Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 29 ( 2021-10-10), p. 3261-3272

Abstract: Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy. PATIENTS AND METHODS One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital. RESULTS Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed. CONCLUSION Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.20.01739

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2021

detail.hit.zdb_id: 2005181-5

In: New England Journal of Medicine, Massachusetts Medical Society, Vol. 378, No. 25 ( 2018-06-21), p. 2386-2398

Type of Medium: Online Resource

ISSN: 0028-4793 , 1533-4406

URL: Article

DOI: 10.1056/NEJMoa1716984

Language: English

Publisher: Massachusetts Medical Society

Publication Date: 2018

detail.hit.zdb_id: 1468837-2

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 561-561

Abstract: BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations are seen in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for mIDH1 AML. Ivosidenib suppresses production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To determine the safety and efficacy of single-agent ivosidenib in patients with untreated AML enrolled in the first-in-human, phase 1, dose escalation and expansion study of patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Enrollment completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. MTD was not reached; 500 mg QD was selected as the dose for expansion cohorts. Overall response rate (ORR) was defined as complete remission (CR) + CR with incomplete hematologic or platelet recovery + partial response + morphologic leukemia-free state. CR with partial hematologic recovery (CRh) was defined as CR except absolute neutrophil count 〉 0.5 × 109/L [500/µL] and platelet count 〉 50 × 109/L [50,000/µL]). Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present data for all patients with untreated AML whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 34 patients with untreated AML (9 from dose escalation, 25 from expansion) who received ivosidenib 500 mg QD. Baseline characteristics for these 34 patients were: 19 male/15 female with median age 76.5 years (range 64-87); 56% were ≥75 years of age; 79% had secondary AML and 53% had prior MDS; 41% had ≥1 hypomethylating agent for antecedent hematologic disorder. As of 10Nov2017, 9 of 34 (26.5%) patients remained on treatment. Three (8.8%) patients discontinued treatment for allogeneic stem cell transplantation. Median duration of exposure to ivosidenib was 4.3 months (range 0.3-29.1). Treatment was well tolerated; the most common adverse events (AEs) (n=34) of any grade, irrespective of causality, occurring in ≥20% of patients were diarrhea (50.0%), fatigue (44.1%), nausea (38.2%), decreased appetite (32.4%), leukocytosis (26.5%), anemia (26.5%), peripheral edema (26.5%), dyspnea (23.5%), thrombocytopenia (23.5%), hypomagnesemia (23.5%), constipation (20.6%), dizziness (20.6%), and insomnia (20.6%). The majority of AEs were grade 1-2 and reported as unrelated to treatment. IDH differentiation syndrome (IDH-DS) was seen in 6 of 34 (17.6%) patients, and was grade ≥3 in 3 (8.8%); ivosidenib was held due to IDH-DS in 3 patients (8.8%), but IDH-DS did not lead to permanent treatment discontinuation or death. CR rate was 26.5% (95% CI 12.9%, 44.4%), CR+CRh rate was 41.2% (95% CI 24.6%, 59.3%), and ORR 58.8% (95% CI 40.7%, 75.4%; 20/34 patients). Median durations of CR, CR+CRh, and overall response were not estimable (lower bound of 95% CI 4.2, 6.5, and 4.2 months, respectively); 12-month durations of response were 75.0%, 56.4%, and 54.3%, respectively. Of patients who were transfusion dependent at baseline, 38.1% became transfusion independent for ≥56 consecutive days on treatment. Longitudinal mIDH1 VAF data were available for 23 patients with untreated AML in expansion: IDH1 mutation clearance was seen in 6 of 11 patients who achieved CR+CRh, including 3 of 7 patients with CR and 3 of 4 with CRh. The relationship between baseline co-occurring mutations and response will be presented. CONCLUSION: Ivosidenib monotherapy was well tolerated in patients with untreated mIDH1 AML, and induced durable remissions and transfusion independence in a molecularly defined, poor prognosis, elderly patient population with high rates of secondary AML, and prior hypomethylating agent exposure. These results support the role of ivosidenib as an effective, oral, targeted treatment for patients with untreated mIDH1 AML who are not eligible for intensive chemotherapy. Disclosures Roboz: Argenx: Consultancy; Orsenix: Consultancy; Jazz Pharmaceuticals: Consultancy; Cellectis: Research Funding; Sandoz: Consultancy; Aphivena Therapeutics: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Celgene Corporation: Consultancy; Bayer: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Orsenix: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Celltrion: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Eisai: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Cellectis: Research Funding; Janssen Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Eisai: Consultancy; Argenx: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; Aphivena Therapeutics: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Stein:Agios: Consultancy; Bayer: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Mims:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Altman:Pfizer: Other: payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Ariad: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Incyte: Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; FujiFilm: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celator: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work. Arellano:Cephalon: Research Funding. Mannis:Agios: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; NKarta: Membership on an entity's Board of Directors or advisory committees. Pollyea:Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Kantarjian:Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria, Research Funding. Tallman:AbbVie: Research Funding; BioSight: Other: Advisory board; AROG: Research Funding; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; Cellerant: Research Funding. Choe:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership. Stone:Merck: Consultancy; Cornerstone: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Ono: Consultancy; Fujifilm: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Jazz: Consultancy; Astellas: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Arog: Consultancy, Research Funding; Sumitomo: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Agios: Consultancy, Research Funding; Pfizer: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-110595

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 19 ( 2019-09), p. S220-

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2019.07.094

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 823-823

Abstract: Background: Inotuzumab ozogamicin (INO) and blinatumomab both improve survival in relapsed or refractory acute lymphoblastic leukemia (ALL) compared to conventional chemotherapy. The combination of INO with reduced-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL is safe and highly effective (Kantarjian H et al, Lancet Oncol 2018;19(2):240-8). The addition of blinatumomab to this regimen may further improve outcomes. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. In order to decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). Results: 64 pts have been treated, 5 of whom were in complete remission (CR) at enrollment. Pt characteristics are summarized in Table 1. Median age was 68 years (range, 60-81 years); 27 pts (42%) were ≥70 years. 28% were positive for TP53 mutation, 19% were CRLF2 positive, and 27% had adverse-risk karyotype. 33/58 pts (57%) were CD20+ and received rituximab. Among 59 pts evaluable for morphologic response, 58 (98%) responded (CR, n=51; CRp, n=6; CRi, n=1). MRD negativity by 6-color flow cytometry was achieved in 48/62 pts (77%) after 1 cycle and 59/63 pts (94%) overall. There were no early deaths, and the 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 63 pts who achieved remission, 9 (14%) relapsed, 3 (5%) underwent allogeneic SCT in first remission, 30 (48%) remain on treatment or have completed maintenance, and 21 (33%) died in CR/CRp. The rate of death in CR/CRp was higher in pts ≥70 years of age vs. 60-69 years (50% vs. 22%; P=0.02). Causes of death for pts in CR/CRp included: sepsis (n=7; all in pts 70 years and older), VOD (n=3), gunshot wound (n=1), dementia and deconditioning (n=1), end stage renal disease (n=1), MDS/AML (n=4; 3 in pts 70 years and older) and unknown causes (n=4). 6 pts (9%) developed VOD, 1 after subsequent allogeneic SCT. The rate of VOD was 6/64 (9%) with no difference in VOD in pts who did or did not receive blinatumomab. With a median follow-up of 37 months (range, 2-85 months), 34 pts (53%) were alive, 30 of whom (47%) were in CR and MRD negative status. The 3-year continuous remission and OS rates were 76% and 54%, respectively (Figure 1A). The 3-year continuous remission rate was 69% and 87% for pts age 60-69 and ≥70 years, respectively (P=0.25), and the 3-year OS rate was 63% and 42%, respectively (P=0.13; Figure 1B). The trend for worse survival in the pts ≥70 years was driven predominantly by the increased rate of death in CR/CRp in this older group. The outcomes of pts who did or did not receive blinatumomab were similar. Compared to a similar historical cohort of older pts treated with hyper-CVAD ± rituximab (n=77), mini-hyper-CVD + INO ± blinatumomab resulted in significantly higher 3-year OS (54% vs 32%; P=0.007). Conclusion: Reduced-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, is safe and effective in older adults with newly diagnosed Ph-negative ALL, with an overall response rate of 98% and 3-year OS rate of 54%. Further optimization of this regimen with less chemotherapy in patients 70 years and older is warranted to further decrease the rate of death in remission. Disclosures Short: Takeda Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; Ariad: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jain:Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Daver:Otsuka: Consultancy; Astellas: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Forty-Seven: Consultancy; Agios: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Servier: Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding. Pemmaraju:sagerstrong: Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; Daiichi-Sankyo: Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding. Khoury:Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Konopleva:Ablynx: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Agios: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Borthakur:Merck: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Oncoceutics, Inc.: Research Funding; AbbVie: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; NKarta: Consultancy; Bayer Healthcare AG: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding; Strategia Therapeutics: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Consultancy; Arvinas: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Wierda:Genentech: Research Funding; Juno Therapeutics: Research Funding; KITE pharma: Research Funding; Sunesis: Research Funding; Miragen: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Cyclcel: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; AbbVie: Research Funding; Gilead Sciences: Research Funding. DiNardo:syros: Honoraria; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria. O'Brien:Astellas: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; Kite: Research Funding; Aptose Biosciences, Inc: Consultancy; Acerta: Research Funding; Verastem: Consultancy; GlaxoSmithKline: Consultancy; Eisai: Consultancy; Vaniam Group LLC: Consultancy; TG Therapeutics: Consultancy, Research Funding; Regeneron: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy. Jabbour:AbbVie: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. OffLabel Disclosure: The use of inotuzumab ozogamicin and blinatumomab as frontline therapy for older patients with ALL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125136

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 9-11

Abstract: Background: For patients (pts) with Philadelphia chromosome (Ph)-negative B-cell acute lymphoblastic leukemia (ALL), combination chemotherapy achieves complete remission rates of 80-90%; however, many pts ultimately relapse, leading to a cure rate of only 40-50%. Blinatumomab is highly effective in both the relapsed/refractory setting and for eradication of measurable residual disease (MRD). We hypothesized that early incorporation of blinatumomab in pts with newly diagnosed Ph-negative B-cell ALL would decrease the need for intensive chemotherapy, lead to deeper and more durable responses, and improve survival. Methods: Pts 14-59 years of age with newly diagnosed Ph-negative pre-B-cell ALL, including pts who had received no more than 1 prior cycle of chemotherapy, were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤2 mg/dl and creatinine ≤2 mg/dl. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for up to 4 cycles, followed by 4 cycles of blinatumomab at standard doses. Pts with CD20+ disease (≥1% cells) received 8 doses of ofatumumab (2000 mg) or rituximab (375 mg/m2). Eight administrations of prophylactic IT chemotherapy were given in the first 4 cycles. Maintenance was with alternating blocks of POMP (given in maintenance cycles 1-3, 5-7, 9-11, and 13-15) and blinatumomab (given in maintenance cycles 4, 8, and 12). After 2 pts with high-risk features experienced early relapse prior to blinatumomab administration, for pts #10+ the protocol was amended so that pts with high-risk disease features (e.g. CRLF2+ by flow cytometry, complex karyotype, KMT2A rearranged, low-hypodiploidy/near triploidy, TP53 mutation, or persistent MRD) started blinatumomab after 2 cycles of hyper-CVAD. Results: 39 pts have been treated, 34 of whom are evaluable for efficacy (5 too early for assessment). 6 pts were in complete remission (CR) at enrollment and unevaluable for morphologic response. Pt characteristics of the 34 evaluable pts are summarized in Table 1. Median age was 36 years (range, 17-59 years). At least one high-risk feature was present in 19 pts (56%), including TP53 mutation in 27%, CRLF2+ in 20%, and an adverse-risk karyotype in 26%. 82% of pts received ofatumumab or rituximab. Among 28 pts with active disease at study entry, 100% achieved CR, with 82% achieving CR after the first cycle. MRD negativity by 6-color flow cytometry was achieved in 20/23 responding pts (87%) after 1 cycle and 33/34 pts (97%) overall. There were no early deaths, and the 60-day mortality rate was 0%. With a median follow-up of 22 months (range, 1-40 months), the 2-year continuous remission and OS rates were 79% and 86%, respectively (Figure 1). Overall, 5 pts (15%) relapsed, 12 (35%) underwent allogeneic SCT in first remission (including 1 additional pt who relapsed post-SCT), and 17 (50%) remain in continuous remission and are currently on treatment or have completed maintenance. All relapses occurred in pts with established poor-risk features, including 2 pts with KMT2A rearrangement, 2 pts with TP53 mutation (1 of whom was low hypodiploid), and 1 pt with baseline WBC count of 32 x 109/L. Two of these relapses occurred during hyper-CVAD cycles before the amendment allowing for earlier integration of blinatumomab for pts with high-risk disease features. Treatment was overall well-tolerated. Four pts developed grade 2-3 cytokine release syndrome (grade 2, n=3; grade 3, n=1) which resolved with corticosteroids and interruption of blinatumomab. Overall, 14 (41%) pts had a neurological AE of any grade due to blinatumomab. Only one pt discontinued blinatumomab due to blinatumomab-related adverse event (grade 2 encephalopathy and dysphasia). Conclusion: Sequential combination of hyper-CVAD and blinatumomab is highly effective as frontline treatment of Ph-negative B-cell ALL, with a CR rate of 100% and 97% of pts achieving MRD negativity. Survival data are promising with an estimated 2-year OS of 86%, which compares favorably to historical controls. This study continues to accrue pts. Disclosures Short: Astellas: Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding. Kantarjian:Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; BMS: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding. Kadia:Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Pulmotec: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; JAZZ: Honoraria, Research Funding; Novartis: Honoraria; Astra Zeneca: Research Funding. Thompson:Pharmacyclics: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; AbbVie: Research Funding. Alvarado:Tolero Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aprea Therapeutics: Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Konopleva:Calithera: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Agios: Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Eli Lilly: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Ablynx: Research Funding. Garcia-Manero:AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; H3 Biomedicine: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Kite, Regeneron, Acerta: Research Funding; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab - frontline therapy for ALL

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-138565

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 725-725

Abstract: BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count & gt;0.5 × 109/L [500/µL] and platelet count & gt;50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.725.725

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 18 ( 2018-09), p. S204-S205

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2018.07.057

Language: English

Publisher: Elsevier BV

Publication Date: 2018

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Clinical Lymphoma Myeloma and Leukemia, Elsevier BV, Vol. 19 ( 2019-09), p. S340-

Type of Medium: Online Resource

ISSN: 2152-2650

URL: Article

DOI: 10.1016/j.clml.2019.07.341

Language: English

Publisher: Elsevier BV

Publication Date: 2019

detail.hit.zdb_id: 2540998-0

detail.hit.zdb_id: 2193618-3

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 1 ( 2021-01-01), p. 57-65

Abstract: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1-mutant (m IDH1) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition–related differentiation and apoptosis. PATIENTS AND METHODS This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m 2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922 ). RESULTS Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in 〉 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission. CONCLUSION Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.20.01632

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2021

detail.hit.zdb_id: 2005181-5