THE PROGNOSTIC IMPACT OF CYTOGENETIC SCORES IN PATIENTS WITH HIGHER-RISK MYELODYSPLASTIC SYNDROME TREATED WITH VENETOCLAX AND AZACITIDINE IN A PHASE 1 STUDY
Author(s): ,
Jacqueline S. Garcia
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Andrew H. Wei
Affiliations:
Alfred Hospital and Monash University,Melbourne,Australia
,
Uma Borate
Affiliations:
Knight Cancer Institute, Oregon Health and Science University,Portland,United States
,
Chun Yew Fong
Affiliations:
Olivia Newton John Cancer Research Institute,Melbourne,Australia
,
Maria R. Baer
Affiliations:
University of Maryland,Baltimore,United States
,
Florian Nolte
Affiliations:
Charité University Hospital,Berlin,Germany
,
Pierre Peterlin
Affiliations:
Nantes University Hospital,Nantes,France
,
Joseph Jurcic
Affiliations:
Columbia University Medical Center,New York,United States
,
Meagan Jacoby
Affiliations:
Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine,St. Louis,United States
,
Wan-Jen Hong
Affiliations:
Genentech,South San Francisco,United States
,
Uwe Platzbecker
Affiliations:
University Hospital Leipzig,Leipzig,Germany
,
Olatoyosi Odenike
Affiliations:
University of Chicago Medicine and Comprehensive Cancer Center,Chicago,United States
,
Ilona Cunningham
Affiliations:
University of Sydney,Sydney,Australia
,
Ying Zhou
Affiliations:
AbbVie Inc,North Chicago,United States
,
Martin Dunbar
Affiliations:
AbbVie Inc,North Chicago,United States
,
Jason G. Harb
Affiliations:
AbbVie Inc,North Chicago,United States
,
Relja Popovic
Affiliations:
AbbVie Inc,North Chicago,United States
,
Poonam Tanwani
Affiliations:
AbbVie Inc,North Chicago,United States
,
Sathej Gopalakrishnan
Affiliations:
AbbVie Deutschland GmbH & Co KG,Ludwigshafen,Germany
,
Johannes Wolff
Affiliations:
AbbVie Inc,North Chicago,United States
Guillermo Garcia-Manero
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
EHA Library. S. Garcia J. 06/12/20; 294712; S189
Jacqueline S. Garcia
Jacqueline S. Garcia
Contributions
Abstract

Abstract: S189

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS II

Background
Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor that has been shown to synergize with hypomethylating agents (HMAs) in preclinical and clinical studies of myeloid malignancies including acute myeloid leukemia and myelodysplastic syndrome (MDS). Preliminary analysis of this ongoing open-label, Phase 1b study evaluating the combination of Ven and Azacitidine (Ven+Aza) in the treatment of higher risk (HR)-MDS has shown an overall response rate of 77%.

Aims
The aim of this analysis is to evaluate the prognostic impact of the cytogenetic categories of the revised International Prognostic Scoring System (IPSS-R) among patients with HR-MDS treated with Ven+Aza.

Methods
This study (NCT02942290) is evaluating safety and preliminary efficacy of various dose cohorts and schedules of Ven+Aza in the treatment of HR-MDS. Key inclusion criteria are age ≥18 years, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts <20%, Eastern Cooperative Oncology Group (ECOG) score of ≤2; excluding patients with chronic myelomonocytic leukemia and candidates for undergoing intensive chemotherapy or allogeneic hematopoietic stem cell transplantation. Enrolled patients were treated with escalating doses of Ven (100, 200, and 400 mg orally for 14 or 28 days of each 28-day cycle) + Aza (75 mg/m2, subcutaneously or intravenously from day 1–7 per 28-day cycle). IPSS-R scores were calculated prior to first study dose. Available 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 the presence or absence of a mutation.

Results
As of August 21, 2019, 57 patients [75% male, median age 71 years (range, 26 – 85)] received treatment with Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were evaluated to be at intermediate risk, 13 (24%) at high, and 33 (60%) patients at very high risk. Cytogenetic risk based on IPSS-R were very good in 2 (4%), good in 18 (32%), intermediate in 8 (15%), poor in 13 (23%), and very poor in 15 (26%) patients. Ten genes were found to be 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 (range 0.1–29.1). 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 progression free survival (PFS) was 6.7 (95% CI, 0.7 – not estimable), 9.3 (95% CI, 3.2 – not estimable), and 9.5 months (95% CI, 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 (95% CI, 2.0 – 16.2) and not reached in the other risk groups. The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups respectively, and censored early in the very good risk group.

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. Further analyses evaluating the association of genetic alterations and BCL-2 family member expression on efficacy outcomes will be presented.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Erythroid progenitor, MDS, Mutation analysis



Abstract: S189

Type: Oral Presentation

Presentation during EHA25: All oral abstract presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Session title: Novel treatments for MDS II

Background
Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor that has been shown to synergize with hypomethylating agents (HMAs) in preclinical and clinical studies of myeloid malignancies including acute myeloid leukemia and myelodysplastic syndrome (MDS). Preliminary analysis of this ongoing open-label, Phase 1b study evaluating the combination of Ven and Azacitidine (Ven+Aza) in the treatment of higher risk (HR)-MDS has shown an overall response rate of 77%.

Aims
The aim of this analysis is to evaluate the prognostic impact of the cytogenetic categories of the revised International Prognostic Scoring System (IPSS-R) among patients with HR-MDS treated with Ven+Aza.

Methods
This study (NCT02942290) is evaluating safety and preliminary efficacy of various dose cohorts and schedules of Ven+Aza in the treatment of HR-MDS. Key inclusion criteria are age ≥18 years, no prior therapy for MDS, IPSS score of ≥1.5, bone marrow blasts <20%, Eastern Cooperative Oncology Group (ECOG) score of ≤2; excluding patients with chronic myelomonocytic leukemia and candidates for undergoing intensive chemotherapy or allogeneic hematopoietic stem cell transplantation. Enrolled patients were treated with escalating doses of Ven (100, 200, and 400 mg orally for 14 or 28 days of each 28-day cycle) + Aza (75 mg/m2, subcutaneously or intravenously from day 1–7 per 28-day cycle). IPSS-R scores were calculated prior to first study dose. Available 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 the presence or absence of a mutation.

Results
As of August 21, 2019, 57 patients [75% male, median age 71 years (range, 26 – 85)] received treatment with Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were evaluated to be at intermediate risk, 13 (24%) at high, and 33 (60%) patients at very high risk. Cytogenetic risk based on IPSS-R were very good in 2 (4%), good in 18 (32%), intermediate in 8 (15%), poor in 13 (23%), and very poor in 15 (26%) patients. Ten genes were found to be 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 (range 0.1–29.1). 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 progression free survival (PFS) was 6.7 (95% CI, 0.7 – not estimable), 9.3 (95% CI, 3.2 – not estimable), and 9.5 months (95% CI, 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 (95% CI, 2.0 – 16.2) and not reached in the other risk groups. The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups respectively, and censored early in the very good risk group.

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. Further analyses evaluating the association of genetic alterations and BCL-2 family member expression on efficacy outcomes will be presented.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Erythroid progenitor, MDS, Mutation analysis


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