IDH1 (AG 120) Inhibitor in Patients With IDH1 Mutated Myelodysplastic Syndrome

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Myelodysplastic syndrome (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenia, especially anemia, and often evolving to Acute myeloblastic Leukemia (AML). Main prognostic factors of MDS, for progression to AML and survival, include ...

Myelodysplastic syndrome (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenia, especially anemia, and often evolving to Acute myeloblastic Leukemia (AML). Main prognostic factors of MDS, for progression to AML and survival, include the number and importance of cytopenias, percent marrow blasts and bone marrow cytogenetic abnormalities. These factors are combined in an International Prognostic Scoring System (IPSS) that distinguishes 4 subgroups with significantly different risk of progression to AML and survival (low, intermediate 1 (int 1), intermediate 2 (int 2), high). Low and int 1 subgroups are often grouped together as "favorable " or low risk MDS, and int 2 and high subgroups are " unfavorable " or high risk MDS. On the other hand, only 50 to 60% of the patients respond to Azacitidine, and most responders relapse within 12 to 15 months resulting in a median survival of only about 6 months in these patients,. As a result there is a need for new therapies in patients who fail to respond to azacitidine or decitabine and for whom there is currently no establish treatment. Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are key metabolic enzymes that convert isocitrate to ?-ketoglutarate. IDH1/2 mutations define distinct subsets of cancers, including low-grade gliomas and secondary glioblastomas, chondrosarcomas, intrahepatic chol- angiocarcinomas, and hematologic malignancies. Somatic point mutations in IDH1/2 confer a gain-of-function in cancer cells, resulting in the accumulation and secretion in vast excess of an oncometabolite, the D-2-hydroxyglutarate (D-2HG). Overproduction of D-2HG interferes with cellular metabolism and epigenetic regulation, contributing to oncogenesis. Indeed, high levels of D-2HG inhibit alpha-ketoglutarate-dependent dioxygenases, including histone and DNA demethylases, leading to histone and DNA hypermethylation and finally a block in cell differentiation. preclinical studies have demonstrated that inhibition of IDH1/2-mutant enzymes decreases intracellular D-2-hydroxyglutarate (D-2HG) levels, reverses epigenetic dysregulation, and releases the differentiation block. AG-120, a selective inhibitor of the IDH1 mutant enzyme Overall, in myeloid malignancies, AG120 have been mainly used in generally heavily pretreated AML, with about 40% of responses in patients with the respective IDH 1 mutation, and a median response duration exceeding 1 year when CR or PR was achieved. Based on these results, we hypothesize that the IDH1 inhibitor (AG 120) may be an effective therapeutic option in patient with IDH1 mutation-positive myelodysplastic syndrome This is an open-label, single-arm multicenter, phase II study The efficacy of AG 120 will be studied in 3 different groups of MDS patients with IDH-1 mutation: Cohort A: Higher risk MDS without response (Complete response (CR), Partial Response (PR) ,stable disease with HI) after at least 6 cycles of azacitidine or relapse after a response Cohort B: Untreated higher risk MDS without life threatening cytopenias (ie Absolute neutrophil count (ANC )< 500/mm3 or any recent infection, platelets below 30,000/mm3 or any bleeding symptom). Azacitidine will be added after 3 cycles of AG 120 in the absence of significant IWG 2006 criteria response Cohort C: Lower risk MDS with anemia resistant to erythropoietic stimulating agents (primary or secondary resistance)

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