ALBERT

Description: Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with myelodysplastic syndrome (MDS) and have been associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 enzyme (mIDH1) and is approved in the US for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in patients ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy, and in adult patients with relapsed or refractory (R/R) AML. The first-in-human, phase 1 dose escalation and expansion study of ivosidenib (NCT02074839) enrolled adults with mIDH1 advanced hematologic malignancies, including R/R MDS, and the study is ongoing. In the initial phase of the study (DiNardo et al. N Engl J Med 2018), the 12 patients with R/R MDS received 500 mg ivosidenib once daily and were characterized as follows: 75% were male, median age was 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies was 1 (range 1-3). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n=4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n=3 each, 25.0%). No AEs led to permanent discontinuation of treatment. Response was assessed according to International Working Group 2006 criteria for MDS. According to investigators, five of 12 patients achieved complete remission (CR) (41.7%; 95% CI 15.2%, 72.3%); median duration of CR was not estimable for these patients (95% CI 2.8 months, not estimable). Nine of 12 patients were transfusion independent for at least 56 days during study treatment. Mutation clearance was observed in one of the 5 CR patients. Here we report the design of a new sub-study of this trial, which is being undertaken to further assess the safety, tolerability, and clinical activity of treatment with ivosidenib in patients with R/R MDS. Methods: This sub-study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Adults with R/R MDS with an IDH1 mutation will be enrolled in the MDS sub-study. These individuals must have R/R disease after treatment with standard agents indicated for MDS. Eligible patients must have a platelet count of ≥20,000/μL, and adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN]; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance 〉40 mL/min). Additional key inclusion criteria are bone marrow blasts 〉5% and/or transfusion dependence. Ivosidenib is to be administered at a dose of 500 mg once daily orally on Days 1 to 28 of 28-day cycles. The addition of the MDS sub-study to this phase 1 clinical study in patients with hematological malignancies will provide additional insights into the use of ivosidenib for the treatment of mIDH1 R/R MDS. Disclosures Foran: Agios: Honoraria, Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria. Watts:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. De Botton:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Syros: Consultancy; Forma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria. Tallman:UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Oluyadi:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Kantarjian:Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Ivosidenib (AG-120) is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and 2) adult patients with relapsed or refractory AML. It is being evaluated in clinical trials for mutant IDH1 advanced hematologic malignancies.

Description: Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion–dependent and 53 (40.2%) platelet transfusion–dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498.

Description: Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with acute myeloid leukemia (AML). Ivosidenib (IVO; AG-120) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) approved for treatment of mIDH1 relapsed/refractory AML, and newly diagnosed (ND) AML ineligible for intensive chemotherapy (IC). Here we report the genetic mutation and multiparameter flow analyses on longitudinal samples collected from pts receiving IVO + azacitidine (AZA) in the phase 1b portion of the ongoing phase 1b/2 study of mIDH1/2 inhibitors + AZA in pts with IC-ineligible ND AML (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on Days 1-7 in 28-day cycles. The secondary efficacy endpoint of complete remission (CR) plus CR with partial hematologic recovery (CR+CRh) rate was sponsor derived, and CRh was defined as CR with absolute neutrophil count 〉0.5 × 109/L and platelets 〉50 × 109/L. Genomic DNA from baseline and longitudinal bone marrow (BMMCs) and peripheral blood mononuclear cells (PBMCs) were used for molecular studies. Co-occurring mutation profiling of 20/23 (14 CR/CRh) pts by targeted next-generation sequencing (NGS) using the ACE Extended Cancer Panel was performed, with 500× average target coverage for the full coding region of 1400 genes (detection limit 2%). mIDH1 variant allele frequency (VAF) for 23/23 (16 CR/CRh) pts was also tested by a highly sensitive BEAMing digital PCR assay (detection limit 0.02-0.04%). Multiparameter flow cytometry was conducted centrally on bone marrow aspirate from 14/23 (12 CR/CRh) pts (detection limit 1%). Fisher's exact test (two-sided) was applied for statistical analysis. Results: As of February 19, 2019, 23 pts received IVO+AZA (11 male; median age 76 years [range 61-88]). Median duration of treatment was 15.1 months (range 0.3-32.2); 10 pts remained on treatment as of the data cutoff. Overall response rate was 78% (18/23 pts): CR 61% (14/23), CR with incomplete hematologic or platelet recovery 9% (2/23), and morphologic leukemia-free state 9% (2/23). CR+CRh rate was 70% (16/23). The top 3 most frequently co-mutated genes at study entry were RUNX1 (7/20 pts, 35%), SRSF2 (7/20, 35%), and DNMT3A (4/20, 20%). Given the small sample size, no gene or pathway identified at baseline was statistically associated with clinical response or resistance. Interestingly, CR/CRh was achieved in ND AML pt populations who typically have a poor prognosis, or did not achieve a CR/CRh response to single-agent IVO therapy: 3/3 pts with poor risk karyotypes (local cytogenetics), 1/2 harboring TP53 mutations, and 3/5 with RTK pathway (KRAS, NRAS, PTPN11) mutations. Longitudinal mutation clearance (MC) of mIDH1 and the most frequent baseline co-mutations in CR/CRh and non-CR/CRh pts are summarized in the Table. IDH1-MC in BMMCs was observed in 13/14 (93%) CR/CRh pts by NGS and in 11/16 (69%) by digital PCR. Utilizing the 2-log more sensitive digital PCR assay specific to mIDH1, there was strong concordance in the mIDH1 VAF observed in BMMCs and PBMCs (Pearson correlation coefficient [r]=0.919) with 12/16 (75%) CR/CRh pts achieving MC in PBMCs, and 11/12 (92%) achieving MC in both BMMCs and PBMCs. These IDH1-MC rates are higher than those previously observed in IC-ineligible ND AML pts treated with single agent IVO (Roboz et al. ASCO 2019; NCT02074839). Similarly, in CR/CRh pts with available baseline co-mutation data by NGS, all mutations were cleared in 11/14 (79%) pts, apart from mutations in the "DTA" (DNMT3A/TET2/ASXL1) genes typically associated with clonal hematopoiesis. In contrast, mutations in the "DTA" genes were cleared in 2/5 (40%) CR/CRh pts. Orthogonal evaluation of the depth of these remissions by flow cytometry found that 10/12 (83%) CR/CRh pts achieved measurable residual disease (MRD) negativity. Conclusion: Combination of IVO+AZA in IC-ineligible ND AML leads to a high rate of clinical response with molecular remissions. The strong association between MC, clinical response, and flow cytometry MRD in this phase 1b study warrants further investigation of single gene mIDH1 VAF as a biomarker for monitoring response in pts with mIDH1 AML treated with IVO+AZA. Furthermore, the high concordance of mIDH1 VAF between BMMCs and PBMCs indicates that peripheral blood could be a surrogate tissue for monitoring mIDH1 VAF in these pts. Disclosures Daigle: Agios: Employment, Equity Ownership. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. DiNardo:jazz: Honoraria; syros: Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. Stein:Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Schuh:Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Agios: Honoraria, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Ariad: Research Funding. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Vyas:Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Forty Seven, Inc.: Research Funding; Abbvie: Speakers Bureau; Astellas: Speakers Bureau. Wu:Agios: Employment, Equity Ownership. OffLabel Disclosure: Ivosidenib is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy; 2) Adult patients with relapsed or refractory AML. It is being investigated in clinical trials in combination with azacitidine in patients with IDH1-mutant newly diagnosed AML.

Description: The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5–20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson’s disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.