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Olutasidenib (FT-2102), an IDH1m Inhibitor As a Single Agent or in Combination with Azacitidine, Induces Deep Clinical Responses with Mutation Clearance in Patients with Acute Myeloid Leukemia Treated in a Phase 1 Dose Escalation and Expansion Study
Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients (pts) and approximately 3-4% of MDS pts. Olutasidenib is a highly potent, selective small molecule inhibitor of IDH1m with the therapeutic potential to restore normal cellular differentiation. Azacitidine (AZA) has shown synergistic effects with IDHm inhibitors on releasing differentiation block in IDHm leukemia models in vitro. Methods: The Phase 1 study (NCT02719574) assessed the safety, PK/PD, and clinical activity of olutasidenib in patients with IDH1m AML or MDS. Eligibility criteria included: IDH1m AML or MDS [relapsed/refractory (R/R) or treatment naïve (TN) pts not eligible for or refusing standard therapy], adequate liver and renal function. There were no restrictions for concomitant non-anticancer medications. IDH1m variant allele frequency (VAF) and co-mutations were measured at baseline and during treatment. Available safety data are presented for all pts (AML/MDS); efficacy data are presented for AML pts only. Results: As of April 12, 2019, 32 pts had been treated with single agent (SA) olutasidenib and 46 pts with olutasidenib in combination (COMBO) with AZA; median time on treatment was 4.2 mo for SA (range: 10% of pts, including thrombocytopenia (28% vs 33%), febrile neutropenia (22% vs 28%), anemia (22% vs 20%), pneumonia (16% vs 11%), and leukocytosis (13% vs 15%); COMBO-treated pts had more Gr 3/4 neutropenia (6% vs 28%), fatigue (6% vs 15%), and nausea (0% vs 9%). No QTcF prolongation was reported in SA while 3 (7%) pts treated with COMBO reported prolonged QTcF (1 Gr 3). Ten (13%) pts had differentiation syndrome (4 SA; 6 COMBO), which resolved with temporary interruption of olutasidenib and treatment with dexamethasone, hydroxyurea, and/or supportive care. None led to treatment discontinuation. Nineteen (24%) pts died on treatment or within 28 days of the last dose, no deaths were considered treatment-related. For AML pts, clinical responses occurred in 39% SA and 54% COMBO (CR 15% and 23%, respectively; Table 1). CRs were durable (up to >27 mo); disease control (SD >13 mo) was observed in pts without an IWG-defined response. Of the 59 AML pts (23 SA; 36 COMBO) who were transfusion-dependent at baseline, 26 (11 [48%] SA; 15 [42%] COMBO) and 21 (9 [39%] SA; 12 [33%] COMBO) became transfusion-independent (seen in all response categories) during 28 and 56 days on treatment, respectively. For R/R AML pts, median survival was 8.7 mo for SA and 12.1 mo for COMBO; for TN AML pts, median survival was 8.8 mo for SA (n=4) and not reached for COMBO. For R/R and TN AML patients with available pre- and on-treatment samples, IDH1m clearance or significant reduction (VAF <1%) was observed in 10/25 pts (40%) achieving an objective response and in 3/6 pts (50%) with stable disease. Mutation and 2-HG analyses suggest that pts who progressed on olutasidenib had a non-IDH1m-driven mechanism; updated analyses will be presented. Conclusions: SA and COMBO olutasidenib has shown favorable safety and clinical activity in IDH1m R/R AML with a SA ORR of 41% (95% CI: 21, 64) and a COMBO ORR of 46% (27, 67), and durable disease control. Olutasidenib induces deep responses with IDH1 mutation clearance in a subset of treated pts. Phase 2 investigations of SA and COMBO olutasidenib at the RP2D are ongoing in multiple IDH1m AML populations. Additional combinations are also being explored. Disclosures Watts: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Baer:Forma: Research Funding; Kite: Research Funding; Astellas: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Abbvie: Research Funding; Al Therapeutics: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Prebet:pfizer: Honoraria; novartis: Honoraria; pfizer: Honoraria; Boehringer Ingelheim: Research Funding; novartis: Honoraria. Lee:Helsinn: Consultancy; Jazz Pharmaceuticals, Inc: Consultancy; Roche Molecular Systems: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Karyopharm Therapeutics: Consultancy; Ai Therapeutics: Research Funding. Schiller:Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Astellas: Research Funding; Agios: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding; Amgen: Other, Research Funding. Dinner:Agios: Consultancy; Pfizer: Consultancy; AstraZeneca: Consultancy. Pigneux:Roche: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria; Daichi: Honoraria; Astellas: Honoraria; Novartis: Honoraria. Montesinos:Abbvie: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Other: Research support, Research Funding, Speakers Bureau. Wang:Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Agios: Other: Advisory role. Seiter:Novartis, Incyte, Celgene, Astellas, Sanofi: Speakers Bureau; Novartis, Astellas,: Consultancy; Novartis, Forma, Sun Pharma, Celgene, Jazz, Roche: Research Funding. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. De Botton:Agios: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Pierre Fabre: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Janssen: Consultancy; FORMA: Consultancy, Research Funding; Syros: Consultancy; Bayer: Consultancy; Abbvie: Consultancy; Daiichi: Consultancy; Astellas: Consultancy. Jonas:AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses; AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ferrell:Astex Pharmaceuticals: Re
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Effects of the Therapeutic Armamentarium on Survival and Time to Next Treatment in CMML Subtypes: An International Analysis of 950 Cases Coordinated By the AGMT Study Group
Background Chronic myelomonocytic leukemia (CMML) is an ultrarare stem cell disorder defined by the presence of monocytosis (≥1.0 G/l, ≥10%). Depending on white blood cell (WBC) count, CMML can be divided into a myelodysplastic (MD) (WBC ≤13 G/l) and a myeloproliferative (MP) variant (WBC >13 G/l). Although hypomethylating agents (HMA) have been shown to prolong overall survival (OS) in MDS patients (pts) in prospective, randomized phase III trials, only 6-14 MD-CMML pts were included, and MP-CMML pts were excluded [Silverman 2002; Kantarjian 2006; Fenaux 2009]. EMA approval of azacitidine (AZA) in CMML is thus based on limited experience and restricted to MD-CMML with 10-29% bone marrow blasts (BMB), whereas decitabine (DAC) is not approved for treatment (trt) of CMML in the EU. Smaller analyses and single-arm trials of HMA in CMML exist [Wijermans 2008; Ades 2013; Pleyer 2014; Zeidan 2017; Duchmann 2018; Santini 2018; Coston 2019; Diamantopoulos 2019], but it is still unclear whether HMA provide a benefit in CMML (subgroups) compared with other trts.
Aim Evaluate the impact of HMA and hydroxyurea (HU) trt on OS and time to next trt (TTNT).
Methods Data were collected from 7 European study groups and 2 US MDS Centers of Excellence; database lock 27.05.19; Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.3.
Of 1657 CMML pts, only those who received trt (n=950), with documented WBC and BMB at 1st line, were included in these analyses (n=845, cohort 1). Pts were stratified according to the EMA approved AZA indication, and inclusion/exclusion criteria of the GFM-DAC-CMML trial assessing DAC +/- HU vs HU (NCT02214407) (diagnosis of CMML, no prior trt [except supportive care, erythropoietin or ≤6 weeks HU], WBC ≥13 G/l and ≥2 of the following: BMB ≥5%, clonal cytogenetic abnormality [other than -Y], hemoglobin 16 G/l, platelet count 2 excluded) (n=486; cohort 2).
Results In cohort 1, pts receiving HMA 1st line (n=375) had longer OS (19.8 vs 16.3 months [mo], P=0.0102) and TTNT (13.2 vs 6.7 mo, P=0.0001) than pts treated with non-HMA 1st line (n=470). Survival benefit was longer when comparing pts who received HMA (any time) (AZA [n=442], DAC [n=37], both [n=27]) with those that never received HMA (never HMA; n=339) (23.0 vs 13.0 mo, P<0.0001). Median OS was longer for MD-CMML (n=294) vs MP-CMML pts (n=551) (25.5 vs 15.0 mo, P<0.0001). OS was shorter for all pts with 1st line HU preceding any 2nd line trt (9.4 vs 19.6 mo; P<0.0001; Fig A), for MP-CMML pts separately (8.7 vs 15.6 mo, P=0.0001), and for the subset with HU preceding 2nd line HMA (11.6 vs 19.8 mo; P=0.0016; Fig B).
The following were significantly less common in pts treated with HMA vs those that were not: diagnosis in the pre-HMA era (8 vs 43%), MP-CMML (48 vs 66%), splenomegaly (27 vs 36%), ECOG≥2 (12 vs 24%), 1 trt line (43 vs 74%). WHO subtype, karyotype, transfusion dependence, LDH, CPSS score, AML transformation and therapy-related CMML were comparable between cohorts.
HMA are not approved in the EU for CMML pts with <10% BMB. In this subgroup (n=588), median OS was longer for MD-CMML vs MP-CMML (28.1 vs 17.0 mo, P<0.0001) and for pts who received HMA vs never HMA (26.5 vs 14.8 mo, P=0.0003). Pts with <10% BMB and MD-CMML (n=206) did not seem to benefit from HMA vs non-HMA trt (median OS 28.4 vs 25.3 mo, P=0.9908; Fig C), whereas the MP-CMML subgroup (n=382) did (24.4 vs 13.0 mo, P<0.0001; Fig D).
HMA are also unapproved in the EU for MP-CMML pts with ≥10% BMB. In pts with ≥10% BMB (n=257), median OS was longer for MD-CMML vs MP-CMML (19.4 vs 11.2 mo, P=0.0023) and for pts who received HMA vs never HMA (18.3 vs 7.0 mo, P<0.0001). Both MD-CMML (OS 21.7 vs 10.9 mo, p=0.0134; Fig E) and MP-CMML pts (15.6 vs 6.3 mo, P<0.0001; Fig F) benefited from HMA trt vs never HMA.
In cohort 2, 1st line trts were HU (n=214), HMA (n=187) and others (n=85). Comparing HMA vs HU 1st line, median OS was 15.6 vs 14.5 mo (P=0.0307) and median TTNT was 8.8 vs 6.5 mo (P=0.0452; Fig G). OS and TTNT were comparable for HU vs other trts (Fig G). Similar observations were made in the larger cohort 1 (Fig H).
Conclusions HMA show promising results with survival benefits of +11.4, +10.8 and +9.3 mo in pts with MP-CMML <10%, and MD- or MP-CMML ≥10% BMB. In MP-CMML pts fulfilling GFM-DAC-CMML trial inclusion criteria, survival and TTNT were longest in pts receiving HMA 1st line as compared to HU or other trts. Preceding HU portends poor prognosis (-10.2 mo).
Disclosures
Pleyer: Abbvie: Other: Advisory board; Novartis: Other: Advisory board; Inflection Point Biomedical Advisors: Other: Advisory board; Celgene: Other: Advisory board; Agios: Other: Advisory board. Leisch:Novartis: Honoraria, Other: Travel support; Bristol-Myers-Squibb: Honoraria; Celgene: Other: Travel support. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Kaivers:Jazz Pharmaceuticals: Other: Travel Support. Heibl:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Roche: Honoraria; Daiichi Sankyo: Honoraria; Mundipharma: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler:Novartis: Honoraria; Roche: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; AOP: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Ratiopharm: Honoraria. Valent:Blueprint: Research Funding; Pfizer: Honoraria; Deciphera: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Medina de Almeida:Novartis: Speakers Bureau; Celgene: Speakers Bureau. Jerez:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sanz:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman - La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen - Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Membership on an entity's Board of Directors or advisory committees, Research Funding. Greil:Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Janssen-Cilag: Honoraria; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Eisai: Honoraria; Genentech: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding.
OffLabel Disclosure:
Azacitidine is not approved for the treatment of MP-CMML or CMML with <10% BM blasts, decitabine is not approved for treatment of CMML in the EU, hydroxyurea is not approved for the treatment of CMML in the EU