P757: RESULTS OF A PHASE 1 STUDY OF AZACITIDINE COMBINED WITH VENETOCLAX FOR TREATMENT-NAIVE AND RELAPSED HIGH-RISK MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA

Abstract

Background: Patients (pts) with higher-risk myelodysplastic syndromes (HR-MDS) who are ineligible for allogeneic stem cell transplant (SCT) have limited treatment options beyond the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC). Responses to HMA monotherapy are time-limited and prognosis after HMA-failure is dismal. Venetoclax (VEN) is an oral small molecule BCL-2 inhibitor with the potential to prolong/deepen responses when combined with an HMA. Aims: To evaluate the safety/tolerability, recommended phase 2 dose (RP2D), and preliminary efficacy of VEN in combination with AZA for the treatment of HR-MDS/CMML. Methods: This was a single-center dose-escalation phase 1 study with “3 + 3” design. Key inclusion criteria were a diagnosis of MDS or CMML by WHO 2016, age ≥ 18 yrs, int-2 or high risk by IPSS, and bone marrow (BM) blasts of 5-19%. Pts could be treatment-naïve or relapsed/refractory, defined as failure after 4+ cycles of HMA. Prior VEN exposure was not permitted. Treatment consisted of AZA 75 mg/m2 on D1-5 and escalating doses of VEN on D1-7 or 1-14 (Table 1) every 28D. VEN dosing was adjusted for pts on concomitant CYP3A inhibitors. The primary objective was safety/tolerability and determination of the RP2D. Secondary objectives were response rates, overall survival (OS), and progression-free survival (PFS). Adverse events (AEs) were graded as per the CTCAE v5.0 and responses assessed using the modified IWG 2006 criteria. All pts provided informed consent. The study was registered on ClinicalTrials.gov (NCT04160052). Results: Data cutoff was February 19th, 2022. 23 pts (13 HMA-naïve MDS, 4 HMA-naïve CMML, 4 HMA-failure MDS, 2 HMA-failure CMML) were enrolled. The median age was 68 years (range 58-84) and median BM blasts 11% (range 6-19%). IPSS was int-2 in 78% of pts and high in 22% of pts. 8/23 (35%) had complex cytogenetics, 6/23 (26%) had TP53 mutations, and 5/23 (22%) had therapy-related MDS/CMML. A single dose-limiting toxicity (DLT) occurred at dose level +2 (BM aplasia and delayed count recovery). The maximum tolerated dose (MTD) was not reached. The most common grade 3/4 AEs were neutropenia (39%), thrombocytopenia (39%), anemia (13%), and infections: pneumonia (30%), neutropenic fever (17%), diverticulitis (9%), sepsis (9%), cellulitis (4%), and splenic abscess (4%). The RP2D was established at AZA 75 mg/m2 on D1-5 plus VEN 400 mg on D1-14. 3 deaths occurred on study, all from sepsis. 30 and 60-day mortality were 4% and 9%, respectively. Other reasons for discontinuing therapy included progression of MDS/CMML (n=6), transformation to AML (n=4), SCT (n=4), and social reasons (n=1). The ORR by intention-to-treat (ITT) analysis was 82% (14/17; 3 CR, 5 mCR+HI, 6 mCR) in the HMA-naïve cohort and 100% (6/6; 6 mCR) in the HMA-failure cohort. A median of 3 cycles (range 1-11) were given. Responses occurred after a median of 1 cycle (range 1-2) and lasted a median of 4.5m (range 1.2m to 21.2m). At a median follow-up of 13.2m, median OS was not reached (1-year OS 68.6%) in the HMA-naïve cohort and 8.3m (1-year OS 22%) in the HMA-failure cohort. Median PFS was 13.1m (1-year PFS 51.5%) in the HMA-naïve cohort and 6.8m (1-year PFS 0%) in the HMA-failure cohort. Image:Summary/Conclusion: AZA combined with VEN is tolerable and yields a high ORR in HR-MDS/CMML, with or without prior HMA. Rates of myelosuppression and infection are high and careful monitoring is required. The RP2D is AZA 75 mg/m2 on D1-5 plus VEN 400 mg on D1-14, every 28D. The phase 2 dose expansion component of this study is ongoing.