Quizartinib and High-dose Ara-C plus Mitoxantrone in Relapsed/Refractory AML with FLT3-ITD
Abstract Background: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3 -ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at two years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib, is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and an acceptable toxicity profile. Methods: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m² bidaily day one to day three, mitoxantrone 10mg/m² days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR or complete remission with incomplete hematologic recovery (CRi) as primary endpoints. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. Addressing the primary endpoint, CR/ CRi, after salvage therapy, the sample size required is of maximum 80 patients, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 30 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.Ethics and Dissemination: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03989713; EudraCT Number: 2018-002675-17. KEYWORDS (LIMIT: 3-10): Quizartinib, relapse, refractory, acute myeloid leukemia, measurable residual disease. matched threshold crossing approach.
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
ResearchSquare.com - (2023) vom: 18. Sept. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Jaramillo, Sonia [VerfasserIn] |
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| doi: |
10.21203/rs.3.rs-1117424/v1 |
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| 520 | |a Abstract Background: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3 -ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at two years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib, is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and an acceptable toxicity profile. Methods: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m² bidaily day one to day three, mitoxantrone 10mg/m² days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR or complete remission with incomplete hematologic recovery (CRi) as primary endpoints. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. Addressing the primary endpoint, CR/ CRi, after salvage therapy, the sample size required is of maximum 80 patients, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 30 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.Ethics and Dissemination: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03989713; EudraCT Number: 2018-002675-17. KEYWORDS (LIMIT: 3-10): Quizartinib, relapse, refractory, acute myeloid leukemia, measurable residual disease. matched threshold crossing approach | ||
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