An Oral Combination Study of Novel Nucleoside Analogue Sapacitabine and BCL2 Inhibitor Venetoclax to Treat Patients with Relapsed or Refractory AML or MDS
Acute myeloid leukemia (AML) is characterized by clonal proliferation of neoplastic myeloid precursor cells resulting in impaired hematopoiesis. Despite initial responses to intensive induction therapy, relapses are frequent and most patients die in less than 5 years (National Cancer Institute 2015)...
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Veröffentlicht in: | Blood 2019-11, Vol.134 (Supplement_1), p.3926-3926 |
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Sprache: | eng |
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Zusammenfassung: | Acute myeloid leukemia (AML) is characterized by clonal proliferation of neoplastic myeloid precursor cells resulting in impaired hematopoiesis. Despite initial responses to intensive induction therapy, relapses are frequent and most patients die in less than 5 years (National Cancer Institute 2015). Nucleoside analogues represent an important category of anti-leukemic cytotoxic drugs. Cytarabine (Ara-C) is the most active drug against AML; azacitidine and decitabine are active treatments of myelodysplastic syndrome (MDS) and AML. Sapacitabine is a novel, orally bioavailable nucleoside analogue with a unique ability to induce single-strand DNA breaks after incorporation into DNA, leading eventually to production of double-strand DNA breaks and/or G2 cell cycle arrest. In phase 1 and 2 clinical trials, sapacitabine has induced complete remission (CR), CR with incomplete platelet count recovery (CRp), partial remission (PR), and major hematological improvement (HI) in patients with AML and MDS. A subset of these responding patients were previously treated with other nucleoside analogues, suggesting that the anti-leukemic activity of sapacitabine is not limited by resistance to other nucleoside analogues (Kantarjian H et al, JCO, 2010, ASH, 2013).
Two clinical studies have demonstrated the synergistic activity of venetoclax in combination with hypomethylating agents or low-dose ara-C in newly diagnosed AML, leading to its recent approval by the FDA for the front-line treatment of this disease. The synergy between venetoclax and cytotoxic therapy in AML models is mediated by combined targeting of the anti-apoptotic BCL2 and MCL1 mechanisms (Teh T-C et al, Leukemia, 2018). Cytotoxic drugs induce apoptosis through genotoxic damage, TP53 activation and increased expression of pro-apoptotic NOXA and PUMA (Villunger A et al, Science, 2003) - features that have also been demonstrated for sapacitabine (Green S et al. Br J Cancer 2010). Although most cytotoxic agents do not directly affect MCL1 levels, increased levels of the pro-apoptotic NOXA and PUMA proteins can inactivate MCL1 to synergize with venetoclax to induce apoptosis.
The combination of CNDAC (2‘-C-cyano-2‘-deoxy-1-β-D-arabino-pentafuranosylcytosine), the active metabolite of sapacitabine, and BCL2 inhibitor ABT737 was studied in AML cell line MV-411. A synergistic increase in apoptosis induction was observed when CNDAC and ABT737 were combined (Frame S. et al, 14th EHA, 2009, Abs 0761).
The above finding |
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ISSN: | 0006-4971 1528-0020 |
DOI: | 10.1182/blood-2019-131930 |