patients were randomized in the first 2 cycles 1:1 to either Sequence A: decitabine 35 mg/ cedazuridine 100 mg in Cycle 1 followed by IV decitabine at 20 mg/m2 in Cycle 2, or Sequence B: IV decitabine in Cycle 1 followed by oral decitabine/cedazuridine in Cycle 2 to do an intra-patient comparison of decitabine PK (primary PK endpoint: decitabine AUC equivalence over 5 days of dosing). Cycles were repeated every 28 days. All patients received oral decitabine/cedazuridine in all subsequent cycles from Cycle 3 onwards until disease progression or unacceptable toxicity. Patients were eligible as per the FDA-approved label of IV decitabine (MDS patients by FAB classification including CMML, or MDS IPSS Intermediate-1, 2 or high-risk patients). Clinical endpoints were best response as assessed by an independent expert panel according to International Working Group (IWG) 2006 response criteria, transfusion independence for at least 8 or 16 consecutive weeks, overall survival, and safety. Adverse events (AEs) were graded by Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Results:

138 subjects were randomized, of whom 133 were treated on study. The median age was 71.0 years (range 44-88), 65% were male, 88% MDS and 12% CMML, 43% were either red blood cells (RBCs) or platelets transfusion-dependent at baseline, 25% had poor-risk cytogenetics, and 42% had baseline bone marrow blasts >5%. At the data cutoff for the response analysis, the median duration of follow up was 12.6 m (range 9.3 to 20.5 m) with median number of treatment cycles of 8 (range 1 to 18). Of the 133 treated patients the best response was complete response (CR) in 28 patients (21%; 95% CI 15-29%), marrow (m)CR with hematological improvement (HI) in 20 patients (15%), mCR without HI in 23 patients (17.3%), and HI in 10 patients (7.5%) for an overall objective response (CR+mCR+HI) in 81 patients (61%; 95% CI 52-69%). Median duration of CR was 7.5 m (range 1.6 to 17.5 m), and median time to CR was 4.3 m (range 2.1 to 15.2 m). Of the 133 treated patients 27 (20%) went on to receive allogeneic hematopoietic cell transplant. Of the 57 patients who were either RBCs or platelets transfusion-dependent at baseline, 30 (53%) became transfusion independent for both RBCs and platelets for at least 8 consecutive weeks, and 19 (33%) were both RBCs and platelets transfusion independent for at least 16 consecutive weeks. Median survival has not been reached. Most common Treatment-Emergent AEs of Grade ≥3 regardless of causality were neutropenia in 51.5%, thrombocytopenia in 50%, anemia in 40%, febrile neutropenia in 26%, leukopenia in 21%, pneumonia in 12%, and sepsis in 7% of patients treated with oral decitabine/cedazuridine (excluding the IV decitabine cycle).

Summary/Conclusions: Efficacy and safety from oral decitabine 35 mg/ cedazuridine 100 mg daily for 5 days every 28 days are consistent with clinical data from standard IV decitabine 20 mg/m2 daily for 5 days. Oral decitabine/cedazuridine is the only oral HMA with systemic exposure equivalent to its injectable drug. Further investigation of oral decitabine/cedazuridine in all-oral combination studies is warranted and underway.

 

The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

View Poster:

The non-peptidomimetic cIAP1/2 and XIAP antagonist tolinapant promotes an anti-tumour immune response in T-cell lymphoma

Summary

Tolinapant (ASTX660) is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP) [1], which is currently being tested in a first in human phase I-II clinical trial in patients with advanced solid tumours and lymphomas (NCT02503423) [2]. IAP antagonists have been reported to exhibit broad immuno-modulatory effects on both the innate and adaptive immune systems. We have investigated the profile of tolinapant in preclinical T cell lymphoma models and evaluated tolinapant’s ability to enhance immune mediated killing of T cell lymphoma cells, both in vitro and in vivo.

References:

  1. G Ward et al., 2018, Mol Cancer Therapeutics Jul;17(7):1381-1391
  2. A Hollebecque et al., 2019, AACR-NCI-EORTC International Conference on Molecular
    Targets and Cancer Therapeutics

Combined inhibition of SHP2 and ERK enhances anti-tumor effects in preclinical models

View Poster:

Combined inhibition of SHP2 and ERK enhances anti-tumor effects in preclinical models

Summary

MAPK signalling is frequently dysregulated in cancer. The pathway can Panel composition and the number of responding cell lines Examples of dose-response curves Anti-tumor activity of SHP2i, ASTX029 and combination in MIA PaCa-2 xenograft be targeted by inhibition of different nodes and is tightly regulated by feedback mechanisms. Resistance to single-agent therapies frequently occurs through several different mechanisms including upregulation of receptor tyrosine kinases (RTKs), therefore, combination therapies are of interest.

The Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a key regulator of MAPK pathway downstream of RTKs and upstream of RAS, whilst ERK acts at the bottom of the pathway phosphorylating multiple substrates.

We investigated the potential of targeting the MAPK pathway through a combination of SHP2 and ERK inhibition in preclinical models. Using a SHP2 inhibitor (SHP2i) discovered by our structure-based drug discovery programme and ASTX029, an ERK inhibitor in a Phase I-II clinical trial (NCT03520075), we tested panels of cell lines representing various indications and genetic backgrounds in vitro and confirmed enhanced tumor growth inhibition by the combination in a xenograft model.

The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 Inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models

View Poster:

The clinical candidate, ASTX029, is a novel, dual mechanism ERK1/2 Inhibitor and has potent activity in MAPK-activated cancer cell lines and in vivo tumor models

Summary

  • The MAPK signaling pathway is commonly upregulated in human cancers due to oncogenic mutations of upstream
    components such as BRAF or KRAS.
  • MAPK pathway inhibition has been clinically validated by BRAF and MEK inhibitors.
  • As the final node in the MAPK pathway, ERK is an attractive therapeutic target for the treatment of MAPK-activated cancers, including those resistant to upstream inhibition.
  • Previously we described the fragment-based discovery of a chemical series targeting ERK[1]. Here we disclose for the first time the structure of the clinical candidate, ASTX029.

References:

  1. Heightman et al., (2018). J Med Chem 61; 4978

2020 AACR: ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, promotes an anti-tumor immune response in pre-clinical models of T-cell lymphoma

View Poster:

ASTX660, a non-peptidomimetic antagonist of cIAP1/2 and XIAP, promotes an anti-tumor immune response in pre-clinical models of T-cell lymphoma

Summary

  • ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumors and lymphomas (NCT02503423) where preliminary activity has been described in a group of T-cell lymphomas (1)
  • Herein, together with its well-characterized pro-apoptotic effect (2), we describe a new role for ASTX660 as an immunomodulatory molecule capable of promoting an anti-tumor immune response in pre-clinical models of T-cell lymphoma. These data add to the description of ASTX660’s mode of action and our ongoing understanding of the preliminary clinical efficacy that has been reported.

References:
1. Samaniego F, et al., Hematological Oncology. 2019;37(S2):527.
2.Ward GA et al., Mol Can Ther. 2018;17(7):1381-91

2020 EHA: Characterization of ASTX660, an antagonist of cIAP1/2 and XIAP, in mouse models of T cell lymphoma

View Poster:

Characterization of ASTX660, an antagonist of cIAP1/2 and XIAP, in mouse models of T cell lymphoma

Abstract:

Background:  ASTX660 is a potent, non-peptidomimetic antagonist of the cellular and X-linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP), which is currently being tested in a first in human phase I-II study in patients with advanced solid tumor and lymphomas (NCT02503423). IAP antagonists have been reported to exhibit broad immuno-modulatory effects on both the innate and adaptive immune systems .

Aims:  We have investigated the profile of ASTX660 in preclinical T cell lymphoma models and evaluated ASTX660’s ability to enhance immune mediated killing of T cell lymphoma cells, both in vitro and in vivo.

Methods:  ASTX660 was tested in a panel of human and mouse tumor cell lines, assessing apoptosis, necroptosis and immunogenic cell death (ICD). ASTX660 was tested in vitro alone or with recombinant death receptor ligands (TNFa, FASL or TRAIL) and with or without caspase-8/RIPK inhibitors to demonstrate mechanism of action. Target engagement along with induction of apoptosis, necroptosis and ICD markers were analysed by Western blotting, and flow cytometry. Murine tumor models in immunocompetent and immunocompromised mice were utilised to evaluate the efficacy of ASTX660 in the presence or absence of an effective immune response. The Nanostring IO360 panel was used to assess immune cell recruitment.

Results:  ASTX660 antagonised IAPs in cell lines, as indicated by a decrease in cIAP1 protein levels and disruption of the XIAP:SMAC protein complex. In murine T cell lymphoma cell lines (BW5147, EL4 and L5178Y), ASTX660 treatment was associated with an increase in apoptosis or necroptosis and ICD biomarkers. In immunocompetent mice, administration of ASTX660 delivered a complete regression of BW5147 tumor growth, which was not seen in mice deficient in T and B cells. These mice remained refractory to subsequent rechallenge after initial complete regression. Biomarker evaluation from this model indicated a potent immunogenic/necroptotic response after ASTX660 dosing and upregulation of immune effector cells.

References:
1. Michie J. et al., The Immuno-Modulatory Effects of Inhibitor of Apoptosis Proteins Antagonists, Cells, 2020, 9(1), 207.
2. A. Hollebecque et al., AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, 2019.

 

2020 EHA: ASTX295, a novel small molecule MDM2 antagonist, demonstrates potent activity in AML in combination with decitabine

View Poster:
ASTX295, a novel small molecule MDM2 antagonist, demonstrates potent activity in AML in combination with decitabine

Abstract:

Background: The tumour suppressor p53 is activated in response to various stress signals to induce transcriptional changes leading to cellular responses such as cell cycle arrest and apoptosis. Activity of p53 is tightly regulated by the E3 ubiquitin ligase MDM2, which inhibits p53 function by, for example, targeting it for proteasomal degradation. Targeting the MDM2-p53 interaction to restore p53 function, is therefore, a promising strategy for cancer therapy and a number of these compounds are in clinical development including ASTX295 (NCT03975387). ASTX295 is a novel, orally bioavailable MDM2 antagonist developed through structure-based drug design that has demonstrated potent activity in a range of p53 wild-type pre-clinical models.

Aims: We investigated the therapeutic potential of ASTX295 alone and in combination with decitabine, a DNA- hypomethylating agent, in AML.

Methods: Primary blasts were isolated from AML patient samples using a combination of antibodies against CD34, CD33, CD45 and CD117. A panel of AML cell lines and primary AML blasts were treated with decitabine and ASTX295 at a range of concentrations, alone and in combination. After treatment, viability was assessed by Alamar blue assay or induction of apoptosis by flow cytometry using a fluorescent caspase substrate or Annexin V.

Effects of drug combinations were analysed using the Combenefit software based on different mathematical models (Loewe, bliss & HSA). Target engagement was confirmed by western blotting.

Results: When tested in a panel of p53 wild-type AML cell lines, ASTX295 exerted a strong anti-proliferative effect in which GI50 <30 nM was observed in 9 out of 11 cell lines. Additionally, p53 activation by ASTX295 triggered apoptosis in both AML cell lines, and primary AML blasts isolated from patients.

Activity of ASTX295 was further enhanced by combining with decitabine. Treatment of AML cell lines with ASTX295 and decitabine showed an increase in growth inhibitory effect and apoptosis compared to respective single agent treatments. This combinatory effect, as assessed by Combenefit, was also observed in primary AML blasts in which 7 of 12 samples tested demonstrated increased apoptosis at or above 300 nM ASTX295 and 100 nM decitabine. Target engagement of ASTX295 and decitabine was confirmed by upregulation of p53 transcriptional targets and decreased DNMT-1 expression.

Summary/Conclusion: Our findings demonstrate that the combination of ASTX295 with decitabine exhibits potent activity against p53 wild-type AML cells, and thus merits further investigation.

2020 EHA: Comparative results of azacitidine and decitabine from a large prospective Phase 3 study in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy

View Presentation:

Comparative results of azacitidine and decitabine from a large prospective Phase 3 study in treatment naïve acute myeloid leukemia (TN-AML) not eligible for intensive chemotherapy

 

Abstract:

Background: Older patients with TN-AML who are ineligible for intensive chemotherapy have limited therapeutic options and poor outcomes. Hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) have been the standard of care in this population for more than a decade and were approved in Europe for patients not candidates for intensive chemotherapy or patients not candidates for hematopoietic cell transplant. However, there is no direct efficacy and safety comparative data of AZA and DEC from a prospective large randomzied study. We took advantage of the largest randomized trial for patients with TN-AML who were not eligible for intensive chemotherapy, ASTRAL-1, to compare efficacy and safety of AZA vs DEC in patients randomized to these 2 treatments

Aims: To compare clinical outcomes between AZA and DEC in TN-AML patients not eligible for intensive chemotherapy

Methods: ASTRAL-1 is a global randomized Phase 3 trial which enrolled 815 patients with TN AML who were not eligible for intensive chemotherapy using stringent criteria including age ≥ 75 year or comorbidities including ECOG PS 3. Patients were randomized 1:1 to either Guadecitabine (G), a next generation HMA (60 mg/m2/d SC days 1-5) or a preselected Treatment Choice (TC) of AZA (75 mg/m2/d IV or SC days 1-7), DEC (20 mg/m2/d IV days 1-5), or low dose Ara-C (LDAC) (20 mg SC BID days 1-10). AML diagnosis and responses were assessed by an independent central pathologist blinded to randomization assignment. Responses were recorded using IWG 2003 criteria. Rates of Complete Response (CR) and Overall Survival (OS) were co-primary endpoints.

Results: 815 patients were randomized to G (408) or TC (407). Preselected TCs were DEC (43%), AZA (42%), or LDAC (15%). Of 407 patients randomized to TC, 338 (83%) were treated with either AZA (171 patients) or DEC (167 patients). Baseline variables were well balanced between AZA and DEC patients with no statistically significant differences in baseline characteristics: median age 76 y for both treatments, with poor PS 2-3 in 47.4% vs 53.9%, poor risk cytogenetics 38% vs 33.5%, secondary AML 38% vs 36.5%, BM blasts > 30% in 63.7% vs 71.3%, and TP53 mutations in 12.9% vs 11.3% for AZA vs DEC respectively. Median follow up was 25.5 months and median number of treatment cycles was 6 for AZA (range 1,31), and 5 for DEC (range 1,34). The ITT analyses showed a CR rate of 17.5% vs 19.2% (p= 0.70); and overall CR (CR+CRp+CRi) of 22.2% vs 25.1% (p= 0.53) for AZA vs DEC respectively. Median OS was 8.7 vs 8.2 months for AZA vs DEC respectively with Hazard Ratio of 0.97 (95% CI 0.77, 1.23; log rank p= 0.8). Additional subgroup analyses by baseline characteristics and molecular genetic mutations will be presented at the meeting. There was no statistically significant difference in the incidence of Grade ≥ 3 AEs (88.9% vs 87.4%), serious AEs (81.9% vs 76.0%), or 30-day all-cause mortality (11.7% vs 7.8%) for AZA vs DEC respectively. There was a trend of higher 60-day all-cause mortality on AZA (20.5%) vs DEC (13.2%) (p= 0.07).

Conclusions/Summary: This is the largest comparison of clinical outcomes associated with AZA and DEC for patients with TN AML not eligible for intensive chemotherapy who were treated in the same prospective study. While patients were randomized between G and each of AZA and DEC separately with no direct randomization of AZA vs DEC, the patients’ characteristics were well balanced in patients randomized to the two HMA treatments. There were no significant differences in CR, overall CR, OS, or safety between AZA and DEC.