MDS-141: the Prognostic Impact of Cytogenetic Scores in Patients with Higher-Risk Myelodysplastic Syndrome Treated with Venetoclax and Azacitidine in a Phase 1 Study

Background/Aims: Venetoclax (Ven), a selective oral BCL-2 inhibitor, has shown synergy with hypomethylating agents (HMAs) such as Azacitidine (Aza), in treatment of higher-risk myelodysplastic syndrome (HR)-MDS. We evaluate prognostic impact of cytogenetic categories of revised International Prognostic Scoring System (IPSS-R) among HR-MDS patients treated with Ven+Aza. Methods: This study enrolled patients age ≥ 18 yrs, untreated for MDS, with IPSS score of ≥1.5, bone marrow blasts < 20%, Eastern Cooperative Oncology Group (ECOG) score of ≤2; excluding chronic myelomonocytic leukemia and intensive chemotherapy or allogeneic hematopoietic stem cell transplantation patients. Patients received escalating doses of Ven 100-400 mg orally (14 or 28 days) + Aza 75 mg/m2 subcutaneously or intravenously (day 1–7) per 28-day cycle; IPSS-R calculated before first study dose. Peripheral blood samples from 38 (67%) patients were analyzed by a targeted next-generation sequencing mutational panel. The variant allele frequency sensitivity for detection was 1%, which was used as a detection cut-off to define presence or absence of mutation. Results: As of 8/21/2019, 57 patients (75% male, median age 71yrs) received Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were at intermediate risk, 13 (24%) at high risk, and 33 (60%) at very high risk. Cytogenetic risk based on IPSS-R: 2 (4%) were very good, 18 (32%) good, 8 (15%) intermediate, 13 (23%) poor, and 15 (26%) very poor. Ten genes were mutated in >10% of patients, including poor prognosis conferring TP53, RUNX1, TET2, ASXL1, SRSF2, STAG2, and IDH1/2. Median follow-up time was 8.9 months. Complete remission (CR)+marrow CR (mCR) rates by IPSS-R cytogenetic risk were: very good 100% (2/2), good 94% (17/18), intermediate 63% (5/8), poor 62% (8/13), and very poor 73% (11/15). Median with 95% confidence interval (CI) in progression-free survival (PFS) was 6.7 (0.7–not estimable), 9.3 (3.2–not estimable), and 9.5 months (2.7–9.5) in the intermediate, poor, and very-poor risk groups, respectively, and not reached in the good and very-good risk groups. Median overall survival (OS) in patients with very poor risk was 16.2 months (2.0–16.2). The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups, respectively. Conclusion: This preliminary analysis shows promising efficacy of Ven+Aza combination treatment across all IPSS-R cytogenetic risk categories and suggests prognostic relevance of the IPSS-R cytogenetic scoring system. Abstract was previously published at EHA25. Venetoclax (Ven), a selective oral BCL-2 inhibitor, has shown synergy with hypomethylating agents (HMAs) such as Azacitidine (Aza), in treatment of higher-risk myelodysplastic syndrome (HR)-MDS. We evaluate prognostic impact of cytogenetic categories of revised International Prognostic Scoring System (IPSS-R) among HR-MDS patients treated with Ven+Aza. This study enrolled patients age ≥ 18 yrs, untreated for MDS, with IPSS score of ≥1.5, bone marrow blasts < 20%, Eastern Cooperative Oncology Group (ECOG) score of ≤2; excluding chronic myelomonocytic leukemia and intensive chemotherapy or allogeneic hematopoietic stem cell transplantation patients. Patients received escalating doses of Ven 100-400 mg orally (14 or 28 days) + Aza 75 mg/m2 subcutaneously or intravenously (day 1–7) per 28-day cycle; IPSS-R calculated before first study dose. Peripheral blood samples from 38 (67%) patients were analyzed by a targeted next-generation sequencing mutational panel. The variant allele frequency sensitivity for detection was 1%, which was used as a detection cut-off to define presence or absence of mutation. As of 8/21/2019, 57 patients (75% male, median age 71yrs) received Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were at intermediate risk, 13 (24%) at high risk, and 33 (60%) at very high risk. Cytogenetic risk based on IPSS-R: 2 (4%) were very good, 18 (32%) good, 8 (15%) intermediate, 13 (23%) poor, and 15 (26%) very poor. Ten genes were mutated in >10% of patients, including poor prognosis conferring TP53, RUNX1, TET2, ASXL1, SRSF2, STAG2, and IDH1/2. Median follow-up time was 8.9 months. Complete remission (CR)+marrow CR (mCR) rates by IPSS-R cytogenetic risk were: very good 100% (2/2), good 94% (17/18), intermediate 63% (5/8), poor 62% (8/13), and very poor 73% (11/15). Median with 95% confidence interval (CI) in progression-free survival (PFS) was 6.7 (0.7–not estimable), 9.3 (3.2–not estimable), and 9.5 months (2.7–9.5) in the intermediate, poor, and very-poor risk groups, respectively, and not reached in the good and very-good risk groups. Median overall survival (OS) in patients with very poor risk was 16.2 months (2.0–16.2). The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups, respectively. This preliminary analysis shows promising efficacy of Ven+Aza combination treatment across all IPSS-R cytogenetic risk categories and suggests prognostic relevance of the IPSS-R cytogenetic scoring system. Abstract was previously published at EHA25.