Oncogenic isocitrate dehydrogenase (IDH)1 and IDH2 mutations at three hotspot arginine residues cause an enzymatic gain of function that leads to the production and accumulation of the metabolite 2-hydroxyglutarate (2HG), which contributes to the development of a number of malignancies. In the hematopoietic system, mutations in IDH1 at arginine (R) 132 and in IDH2 at R140 and R172 are commonly observed in acute myeloid leukemia, and elevated 2HG is observed in cells and serum. However, in angioimmunoblastic T-cell lymphoma (AITL), mutations are almost exclusively restricted to IDH2 R172, and levels of 2HG have not been comprehensively measured. In this study, we investigate the expression pattern of mutant IDH2 in the AITL tumor microenvironment and measure levels of 2HG in tissue and serum of AITL patients. We find that mutant IDH2 expression is restricted to the malignant T-cell component of AITL, and that 2HG is elevated in tumor tissue and serum of patients. We also investigate the differences between the three hotspot mutation sites in IDH1 and IDH2 using conditional knock-in mouse models. These studies show that in the lymphoid system, mutations in IDH2 at R172 produce high levels of 2HG compared with mutations at the other two sites and that lymphoid development is impaired in these animals. These data provide evidence that IDH2 R172 mutations may be the only variants present in AITL because of their capacity to produce significant amounts of the oncometabolite 2HG in the cell of origin of this disease.isocitrate dehydrogenase | AITL | lymphoma | 2-hydroxyglutarate | T cell

Background: Cancer metabolism represents an emerging field of novel cancer target discovery. Somatic point mutations in the metabolic enzymes isocitrate dehydrogenase 1/2 (IDH1/2) confer a novel gain-of-function in cancer cells, which results in the accumulation and secretion of the onco-metabolite, R-2-hydroxyglutarate (2-HG). High levels of 2-HG have been shown to inhibit α᠄KG dependent dioxygenases including histone and DNA demethylases, which regulate the epigenetic state of cells and result in altered cellular differentiation. IDH2 mutations have been identified in a spectrum of solid tumors and hematologic malignancies including chondrosarcoma, glioblastoma, acute myeloid leukemia (AML), and myelodyplastic syndromes (MDS). AG-221 is the first IDH mutant inhibitor in clinical trials; it is an oral, potent, reversible, and selective inhibitor of the mutated IDH2 protein. In a primary human AML xenograft model, AG-221 treatment reduced 2-HG levels and demonstrated a dose dependent survival benefit. Early results of the ongoing first in human phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies are reported here. Study Methods: This phase I study of oral AG-221 is designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD) including assessment of 2-HG levels, and clinical activity in patients with advanced hematologic malignancies. AG-221 is administered orally 2 times per day (BID) in continuous 28-day cycles. Sequential cohorts of up to 5 PK-evaluable patients are enrolled at higher dose levels, followed by multiple planned expansion cohorts. The eligible patient population includes those with relapsed or refractory AML, myelodysplastic syndromes (MDS,) and elderly untreated AML that harbor an IDH2 mutation. Blood and bone marrow is collected at multiple time points for determination of the PK and PD effects of AG-221. Response assessments via bone marrow examination are performed on Days 15, 29, 57, and every 56 days (2 cycles) thereafter. Study Status and Results: The study was activated in September 2013. As of February 26th 2014, a total of 19 patients have been enrolled; 18 with AML and 1 with MDS. All patients were IDH2-mutant positive by local testing. AG-221 doses administered included 30 mg BID (n=7), 50 mg BID (n=5), 75 mg BID (n=5), and 100 mg QD (n=2). Two patients were added to the 30 mg BID cohort to replace PK-unevaluable patients. Fourteen of 19 patients remain on study drug treatment. Therapy has been well tolerated; with no dose-limiting toxicities reported. The maximum tolerated dose has not been reached. Possible drug-related severe adverse events were reported in two patients: grade 2 hyperleukocytosis and grade 3 confusion. In the first cohort there were three deaths due to sepsis within 30 days of study drug termination. One of these was attributed as possibly related to study drug treatment. Preliminary analysis of PK at 30 and 50 mg doses demonstrated excellent oral AG-221 exposure and a mean plasma half-life of greater than 40 hours. Evaluation of the PD response demonstrated sustained reduction in 2-HG plasma levels of up to 97% following AG-221 dosing in cohort 1 and 2. Ten AML patients are evaluable for efficacy at this time: (N=5 at 30 mg BID, N=5 at 50 mg BID), 5 men and 5 women, with a median age (range) of 62.5 years (53-74). Eight patients had an R140Q mutation and two had a R172K mutation. The median number of prior regimens was 2 (1-4) including one patient who had relapsed after an allogeneic bone marrow transplant. Currently, 6 of 10 patients have had objective responses, including 2 complete remissions defined by the International Working Group Criteria (1 at 30mg BID and 1 at 50mg BID). The four other responses are ongoing and will be updated. Marked differentiation of myeloblasts into mature forms, consistent with preclinical models, was associated with responses. Only one patient experienced disease progression. One patient with a CR was removed from study to undergo allogeneic BMT. Five of the 6 responding patients remain on AG-221. Dose escalation continues along with exploration of a once daily dosing regimen. Expansion cohorts are being planned. Conclusions: AG-221, a novel, oral, potent IDH2 mutant inhibitor is well tolerated and shows promising initial clinical and pharmacodynamic activity in patients with relapsed and refractory IDH2 mutant hematologic malignancies, even in the lowest dose cohort. These data provide early validation of mutant IDH2 as a therapeutic target in hematologic malignancies. Additional safety and efficacy data from the ongoing study will be presented. Clinical Trial Information: NCT01915498 Citation Format: Eytan Stein, Martin Tallman, Daniel A. Pollyea, Ian W. Flinn, Amir T. Fathi, Richard M. Stone, Ross L. Levine, Samuel Agresta, David Schenkein, Hua Yang, Bin Fan, Kate Yen, Stephane De Botton. Clinical safety and activity in a phase I trial of AG-221, a first in class, potent inhibitor of the IDH2-mutant protein, in patients with IDH2 mutant positive advanced hematologic malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT103. doi:10.1158/1538-7445.AM2014-CT103

Background: There is an unmet need fortreatments (Tx) for myeloid malignancies, particularly relapsed/refractory (RR) AML, that provide durable remissions without worsening existing cytopenias that place patients (pts) at risk for serious infections or bleeding. Oral AG-221 is a selective, potent inhibitor of the mutant isocitrate dehydrogenase 2 (mIDH2) enzyme associated with hematologic malignancies. A phase 1/2 dose-escalation and expansion study of AG-221 [NCT01915498] is ongoing in pts with advanced hematologic malignancies. Reported here are AG-221 safety and efficacy results with a focus on pts with RR-AML, and the first AG-221 data to show changes in absolute neutrophil count (ANC) in early Tx and associated adverse events (AEs), response by mIDH2 type (R140Q or R172K), and mIDH2 variant allele frequency (VAF) on Tx over time. Objectives: Assess AG-221 safety and efficacy in pts with advanced myeloid malignancies; and in responding RR-AML pts, evaluate response by mIDH2 mutation type, associations between ANC improvement and AEs, and mIDH2 VAF over time. Methods: Pts ≥18 years with mIDH2-positive myeloid malignancies are eligible. AG-221 is administered QD or BID in continuous 28-day cycles. Dosing began at 50 mg QD or 30 mg BID and increased in subsequent cohorts. Response is measured from peripheral blood (PB) and bone marrow (BM) samples on days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Evaluable pts had a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Stable disease (SD) is failure to achieve at least partial remission (PR) but no progressive disease (PD). ANC improvement in this analysis is defined as ≥1.0x109/L increase from baseline (BL). Next-generation sequencing was used to assess mIDH2 VAF longitudinally in a subset of responders, using the FoundationOne Heme test on purified mononuclear cells from BM or PB. Results: At data cut-off (1 July 2015), 198 pts had received AG-221 and 83 (42%) remained on Tx. Median age was 69 yrs (19-100). 70% of pts had an R140Q and 25% had an R172K mutation (5% unknown). Most pts had RR-AML (n=138, 70% [untreated AML 17%, MDS 7%, other 6%]). Among RR-AML pts, 88 (64%) had received ≥2 prior Tx regimens (2 n=46, 3 n=24, ≥4 n=18), including intensive therapy, HMAs, or BM transplant. Median Tx durations overall and for RR-AML pts were 4.5 (95%CI 3.6-5.9) and 5.2 (3.6-6.1) months (mos), respectively. The highest daily AG-221 dose was 450 mg; maximum tolerated dose has not been reached. The most common Tx-related AEs were indirect hyperbilirubinemia (19%) and nausea (18%). Serious AEs (SAEs) were mainly disease-related; 35 pts (18%) had Tx-related SAEs, notably, leukocytosis (n=7). In all, 181 pts (91%), including 128 RR-AML pts, were efficacy evaluable. Objective responses were seen in 74 pts (41%), including 52 RR-AML pts (41%) (Table). Median response durations overall and in RR-AML pts were 6.9 (95%CI 3.7-9.2) and 6.0 (3.7-9.2) mos, respectively. Response rates were consistent in RR-AML pts, regardless of number of prior Tx regimens or mIDH2 type (R140Q 36%, R172K 39%). Eight pts went to transplant, including 5 RR-AML pts (Fig 1). Improvement from BL ANC (median 0.4 x109/L [0-15.5]) occurred in 72 RR-AML pts (56%), including 43 responders, and 23pts (40%) with SD. Among RR-AML responders, ANC increases occurred in cycle 1 (median 0.6 mos; 0.1-9.3), were durable through cycle 6 (Fig 2), and were associated with lower rates of infections and febrile neutropenia at cycles 1, 3, and 6 vs pts without ANC improvement. mIDH2 VAF did not decrease on-Tx in RR-AML pts who achieved a CR, CRp, or PR (Fig 3). Conclusions: AG-221 was well-tolerated and induced responses in pts with advanced myeloid malignancies, including heavily pretreated RR-AML. Response rates in RR-AML were consistent regardless of number of prior Tx regimens or mIDH2 type. mIDH2 VAF did not change from BL in responding pts; however, rapid ANC improvements suggest that despite the persisting mutant clone, differentiation into mature myeloid cells (eg, neutrophils) occurred. These data give insight into the putative mechanism of AG-221 as a differentiation agent associated with early ANC improvement and clinical benefits. Table. All(N=181) RR-AML(N=128) n (%) Overall Response (CR, PR, CRp, CRi, mCR) 74 (41) 52 (41) CR 30 (17) 23 (18) CRp 3 (2) 1 (1) CRi 1 (1) 1 (1) mCR 15 (8) 8 (6) PR 25 (14) 19 (15) SD 81 (45) 57 (45) PD 9 (5) 7 (6) Not evaluable 17 (9) 12 (9) Disclosures Stein: Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy. DiNardo:Novartis: Research Funding. Altman:BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Seattle Genetics: Consultancy; Ariad: Consultancy; Novartis: Consultancy. DeAngelo:Incyte: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Agios: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Celgene: Consultancy. Kantarjian:ARAID: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation. Flinn:Celgene Corporation: Research Funding. Frankel:Stemline: Consultancy, Patents & Royalties, Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Medeiros:Agios Pharmaceuticals: Honoraria; Celgene: Honoraria, Research Funding. Pollyea:Ariad: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Other: Member of data safety monitoring board. Stone:Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Celator: Consultancy; Celgene: Consultancy; Juno: Consultancy; AROG: Consultancy; Merck: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Karyopharm: Consultancy. Yen:Agios Pharmaceuticals: Employment, Equity Ownership. Attar:Agios Pharmaceuticals: Employment, Equity Ownership. Xu:Celgene Corporation: Employment, Equity Ownership. Tosolini:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership. De Botton:Agios Pharmaceuticals: Research Funding.

No abstract

No abstract