Modified International Working Group Research Articles

Abstract CT060: Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS)

Abstract Background:Evorpacept (EVO) is a high affinity CD47-blocking fusion protein with an inactive human immunoglobulin Fc region designed to enhance the activity of other anti-neoplastic therapies with minimal additional toxicity. Here, we present final phase 1 results from the ASPEN-02 study. Methods:ASPEN-02 is an open-label, multicenter phase 1/2 study designed to evaluate the safety and activity of EVO in combination with azacitidine (AZA) in subjects with newly diagnosed (ND) higher-risk (HR) or relapsed/refractory (R/R) MDS. Adult subjects with ND HR (IPSS-R > 3.5) or R/R MDS were enrolled into phase 1 cohorts receiving escalating doses of EVO (20 mg/kg Q2W, 30 mg/kg Q2W, and 60 mg/kg Q4W) combined with AZA (75 mg/m2 IV/SC x 7d) in a 28-day treatment cycle. A phase 1 dose expansion portion enrolled adults with ND HR MDS into two dosing cohorts determined to be safe at EVO 40 mg/kg Q4W and 60 mg/kg Q4W. This clinical trial is registered at clinicaltrials.gov: NCT04417517. Results: As of June 2, 2023, 65 subjects were treated in the phase 1 portion, including 13 subjects with R/R MDS [EVO doses of 20 mg/kg Q2W (n=1) or 60 mg/kg Q4W (n=12)], and 52 subjects with ND HR MDS [EVO doses of 40 mg/kg Q4W (n=23) and 60 mg/kg Q4W (n=29)]. Of 52 ND HRMDS subjects, 9 (17.3%) had therapy-related MDS. Multi-hit TP53 mutations were present at baseline in 2/13 (15.4%) R/R MDS and 3/52 (5.8%) ND HR MDS patients. 13/13 (100%) R/R MDS patients had received prior hypomethylating agents or cytotoxic chemotherapy. Median age was 70 (range 24 - 88) years, and baseline ECOG scores were 0 (n=27, 41.5%), 1 (n=31, 47.7%), or 2 (n=7, 10.8%). No dose-limiting toxicity was observed, and a maximum tolerated dose (MTD) was not reached. Treatment-emergent AEs and treatment-related AEs for EVO were reported in 65/65 (100%) and 35/65 (53.8%) subjects respectively; discontinuation, however, was infrequent. Seven (10.8%) subjects experienced a serious adverse event related to EVO. There were no EVO-related deaths on study. Preliminary PK indicated dose-proportional pharmacokinetics consistent with prior studies. Objective response [complete remission (CR), partial remission (PR), marrow CR (mCR), hematologic improvement (HI)], per modified International Working Group 2006 criteria, was observed in 19/52 (36.5%) ND HR [CR=8, mCR=9, HI=2] and 2/13 (15.4%) R/R [mCR=2] MDS subjects. Conclusion:The myeloid checkpoint inhibitor EVO was well tolerated in combination with AZA with an initial safety and activity profile comparable to that of historical AZA monotherapy. Additional updated data will be provided at the time of presentation. Citation Format: Guillermo Garcia-Manero, Bart L. Scott, Ashwin Kishtagari, Srinivasa R. Sanikommu, Aref Al-Kali, Je-Hwan Lee, Juan M. Bergua Burgues, Maria Diez-Campelo, Harry P. Erba, Carmen Garcia-Hernandez, Guillermo Sanz Santillana, Casey O'Connell, Jun-Ho Jang, Dong-Yeop Shin, Hamid Sayar, Mayank Rao, Richard S. Schwartz, Grace An, Feng Jin, Alison J. Forgie, Athanasios C. Tsiatis, Jessica K. Altman. Phase 1 study of azacitidine in combination with evorpacept for higher-risk myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT060.

Oral Decitabine/Cedazuridine Vs Intravenous Decitabine for Acute Myeloid Leukemia: Final Results of a Randomized, Crossover, Registration-Enabling, Pharmacokinetics Study

Background: Parenterally administered hypomethylating agents (HMAs), decitabine (DEC) and azacitidine (AZA), are approved in Europe for adult patients with acute myeloid leukemia (AML) who are not candidates for standard induction chemotherapy as single agent or in combination with venetoclax. Cedazuridine(C) is a novel, potent, and safe inhibitor of cytidine deaminase (CDA) and when given in combination with decitabine, cedazuridine enables efficient oral availability of decitabine.ASTX727 (DEC-C) is a fixed-dose combination (FDC) tablet of 35 mg DEC and 100 mg cedazuridine, DEC-C has been approved for MDS in the US, Canada, and Australia. Here we present final results using DEC-C in an AML population appropriate for single-agent decitabine treatment. Aims: Describe the final clinical outcomes of patients with AML with additional analysis of genetic profiles. Methods: The ASCERTAIN study used a randomized two-period, two-sequence, two-treatment, crossover study design. Patients were randomized 1:1 to either Sequence A: DEC-C (35 mg DEC/100 mg cedazuridine) in Cycle 1 followed by IV-DEC at 20 mg/m 2 in Cycle 2, or Sequence B: receiving IV-DEC in Cycle 1 followed by DEC-C on Cycle 2 to compare pharmacokinetics (PK) [primary endpoint Area Under the Curve (AUC) equivalence over 5 days of dosing]. All patients received DEC-C from Cycle 3 until treatment discontinuation to assess safety and clinical efficacy. Patients were eligible as per the EMA-approved decitabine label (newly diagnosed AML who are not candidates for standard induction chemotherapy). Clinical responses were assessed according to modified International Working Group (IWG) 2003 response criteria. Pre-treatment peripheral blood was used for DNA isolation from leukocytes, and molecular abnormalities identified using a NGS hematologic malignancy panel. Cox-regression analysis on the various factors (eg binary mutational status, CR, etc.) was used for analyses of risk-factors for overall survival (OS). Results: 89 patients were randomized, of whom 87 were treated. The median age of patients was 78.0 years (range, 61 to 92) with 31 (35.6%) males and 56 (64.4%) females. Cytogenetic risk classification was poor-risk in 33 (37.9%), intermediate-risk in 45 (51.7%), and 9 (10.4%) not evaluated patients. For the primary endpoint, preliminary PK data was available from 69 patients who successfully completed PK assessments for both IV-DEC and DEC-C cycles, and the DEC AUC 0-24 (h*ng/mL) 5-Day geometric mean estimate was 904 for DEC-C and 907 for IV-DEC resulting in an oral/IV geometric LSM AUC ratio of 99.64% (90% CI of 91.23-108.8%). Safety findings were consistent with those anticipated for IV-DEC (related Grade ≥ 3 AEs in more than 10% were thrombocytopenia, neutropenia, anaemia, and febrile neutropenia). As of the database lock (25May2023), median follow up was 24.5 (20.2, 25.0) months (25% of 19.7 and 75% of 25.2 months). The best response was complete response (CR) in 19/87 (21.8%, 95% CI: 13.7, 32.0%); CR with incomplete blood cell count recovery (CRi) in 5 patients (5.7%); and CR with incomplete platelet recovery (CRp) in 2 (2.3%); resulting in composite response rate [CR + CRi] of 27.6%. The median overall survival was approximately 8.9 months (95% CI: 6.0, 13.1).These results obtained with DEC-C are consistent with those observed for IV-DEC. Multiple genes, including ASXL1, TP53, RUNX1, and SRSF2 genes were present in more than 20% of the AML patients. TP53 mutation was associated with worse survival. Summary/Conclusion: This randomized phase 3 study in AML patients not candidates for standard induction chemotherapy demonstrates that Daily X 5 dosing of the oral FDC of DEC-C resulted in an equivalent DEC AUC exposure to IV-DEC at 20 mg/m 2 over 5 days. Pharmacodynamic data showed similar demethylation rates (≤1.1% difference). In addition, safety findings and observed clinical activity (response rates and OS) are consistent with published data from IV-DEC, suggesting that DEC-C has the potential to be an oral alternative to the standard IV-DEC Daily×5 regimen. These findings support the use of DEC-C in patients with AML who are not candidates for standard induction chemotherapy.

A Phase 2 Study of Canakinumab in Patients with Lower-Risk Myelodysplastic Syndromes or Chronic Myelomonocytic Leukemia

Background Myelodysplastic syndromes (MDS) lie on a continuum of myeloid neoplastic progression between clonal hematopoiesis (CH) and acute myeloid leukemia (AML). Interleukin 1 beta (IL-1β)-induced inflammasome activation is a mechanism of cancer initiation and progression. Given that IL-1β upregulation induces aberrant myeloid differentiation of hematopoietic stem and progenitor cells (HSPCs), we hypothesize that IL-1β plays a critical role in MDS pathogenesis, and targeting IL-1β signaling will overcome aberrant MDS HSPCs' myeloid skewing. Here, we report final results of a phase 2 study evaluating the safety and efficacy of canakinumab, an IL-1β inhibitor, in patients with lower-risk MDS or chronic myelomonocytic leukemia (CMML). Methods We conducted a single center, open-label phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged ≥ 18 with IPSS-R ≤ 3.5 MDS/CMML who have previously been treated were included in the study. Patients received 300 mg of canakinumab on day 1 of a 4-week cycle. The primary objective was to determine the clinical activity of canakinumab in MDS/CMML patients. Response was assessed using the modified International Working Group 2006 criteria for MDS (Cheson et al. 2006). Secondary objectives were to evaluate the safety profile including rate of transfusion independence (TI), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). All patients who received 1 dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov (NCT04239157). Findings Between August 2020 and May 2023, 27 patients were enrolled in the phase 2 portion of this study, and 2 patients failed screening. The median age was 74 years with 15 (60%) male patients; 20 patients (80%) were post-hypomethylating agent failure with a median number of prior lines of therapy of 2 (1-5). Transfusion dependency was observed in 24 patients (96%) prior to canakinumab initiation. Fourteen (56%) patients showed normal karyotype. IPSS-R stratification revealed an intermediate-2 risk in 12 (48%) patients and a high risk in one (4%). The most common mutations were SF3B1 (40%), TET2 (32%), DNMT3A (28%), and RUNX1 (24%). IPSS -M risk score was calculated for 24 cases showing one (4%) very low (VL), four (16%) low (L), 14 (16%) moderate low (ML), eight (32%) moderate high (MH), five (20%) high (H), and two (8%) very high (VH) risk categories. Canakinumab was well tolerated and no drug-related toxicities were observed. One death due to sepsis, which was deemed not treatment-related, occurred on the study drug. Out of 23 evaluable patients, the overall response rate was 17·4%, with erythroid and platelet hematological improvement (HI-E and HI-P, respectively) confirmed in 3 (13.0%) patients and 1 (4.3%) patient, respectively. Thirteen patients had stable disease (56·5%) and 6 (26·1%) progressed during therapy, 1 of which transformed to AML (Fig. 1). TI was achieved in 3 patients (median DoR 8·53 months (95% CI 0·41-16·1) and 2 of them maintained TI for over 12 months. With a median follow-up time of 22·6 months (95% CI 15·0-29·4), median OS was 17·3 months (95% CI 14·3-not estimable). We performed separate univariate analyses to evaluate any associations between the IPSS-M and OS/PFS. The median OS in patients with higher-risk MDS by IPSS-M (MH, H, VH) was 15·0 months vs 29·4 months in the lower-risk disease by IPSS-M (VL, L, ML) group (p=0·12). Interestingly, statistically significant findings were observed with 1-year PFS when stratifying patients into higher vs lower risk MDS by IPSS-M (64·3% vs 100·0%, respectively; p=0·022, Fig. 2). Conclusion In this cohort of MDS patients who had experienced multiple lines of prior therapy and exhibited high-molecular-complexity, canakinumab showed limited efficacy (HI 17.3%). Nevertheless, canakinumab showed a good safety profile and yielded sustained long-term responses in patients with single somatic driver mutation in TET2 or DNMT3A. This suggests that clonal complexity, and therefore disease burden, may be a determining factor in response to canakinumab. Therefore, we have amended the protocol of a phase 1/2 clinical trial evaluating the safety and activity of canakinumab in clonal cytopenia of unknown significance (CCUS) and low-molecular complexity MDS patients. Our results will clarify the role of IL-1β signaling in MDS initiation and progression.

Phase Ib, open-label study of add on therapy with CK0804 in participants with myelofibrosis, with suboptimal response to ruxolitinib.

TPS7087 Background: Drugs targeting JAK2 inhibition including ruxolitinib have led to significant improvement in quality of life and survival of myelofibrosis (MF) patients, however almost 30% have suboptimal response and disease remains incurable. Novel therapies are urgently needed. In addition to mutation-driven stem cell-derived clonal myeloproliferation, recent data support role of reactive cytokine- and chemokine-driven inflammatory fibrosis that contribute to MF pathogenesis, specifically, abnormal CXCR4/CXCL12 axis can drive disease progression and extramedullary hematopoeisis. Targeting bone marrow inflammation is emerging as potential therapeutic strategy for MF. Adoptive therapy with allogeneic, cord blood (CB) derived Regulatory T cells (Tregs) have shown to be safe in bone marrow failure patients. CXCR4 enriched CB Tregs (CK0804) show faster egress across transwell membrane in response to SDF1α and preferential homing to bone marrow, in vivo. We hypothesize that multiple infusions of CK0804 may decrease inflammation and improve clinical outcomes in MF. Methods: Single arm study consisting of safety run-in of 9 participants followed by expansion cohort of additional 15 participants using 3+3+3 study design. MF patients receiving ruxolitinib therapy > 3 months prior to enrollment with stable dose for at least 8 weeks prior to Day 1, unlikely to benefit from further ruxolitinib monotherapy in opinion of investigator would be eligible. Each participant will receive single infusion of CK0804 at fixed dose of 100 million Treg cells administered every 28 days. Participants will continue their ruxolitinib therapy. Participants with no treatment limiting toxicity (TLT) after 28 days or those with toxicity with clear alternative explanation (e.g. disease progression) or transient (≤72 hrs) abnormal laboratory values without associated clinically significant signs or symptoms based on investigator determination will receive up to six 28-day treatment cycles AND 6 months of follow up after last infusion of CK0804. Primary Objective: Determine safety and tolerability of CK0804 as add-on therapy in MF, with suboptimal response to ruxolitinib. Primary endpoint: Safety, tolerability and TLTs of CK0804 as assessed by incidence and severity of AE and SAEs determined by NCI CTCAE Version 5.0. Secondary Objective: Determine efficacy of CK0804 as add-on therapy in MF, with suboptimal response to ruxolitinib. Secondary endpoint: Assessment of overall response rate and its duration, using modified International Working Group Myeloproliferative Neoplasm Research and Treatment and European Leukemia Net consensus report; Rate of anemia response and Rate of spleen response by imaging at and after 24 weeks; Symptom burden assessed using Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score scale. Safety data from cohort 1 will be presented. Clinical trial information: NCT05423691 .

Abstract CT242: A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis

Abstract Introduction: Patients (pts) with primary and secondary myelofibrosis (MF) have a reduced life expectancy. While several oral Janus Kinase (JAK)-1/2 inhibitors such as ruxolitinib (RUX) have demonstrated improvements in symptom burden and spleen volume reduction compared to physician choice of best available therapy leading to their approval by the US FDA, responses to these agents are generally time-limited. Additionally, these agents are not considered to be disease-modifying and survival in pts after RUX discontinuation is poor with a median survival of 11-14 months. Thus, novel mechanism-based therapies for pts with suboptimal response or progression on RUX are needed. Preclinical Rationale: JAK2 V617F mutations promote transition from G1 to S-phase of the cell cycle via increased expression of CDC25A in preclinical models and CDC25A expression is upregulated in primary MPN patient samples. Additional cell cycle regulators such as CDK6 and Cyclin D also play a role in MF pathogenesis and drive myeloproliferation. Finally, combination of the CDK4/6 inhibitor ribociclib and RUX demonstrated reduction in spleen and liver size when compared to RUX alone in murine models, suggesting synergy (Rampal et al., CCR 2021). Methods: This multicenter, phase I dose-escalation trial evaluates the safety of RUX + the CDK4/6 inhibitor abemaciclib in pts with primary or secondary MF with intermediate-1/2 or high-risk disease by DIPSS who require treatment and had an inadequate response to RUX. An inadequate response will be defined by (I) palpable splenomegaly ≥5 cm below the left costal margin at study entry AND/OR (II) active MPN symptoms [presence of 1 symptom score ≥5 or 2 symptom scores ≥3 using the screening MPN-SAF TSS. This study follows a conventional “3+3” dose-escalation design, in which pts on a stable dose of RUX (10mg or 15mg BID) with sufficient baseline platelet and absolute neutrophil count will be treated with increasing doses of abemaciclib. Abemaciclib was chosen due to less myelosuppression compared with other CDK4/6 inhibitors. The pre-study dose of ruxolitinib will be maintained to determine the maximum tolerated dose of the combination of RUX+ abemaciclib. The primary endpoint is to determine the safety and tolerability, and to identify the recommended phase II dose of abemaciclib in MF pts on a stable dose of RUX. Secondary endpoints include overall response rate, progression-free and overall survival, and duration of response per the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and the European Leukemia Net (ELN) 2013 consensus definitions. Correlative studies are planned to identify biomarkers predictive of response to RUX + abemaciclib, mechanisms of resistance (e.g., MAP kinase pathway activation), and any disease-modifying effects of combination therapy. Citation Format: Jan P. Bewersdorf, Srdan Verstovsek, Andriy Derkach, Lucia Masarova, Naveen Pemmaraju, Eytan M. Stein, Michael Mauro, Raajit Rampal, Prithviraj Bose. A phase I study of ruxolitinib in combination with abemaciclib for patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT242.

Venetoclax (VEN) Plus Intensive Chemotherapy (IC) with FLAG-IDA in Patients (Pts) with Newly Diagnosed (ND) and Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Background: Despite the high complete remission (CR) rates achieved with IC, relapse rates remain high underscoring the need for novel combination regimens capable of inducing deeper remissions via eradicating measurable residual disease (MRD). Recently, several studies have shown promising clinical activity of VEN when combined with different IC regimens in pts with ND AML with composite CR rates (CRc) above 90% and MRD-ve rates exceeding 80% (Wang 2022; Kadia 2021). FLAG-IDA + VEN has also shown significant clinical activity in pts with ND AML with a CRc rate of 89% and MRD-ve remission rate of 93% (DiNardo 2022). Methods: We conducted a single-center retrospective study to assess the clinical activity of FLAG-IDA + VEN in pts with AML. During induction, VEN was initially given for 14 days which was later on reduced to 7 days due to encouraging results by Kadia et al. Standard cytogenetic (CN) analysis was performed and molecular data was obtained using a 40-gene NGS platform. Responses were assessed using the modified International Working Group response criteria and included CR, CR with incomplete count recovery (CRi), morphologic leukemia-free state (MLFS), and partial remission (PR). Time-to-event analyses were estimated using the Kaplan-Meier method and compared using the log rank test. Results: From March 2020 to May 2022, 24 pts with AML (17 ND and 7 R/R) were treated using FLAG-IDA + VEN (Table 1). Median age was 48 years (range, 21-68) with male predominance (67%). Among the 17 pts with ND AML (8 de novo, 5 AML-MRC, 2 treated-secondary, 2 therapy-related), 3 had extramedullary disease (EMD). The most common ELN CN risk groups were complex (N=5), KMT2A-rearranged (N=4), other adverse (N=3), and diploid (N=3). Eight pts (47%) harbored a RAS mutation. Median time to initiation of therapy was 5 days (range, 2-14). Twelve pts (71%) [KMT2A-rearranged, N=4; complex CN, N=3; diploid, N=3; other adverse, N=1; other intermediate, N=1] achieved CR/CRi including 1 pt with EMD. Median time to ANC (≥ 500) and platelet (≥ 50,000) recovery were 29 days (range, 19- 42) and 25 days (range, 17- 42), respectively. Median number of consolidation cycles given were 1.5 (range, 1- 5). MRD status was available in 6 out of 12 pts and all 6 pts achieved MRD negativity using flow cytometry (<10-3). Median follow-up among ND AML pts was 4.3 months (mths) (range, 0.7- 13.2). Among the 12 responders: (1) 3 pts received allo-SCT [KMT2A-rearranged, N=2; (-7), N=1] after 7, 4, and 3 mths, respectively, and remain alive in CR 10+, 7.5+, and 3+ mths, respectively, after initiation of therapy, (2) 6 pts with ELN favorable (N=3), intermediate (N=2), and adverse (N=1) risk AML remain in CR/CRi for 6+, 4+, 1+, 3+, 2+, and 2+ mths, respectively, (3) 3 pts with ELN adverse risk AML (including 1 pt with de novo MLLr AML and EMD) achieved CR and relapsed after 0.7, 1.7, and 7.6 mths, respectively. One pt died due to progressive disease (PD) 4.7 mths after relapse and the remaining 2 pts are receiving salvage therapy and alive 4.3+ and 5.2+ mths after relapse, respectively. All nonresponders (N=5) had ELN adverse risk AML including 2 pts with EMD and 2 pts with treated secondary AML. All 5 nonresponders died due to PD including 3 pts who had no response to HMA+VEN based salvage therapy. Among the 7 pts with R/R AML, 6 were in salvage 1 and 1 pt received prior allo-SCT. Responses were observed in all pts: 4 CR, 1 CRi, 1 MLFS, and 1 PR. Median time to count recovery in R/R AML pts was 33 days (range, 24-78). Median follow-up in R/R AML pts was 6.2 mths (range, 1.5- 15.6). Of the 5 pts who achieved CR/CRi, 4 were bridged to allo-SCT and 1 pt died in CR after 3 cycles of consolidation due to sepsis. Of the 4 SCT recipients: (1) 2 pts relapsed 2 mths after allo-SCT and died 4 and 6.5 mths, respectively, after allo-SCT; (2) 2 pts (KMT2A-rearranged and NPM1mut) remain alive in CR for 8+ and 14+ mths, respectively. Two pts with complex CN achieved MLFS and PR after 1 cycle of therapy and died due to PD and fungal pneumonia after 5.3 and 1.5 mths of starting therapy, respectively. Median overall survival (OS) for pts with ND AML and R/R AML were 13.2 mths (95% CI: Not reached) and 6.2 mths (95% CI: 5-7), respectively (p=0.62; Figure 1). Among pts with ND AML, median OS was not reached among responders and was 2.6 mths in non-responders (p=0.002). Conclusion: FLAG-IDA + VEN is a feasible and active regimen in AML. Longer follow-up and larger multicenter studies are needed to confirm the efficacy of this regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Real-world data on efficacy and safety of azacitidine therapy in chronic myelomonocytic leukemia in China: results from a multicenter, retrospective study

SummaryChronic myelomonocytic leukemia (CMML) is a rare and aggressive myeloid malignancy with overlapped features of myelodysplastic syndromes/myeloproliferative neoplasms. Azacitidine (AZA), a hypomethylating agent, has been approved for the treatment of CMML in China, but real-world data are limited. Medical records of CMML patients who had received subcutaneously injected AZA were reviewed from January 2018 at five participating sites in China. Response was assessed according to the modified International Working Group (IWG 2006) criteria. Between January 2018 and November 2020, a total of 24 patients with CMML were included with a median age of 63 years. Patients received a median of 3 cycles of AZA treatment (range, 1–8). Overall response rate (ORR) was 37.5% (9 of 24); CR rate, PR rate, and mCR/HI rate were 8.3% (n = 2), 8.3% (n = 2), and 20.8% (n = 5), respectively. At a median duration of follow-up of 14.0 months (range 0.0–22.0 months), the median overall survival (OS) was 23.0 months. Univariate analysis revealed that ≥ 3 cycles of treatment was significantly associated with a higher 1-year OS rate compared with < 3 cycles of AZA treatment. Treatment was generally well-tolerated. The most common (> 10%) AEs were thrombocytopenia (n = 7, 29.2%), pneumonitis (n = 4, 16.7%) and fever (n = 3, 12.5%). This study provides valuable real-life data in China on the treatment schedules, efficacy and safety of AZA in the treatment of CMML.

Efficacy and safety of venetoclax in combination with azacitidine or decitabine in an outpatient setting in patients with untreated acute myeloid leukemia.

7044 Background: Venetoclax (Ven), a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine (Aza) or decitabine (Dec) is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients (pts) who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated Ven + HMA in an inpatient setting due to concerns of tumor lysis syndrome (TLS). This Phase 3b, single-arm, multicenter, open-label study (NCT03941964) evaluated the efficacy and safety of Ven + HMA in a US community-based outpatient setting. Methods: Pts with ND AML who were ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed an appropriate candidate for outpatient initiation of Ven + HMA by the investigator were eligible. Pts received Ven (400 mg) in combination with Aza (75 mg/m2) or Dec (20 mg/m2) for up to 6 cycles during the study period. Pts could continue receiving commercially acquired Ven after the study period. All pts received TLS prophylaxis. The primary endpoint was the composite complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) per modified International Working Group criteria. Secondary endpoints included CR or CRi rates and transfusion independence (TI). TLS was assessed per Howard criteria (Howard. N Engl J Med. 2011;364:1844). Results: At the 19 Oct 2021 cutoff date, 60 pts were enrolled and treated (Ven + Aza, n=30; Ven + Dec, n=30). Efficacy outcomes are shown in the Table. The composite CR rate was 58%. CR and CRi rates were 13% and 45%, respectively. Most pts (&gt;50%) maintained TI, and 41% and 57% of pts dependent on red blood cells or platelets, respectively, converted to TI. Bone marrow blast clearance was achieved in 42 pts (70%) at a median 26 days after treatment initiation. The most common (≥50%) AEs were anemia (75%), neutrophil count decrease (55%), white blood cell count decrease (52%), and nausea (50%). Serious AEs occurred in 67% of pts, most commonly (≥15%) febrile neutropenia (28%) and sepsis (15%). Two pts (3%) had TLS; neither event led to treatment discontinuation. Of pts who achieved blast clearance, 12/42 (29%) had a new event of myelosuppression post-blast clearance and prior to the next cycle. Conclusions: The results of this US community-based study indicate that Ven + HMA is an effective treatment option for pts with ND AML and, with appropriate TLS prophylaxis and monitoring, can safely be initiated in an outpatient setting. Clinical trial information: NCT03941964. [Table: see text]

Platelet Doubling After First Decitabine Cycle Predicts Response and Survival of Myelodysplastic Syndrome Patients.

Although the effect of decitabine on myelodysplastic syndrome (MDS) has been demonstrated, merely a proportion of patients respond to therapy, and no well-recognized predictors have been identified. This study was conducted to investigate the effectiveness of decitabine in real-world clinical practice, and determine the predictive factors of response and overall survival (OS) in MDS patients. Clinical and pathological data were collected from 94 patients and analyzed. These patients were reclassified according to the 2016 World Health Organization classification criteria, and restratified by International Prognostic Scoring System prognostic scores. The response evaluation was performed according to the 2006 modified International Working Group response criteria. In this study, 62% of patients responded to decitabine. Among these patients, 15 patients (16%) obtained complete remission (CR), 15 patients (16%) obtained marrow CR with hematologic improvement (HI), 20 patients (21%) obtained marrow CR without HI, and 8 patients (9%) only obtained HI, and no patient botained partial remission. The OS of the responders was significantly longer than that of non-responders (67 months vs. 7 months, P<0.001). The OS in patients with and without platelet doubling was significantly different in both the low/intermediate and high/very high risk groups (P=0.0398 and P=0.0330). The multivariate analysis revealed that platelet doubling after the first decitabine cycle is an independent predictor of response and OS in MDS patients (P=0.002 and P=0.008). Decitabine is effective for treating MDS patients in real-world clinical practice. Furthermore, platelet doubling after the first decitabine cycle can be used as a predictor of response and survival in MDS patients.

Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Evaluation of International Working Group 2006 Response Criteria in Patients with Higher-Risk Myelodysplastic Syndromes (HR-MDS) Treated with Hypomethylating Agent Monotherapy in the Frontline Setting

Heterogeneous Definitions of Secondary Acute Myeloid Leukemia (AML) Yield Distinct Outcomes in Response to First-Line Treatment with Hypomethylating Agents (HMA) and Venetoclax (Ven)

Background:The combination of HMA and venetoclax is now standard of care for patients with AML who are not candidates for intensive chemotherapy. Elderly patients are more likely to have secondary AML (sAML), although the presence of an antecedent hematologic malignancy is often not apparent by history. Lindsley et al (Blood, 2015) showed that a somatic mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 is >95% specific for sAML and associated with worse outcomes. While outcomes with HMA/ven in patients meeting standard criteria for sAML have recently been reported (Pullarkat, ASCO 2021), we set out to conduct a real-world analysis of sAML patients receiving HMA/ven, including those with a secondary mutation profile (SMP) as described by Lindsley et al. We hypothesized that-when treated with HMA/ven-outcomes of patients with SMP may be most similar to those with de novo AML.Methods:Patients diagnosed with AML at Stanford Cancer Institute from 4/2017-3/2021 and treated with front-line HMA/ven were retrospectively reviewed. These included patients previously treated with HMA monotherapy for an antecedent hematologic malignancy and those who had previously received ≤ 3 cycles of HMA monotherapy for AML. Responses were classified per the modified International Working Group response criteria. Overall survival (OS) was assessed for all patients, and for patients who had a complete response (CR) or CR with incomplete hematologic recovery (CRi), duration of response (DoR) was also assessed. Statistical analyses were performed in R using the logrank test, with hazard ratios (HR) computed using the Cox proportional hazards model. For multivariate analyses, p-values for a specific variable were calculated using Cox proportional hazards regression.Results:82 patients met criteria for inclusion; 78 had valid response assessments and 49 (62.8%) had achieved a CR or CRi at first response assessment. Median age was 72 years, with 3 patients younger than 60. 62 patients were male, median ECOG performance status (PS) was 1, median Charlson Comorbidity Index (CCI) was 6, median time to death or end of follow-up from the start of treatment was 366 days, and 58% of patients had adverse risk AML per ELN guidelines. Fig 1a demonstrates demographics for de novo, sAML (excluding SMP), and patients with SMP AML. 13 patients met criteria for AML-MRC, 23 patients had prior history of antecedent hematologic malignancy (18 with MDS or CMML, 5 with MDS/MPN overlap or MPN), 12 had tAML, and 20 patients possessed a SMP and did not meet criteria for the other three categories of sAML. 14 patients with de novo AML were characterized by the absence of any of the above factors. Patients with de novo AML were less likely to have adverse risk disease (29% vs. 64% in others) and had lower CCI scores (mean 5.1 vs. 6.2) but had no significant differences in age, gender, follow-up time, or PS.There was no statistically significant difference in rates of CR/CRi between the different subgroups or the different types of sAML; 69% of patients with de novo AML, 79% of SMP patients, and 57% of patients with other types of sAML achieved a CR or CRi. However, SMP patients had response durations and OS patterns similar to patients with de novo AML (Fig 1b and 1c), and when grouped with de novo patients, both DoR (HR = 3.5, p = 0.047, Fig 1d) and OS (HR = 2.1, p = 0.042, Fig 1e) were significantly longer than those of the sAML patients. Neither DoR nor OS were significantly longer when the SMP patients were grouped with sAML patients (respectively: HR = 3.3, p = 0.22, Fig 1f; HR = 1.5, p = 0.37, Fig 1g). In multivariate Cox proportional regression adjusting for age, ELN risk category, CCI, and PS, worse OS for sAML patients was maintained relative to the SMP and de novo patients (HR 2.9, p = 0.036), although the difference in DoR was no longer significant (HR 4.4, p= 0.10).Conclusions:Patients meeting standard definitions of sAML had worse outcomes than those with de novo AML when treated with HMA/ven in a retrospective, real-world analysis. Although a secondary mutation profile as described by Lindsley et al may be helpful in identifying patients with sAML, when treated with HMA/ven, patients with this profile have outcomes that align more closely with those of patients with de novo AML. [Display omitted] DisclosuresMannis: Astex, Forty Seven Inc/Gilead, Glycomimetics, and Jazz Pharmaceuticals: Research Funding; AbbVie, Agios, Astellas Pharma, Bristol Myers Squibb, Genentech, MacroGenics, Pfizer, and Stemline: Consultancy.

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax Combined with Hypomethylating Agents

Venetoclax and Azacitidine in the Treatment of Patients with Relapsed/Refractory Myelodysplastic Syndrome

Venetoclax and Azacitidine in the Treatment of Patients with Relapsed/Refractory Myelodysplastic Syndrome

A Phase 1 Trial of the Combination of Ibrutinib and Azacitidine for the Treatment of Higher Risk Myelodysplastic Syndromes: University of California Hematologic Malignancies Consortium (UCHMC) Study 1503

Introduction: Higher risk myelodysplastic syndromes (HR-MDS) have poor outcomes, particularly after hypomethylating agent (HMA) failure. The HMA azacitidine (AZA) is a standard of care for HR-MDS and works through several mechanisms, including inhibition of NF-kB signaling. Ibrutinib (IBR) inhibits Bruton9s Tyrosine Kinase (BTK) and has an antiproliferative effect on myeloblasts in preclinical models through BTK binding and inhibition of NF-kB signaling. IBR also has immunomodulatory activity mediated through binding interleukin-2-inducible kinase (ITK) and promoting Th1-polarized immunity, which is decreased in HR-MDS. These features suggest that the combination of IBR and AZA may improve outcomes in HR-MDS. Methods: This is an ongoing multicenter prospective Phase 1 dose-escalation trial of IBR in combination with AZA in patients with HR-MDS (NCT02553941). Results of the dose escalation phase are reported. Eligibility included World Health Organization or French-American-British classification-defined MDS and Revised International Prognostic Scoring System (IPPS-R) intermediate or higher risk. Any prior therapy was allowed or patients could be untreated if unfit for, or had refused, high intensity chemotherapy. Transfusion-dependent patients were eligible. Patients received AZA 75 mg/m2 IV/SC daily for 7 days and IBR orally daily for 28 days. Cycles repeated every 28 days. Dose-escalation used a 3+3 design with IBR dose levels of 420 mg (Cohort 1) and 560 mg (Cohort 2). The primary objective was to determine the safety and tolerability of IBR in combination with AZA. Adverse events (AEs) were monitored throughout treatment, and dose-limiting toxicities (DLT) were assessed during cycle 1. The secondary objective was to assess preliminary efficacy using modified International Working Group Response Criteria. Exploratory objectives evaluated pharmacodynamic and biological effects of the combination, including BTK occupancy in CD34+ bone marrow mononuclear cells (BMMC). Results: As of June 1, 2017, 9 patients [89% male, median age 80 years (range 64-81)] were enrolled into Cohort 1 (n=3) and Cohort 2 (n=6). MDS subtypes included single lineage dysplasia (n=1), multilineage dysplasia (n=1), excess blasts (EB)-1 (n=2), EB-2 (n=3), refractory anemia with EB in transformation (n=1) and unclassifiable (n=1). IPSS-R scores were intermediate (n=2), high (n=2) and very high (n=5). Three patients were HMA-naive and six had prior HMA therapy [AZA (n=3), decitabine (n=2), both (n=1)]. All patients completed cycle 1. No DLTs were observed. All patients experienced at least one treatment-emergent adverse event (TEAE). Seven patients experienced a grade 3-4 TEAE with neutropenia (n=6), thrombocytopenia (n=3) and febrile neutropenia (n=3) most common. Four patients (three in Cohort 1 and one in Cohort 2) experienced a serious adverse event including febrile neutropenia (n=3) and gastric hemorrhage (n=1). No patients experienced atrial fibrillation. Median time on study was 160 days (range 42-283) with a median of five cycles (range 1-10) received. Six patients remain on IBR plus AZA, and three patients have discontinued study therapy (two disease progression and one withdrawal of consent and subsequent death on hospice). Four patients have reduced AZA to 5 days per cycle per investigator discretion, and four patients have had interruptions of IBR dosing due to febrile neutropenia (n=3) and concurrent azole use (n=1). Three patients (33%) achieved complete remission (CR), one (11%) had a partial remission (PR), and five (55%) had stable disease (SD). All three CRs occurred in patients without prior HMA exposure and included one complete and two partial cytogenetic responses. CR was achieved after 1, 4 and 6 cycles in these patients. One patient (11%) with SD had a hematologic improvement-erythroid response (HI-E). The overall hematologic normalization rate (CR+PR+HI) was 55%. BTK occupancy in CD34+ BMMC after cycle 1 was 42.0% and 51.7% in two patients at IBR 420 mg and 41.5% in one patient at IBR 560 mg. Conclusions: The combination of IBR and AZA demonstrates a tolerable safety profile in patients with HR-MDS. No DLTs were observed at either IBR dose level. The combination shows promising preliminary efficacy, including responses in patients with prior HMA exposure. CD34+ BMMC BTK occupancy was seen. An expansion cohort at the IBR 560 mg dose level in AZA-naive patients is ongoing. Disclosures Jonas: AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees; Rigel: Consultancy. Logan: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Astellas: Research Funding; Shire: Consultancy; Kite: Research Funding; Amgen: Consultancy; Pharmacyclics: Research Funding; Jazz: Consultancy. Abedi: Takeda: Speakers Bureau; Seattle Genetics: Speakers Bureau; Gilead: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding; Celgene: Membership on an entity9s Board of Directors or advisory committees, Research Funding, Speakers Bureau; California Institute of Regenerative Medicine: Research Funding. Bejar: Celgene: Consultancy, Honoraria, Other: DSMB, Steering Committee, Research Funding; Genoptix: Consultancy, Honoraria, Patents & Royalties; AbbVie/Genetech: Honoraria, Other: Ad-hoc advisory board; Foundation Medicine: Honoraria, Other: Ad-hoc advisory board; Otsuka/Astex: Honoraria, Other: Ad-hoc advisory board; Modus Outcomes: Consultancy, Honoraria. Wieduwilt: Reata Pharmaceuticals: Equity Ownership; Sigma-Tau: Research Funding. Curtin: Amgen, Celgene, Onconova, Pharmacyclics: Research Funding.

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

The Impact of the Administration Schedule and Mutational Profile on Outcomes of Patients with Relapsed and Refractory Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Large, International, Multi-Center Analysis

Venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with therapy-related myeloid neoplasms, antecedent myelodysplastic syndromes, or myelodysplastic/myeloproliferative neoplasms.

7011 Background: Patients (pts) with therapy-related myeloid neoplasms (tMN), antecedent myelodysplastic syndrome, or antecedent myelodysplastic/myeloproliferative neoplasms (A-MDS/MPN) may have poor outcomes due to age and adverse genetic/karyotypic features. In the VIALE-A study, pts with tMN and A-MDS/MPN unfit for intensive chemotherapy treated with venetoclax (Ven) and azacitidine (Aza) demonstrated superior response rates and overall survival (OS) than Aza alone. Herein, the efficacy and safety of Ven+Aza among pts with tMN and A-MDS/MPN are described. Methods: Data were pooled from pts enrolled in VIALE-A (NCT02993523) comparing pts who received Ven+Aza or placebo (Pbo)+Aza and a prior phase 1b study (NCT02203773) where pts received Ven+Aza. Enrolled pts were ≥18 years, treatment-naïve with no prior exposure to hypomethylating agents, and ineligible for intensive chemotherapy. Pts on Ven+Aza received Ven 400 mg orally (days 1–28) and Aza (75 mg/m2; days 1-7/28-day cycle). Composite complete remission rate (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]), duration of response (DoR), and OS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: In this pooled analysis, tMN was observed in (Ven+Aza/Pbo+Aza) 31/9 and A-MDS/MPN in 59/26 pts. Poor-risk cytogenetics were observed in 18 (58%)/6 (67%) with tMN (5 or 5q deletion [del]: 4/1 ; 7 or 7q del: 6/1 ; complex [≥ 3 clonal abnormalities]: 10/4), and 19 (32%)/13 (50%) with A-MDS/MPN (5 or 5q del: 10/5; 7 or 7q del: 6/1; complex: 14/9). TP53 mutation was observed in 5/3 pts with tMN and 8/0 pts with A-MDS/MPN. Pts with tMN received a median (Ven+Aza/Pbo+Aza) of 5/4 cycles of treatment. CRc was achieved by 19 (61%)/1 (11%). The mDoR was not reached (NR) (95% CI: 17.8, NR)/8.5 (NR, NR) months. The mOS was 16.4 (95% CI: 4.1, NR)/11.3 (0.6, 17.5) months. Pts with A-MDS/MPN received a median (Ven+Aza/Pbo+Aza) of 9/5 cycles of treatment. CRc was achieved by 39 (66%)/7 (27%) pts with mDoR of 17.3 (95% CI: 9.6, NR)/5.8 (1.1, NR) mos. The mOS was 15.9 (95% CI: 11.5, NR)/10.1 (4.7, 14.5) mos. Common grade≥3 adverse events (Ven+Aza/Pbo+Aza) were febrile neutropenia (tMN: 39%/11% and A-MDS/MPN: 36%/12%) neutropenia (tMN: 29%/33%; A-MDS/MPN: 39%31%), and thrombocytopenia (tMN: 32%/33%; A-MDS/MPN: 39%/62%). Conclusions: Ven+Aza compared to Aza monotherapy resulted in higher CRc rates with longer DoR and median OS among treatment-naïve pts with tMN and A-MDS/MPN ineligible for intensive chemotherapy. The safety profile was similar to overall pts with the Ven+Aza combination. Outcomes by cytogenetic and molecular risk-groups will be presented. Clinical trial information: NCT02993523, NCT02203773.

Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine.

7018 Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD&lt;10-3) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p&lt;0.001). There is limited evidence of the clinical significance of MRD monitoring in pts receiving low-intensity chemotherapy. Herein, we explored the outcomes of pts treated with Ven+Aza who achieved both CRc and MRD&lt;10-3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m2; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as &lt;1 residual blast /1000 leukocytes (&lt;10-3). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD&lt;10-3 and 133/211 (63%) had MRD≥10-3. Median age (MRD&lt;10-3/ MRD≥10-3) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD&lt;10-3/ MRD≥10-3) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD&lt;10-3/ MRD≥10-3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD&lt;10-3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD&lt;10-3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD&lt;10-3response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD&lt;10-3/ MRD≥10-3) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD&lt;10-3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]

TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia

TP53 Abnormalities Correlate with Immune Infiltration and Associate with Response to Flotetuzumab Immunotherapy in Acute Myeloid Leukemia

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

A Phase II Study of Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Initial Results of a Phase I/II Study of Venetoclax in Combination with Azacitidine in Treatment-Naive and Relapsed/Refractory High-Risk Myelodysplastic Syndrome (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Introduction: Venetoclax (VEN) is an oral BCL2 inhibitor, that has been shown to overcome apoptotic stress in cells from patients (pts) with high-risk myelodysplastic syndrome (MDS). Pre-clinical evidence indicates that VEN plus azacytidine (Aza) combination results in synergistic effects in myeloid malignancies. The objective of this trial is to evaluate the safety, tolerability, and overall response rate (ORR) of VEN in combination with Aza in pts with treatment-naive high-risk MDS or chronic myelomonocytic leukemia (CMML) and pts that were relapsed/refractory (R/R) to prior hypomethylating agent (HMA) therapy. Methods: This is a single-arm phase I/II clinical trial for pts with treatment-naive high-risk MDS or CMML, or pts with R/R MDS or CMML post-HMA failure (NCT04160052). Pts with prior BCL2 inhibitor therapy or low-risk disease (IPSS low or Int-1) are excluded. Aza is administered at 75mg/m2 IV or SC for 5 days on days 1-5 of each treatment cycle. VEN is studied at 100 mg, 200 mg, or 400 mg daily, on days 1-7 or 1-14 of each cycle. The primary endpoint is to determine the maximum tolerated dose and dose-limiting toxicity (DLT) of VEN in combination with Aza, as well as to evaluate ORR, defined as achieving complete remission (CR), marrow complete remission (mCR), partial response (PR), or hematologic improvement (HI) lasting ≥4 weeks. Response is assessed based on the modified International Working Group 2006 criteria (Cheson et al Blood 2006). Overall survival (OS) is calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) is calculated from the start date of treatment to the date of disease progression, or last follow-up. Duration of response is calculated from the date of response to the date of disease progression, or last follow-up. Safety profile events were recorded according to the CTCAE v5.0. Results: To date 9 pts were enrolled. Four pts received VEN at 100mg dose, 3 pts at 200mg dose, and 2 pts at 400mg dose on days 1-7. There has been no protocol defined DLTs. The median age was 66 years (range, 59-83), 89% were male, 67% with MDS, 67% with normal karyotype. Five pts (56%) were treatment-naive, and 4 (44%) with R/R disease. Of the treatment-naive cohort (N=5), 4/5 (80%) pts had normal karyotype and none had TP53 mutations. ORR rate in this treatment-naive cohort was 100%, all pts achieving mCR, of which 1 (20%) had neutrophil response. Of the R/R cohort (N=4), cytogenetics were normal in 2/4 (50%) and complex in 2/4 (50%), and 2/4 (50%) had TP53 mutations. ORR in this R/R cohort was 3/4 (75%), all achieving mCR. One pt (25%) had stable disease (Table 1 and Figure 1). With a median follow-up duration of 3.6 months (95% CI: 1.4-8.4), 3 (33%) had disease progression and 1 (11%) died. Pts received median 2 courses of therapy (range, 1-4). One pt went to transplant. Median progression-free survival (PFS) for the entire cohort was 4.6 months (95% CI: 3.4-NA) and median OS has not been reached (Figure 2). Median duration of response is 4.1 months (95% CI: 2.4-NA). Possibly/probably related grade 3/4 adverse events included neutropenia in 4/9 (44%), thrombocytopenia in 3/9 (33%), and anemia in 1/9 (11%) pts. There were no grade 5 events (Table 2). Conclusions: The administration of VEN with Aza appears safe and well tolerated in treatment-naive and R/R pts with high-risk MDS and CMML. The study continues to accrue. Disclosures Thompson: Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Alvarado:BerGenBio ASA: Research Funding; FibroGen: Research Funding; Sun Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Tolero Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Janssen: Honoraria; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding. Garcia-Manero:Amphivena Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding.