Genomic Profiling in Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) Following HMA Failure: Baseline Results from the Inspire Study (04-30)

• Published in: Blood 2019-11, Vol.134 (Supplement_1), p.3015-3015
• Main Authors: Garcia-Manero, Guillermo, Jonasova, Anna, Luger, Selina M., Al-Kali, Aref, Valcárcel, David, Warlick, Erica D., Jedrzejczak, Wieslaw W., Díez-Campelo, María, Zbyszewski, Patrick S., Cavanaugh, Christopher, Woodman, Richard C., Fruchtman, Steven M., Takahashi, Koichi
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2019-131632

Background: More than 45 mutations have been identified in association with HR-MDS. In the majority of patients with MDS (80%) co-mutations are present and the prognostic contribution of each individual mutation remains elusive, especially after adjusting for clinical variables such as IPSS-R score. N-RAS and K-RAS mutations as well as regulators of the Ras pathway (e.g. PTPN11, NF1) are frequently observed (15-20%) in HR-MDS, however their clinical impact is unclear, especially in de novo MDS. Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic that has the potential to block RAS-RAF-MEK-ERK and PI3K-AKT-mTOR signaling pathways (Athuluri-Divakar 2016). Rigosertib has the potential to also inhibit wildtype upregulation of RAS. We report here genomic profiling at the time of study entry in the ongoing phase 3 randomized global study (known as INSPIRE) in patients with HR-MDS after failure of HMA therapy. Methods: INSPIRE (NCT02562443) is a global randomized Ph3 trial in pts with HR-MDS after HMA failure with an overall target enrollment of 360 pts with currently 298 pts randomized. Pts are randomized 2:1 to rigosertib or physician's choice of treatment. The primary endpoint is overall survival (OS). All pts failed to respond or progressed on HMA therapy. Key inclusion criteria includes: age < 82 years, RAEB-1, RAEB-2 or RAEB-t; intermediate risk (IR), high risk (HR) and very high risk (VHR) per IPSS-R; ≥ 1 cytopenia; duration of prior HMA ≤ 9 cycles within 12 months; last dose of HMA ≤ 6 months before enrollment; baseline blast counts between 5-29% and one of the following: progression any time after initiation of HMA treatment, intolerance to HMA, failure to achieve complete remission (CR), partial remission (PR), or hematologic improvement (HI) after six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC, or relapse after initial CR, PR or HI. Bone marrow samples were collected at study baseline and throughout the study for mutational analysis as an exploratory endpoint. Baseline blast counts are described as % reported in bone marrow aspirate at screening. Genomic DNA was extracted from diagnostic bone marrow or peripheral blood samples and targeted capture deep sequencing of 295 genes were performed (median sequencing depth 500x) using Agilent's SureSelect custom panel. Modified Mutect and Pindel were used to identify high-confidence somatic mutations. Results: All data is presented as blinded aggregate results for