Preclinical Assessment of Alvocidib in Combination with 5-Azacytidine in High-Risk Myelodysplastic Syndromes
| Autor: | Christel Weiss, Verena Nowak, Wolf-Karsten Hofmann, Arwin Mehralivand, Georgia Metzgeroth, Daniel Nowak, Jason M. Foulks, Johann-Christoph Jann, Julia Obländer, Mohamad Jawhar, Nanni Schmitt, Nadine Weimer, Vladimir Riabov, Iris Palme, Qingyu Xu, Eva Altrock, Alina Wein, Alexander Streuer |
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| Rok vydání: | 2021 |
| Předmět: | |
| Zdroj: | Blood. 138:4649-4649 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2021-150778 |
| Popis: | Hypomethylating therapy with 5-azacytidine (5-Aza) is a standard-of-care for patients with higher-risk myelodysplastic syndromes (MDS). Response is induced in approximately 50% of 5-Aza treated patients. However, despite robust efficacy in responders, relapse is almost certain. Recently, inhibitors of anti-apoptotic BCL-2 protein family members have shown potent activity against AML and higher-risk MDS in combination with 5-Aza. Alvocidib (Alv), a cyclin-dependent kinase 9 inhibitor and indirect transcriptional repressor of the anti-apoptotic BCL-2 family member MCL-1, has shown anti-leukemic effects in combination with 5-Aza in a phase 1 study of AML (Lee DJ et al, Expert Opin Investig Drugs 2019; Zeidner JF et al, Leuk Res 2015). Additionally, Alv has entered a phase 1b/2 study in patients with higher-risk MDS (NCT03593915). In order to possibly identify biomarkers of response, we performed a comprehensive pre-clinical in vitro assessment of Alv combined with 5-Aza using a clinically well-characterized cohort of n=40 MDS (high risk) patients and n=11 healthy controls. CD34+ HSCs were purified from bone marrow (BM) aspirates using positive selection with MACS microbeads. CD34+ cells of healthy controls were obtained from femur head replacement surgery bone specimens. Hematopoietic stem cells (HSCs) were expanded for four days in StemSpan SFEM II medium containing StemSpan Myeloid Expansion Supplement (Stem Cell Technologies) and treated with 5-Aza for 48h, Alv for 24h or their sequential combination (5-Aza for 48h followed by Alv for 24h). Cell viability was determined using CellTiter-Glo and Annexin-V apoptosis assays. MDS recurrent mutations in BM mononuclear cells were assessed using myeloid NGS panel deep sequencing containing 67 genes. The combination of 5-Aza+Alv showed an additive cytotoxic effect on CD34+ MDS cells in CellTiter- Glo cell viability assays (median cell viability = 74%, 73.8% and 55% for 5-Aza, Alv and combination respectively, p Disclosures Schmitt: Affimed GmbH: Research Funding. Jawhar: Celgene: Other: Travel support; Takeda: Honoraria, Other: Travel support; Stemline: Consultancy, Honoraria; Blueprint Medicines: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Foulks: Sumitomo Dainippon Pharma Oncology: Patents & Royalties: WO2021102343A1; Sumitomo Dainippon Pharma Oncology: Patents & Royalties: CA3103995A1; Sumitomo Dainippon Pharma Oncology: Patents & Royalties: US11040038B2. Hofmann: Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Nowak: Celgene: Honoraria; Takeda: Honoraria; Affimed: Research Funding; Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; AbbVie: Other: Investigator on funded clinical trial; Tolero Pharma, Pharmaxis, Apogenix: Research Funding. |
| Databáze: | OpenAIRE |
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