Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

Autor:	Daver NG; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX., Dail M; Genentech, Inc, South San Francisco, CA., Garcia JS; Dana-Farber Cancer Institute, Boston, MA., Jonas BA; University of California Davis Comprehensive Cancer Center, Sacramento, CA., Yee KWL; Princess Margaret Cancer Centre, Toronto, ON, Canada., Kelly KR; Division of Hematology, University of Southern California, Los Angeles, CA., Vey N; Hematologie Clinique, Institut Paoli-Calmettes, Marseille, France., Assouline S; Jewish General Hospital, Montreal, QC, Canada., Roboz GJ; Weill Cornell Medical College, New York Presbyterian, New York, NY., Paolini S; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia 'Seràgnoli,' Bologna, Italy., Pollyea DA; Division of Hematology, School of Medicine, University of Colorado, Aurora, CO., Tafuri A; Hematology, Department of Clinical and Molecular Medicine, University Hospital Sant'Andrea-Sapienza, Rome, Italy., Brandwein JM; Division of Hematology, University of Alberta, Edmonton, AB, Canada., Pigneux A; Bordeaux Haut-Lévêque University Hospital, Pessac, France., Powell BL; Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC., Fenaux P; Hôpital Saint-Louis, Université Paris Diderot, Paris, France., Olin RL; University of California San Francisco, San Francisco, CA., Visani G; Hematology, Ospedale San Salvatore, Pesaro, Italy., Martinelli G; IRCCS Istituto Romagnolo per lo Studio dei Tumori 'Dino Amadori,' Meldola, Italy., Onishi M; Genentech, Inc, South San Francisco, CA., Wang J; Genentech, Inc, South San Francisco, CA., Huang W; Genentech, Inc, South San Francisco, CA., Green C; Genentech, Inc, South San Francisco, CA., Ott MG; F. Hoffmann-La Roche Ltd, Basel, Switzerland., Hong WJ; Imago BioSciences, South San Francisco, CA., Konopleva MY; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX., Andreeff M; Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Mar 16; Vol. 141 (11), pp. 1265-1276.
DOI:	10.1182/blood.2022016362
Abstrakt:	This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044. (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu