A Multicenter, Prospective, Non-Randomized, Phase I-II Trial to Asses the Efficacy and Safety of the Combination or Oral Quizartinib and the FLAG-IDA Chemotherapy Regimen in First Relapsed/Refractory Acute Myeloid Leukemia (R/R AML)
Authors: Zambrano Javier Martinez , Bernal Teresa , Rodriguez-Veiga Rebeca , Perez Simon Jose Antonio , Arnan Montserrat , Vives Susana , Bergüa Burgues Juan Miguel , Martinez Lopez Joaquin , Rubio Vicente , Sanchez-Garcia Joaquin , Serrano Josefina , Fernandez Moreno Ainhoa , Novo Garcia Andres , Marchante Cepillo Inmaculada , Herrera Puente Pilar , Rodriguez Medina Carlos , Torres Miñana Laura , Noriega Concepcion Victor , Cervera Calvo Marta , Pierola Ana Alfonso , Acuña-Cruz Evelyn , Cano-Ferri Isabel , Gómez Casares Maria Teresa , Martinez-Cuadron David , Montesinos Pau 
Published: December 2024

Introduction
Prognostic of Acute Myeloid Leukemia (AML) patients who are refractory or relapse (R/R) after induction therapy is dismal with no standard salvage treatment being superior to another. FLAG-ida could offer a 51% complete remission (CR) rate, a 10% induction death and 9 months median overall survival (OS). The addition of quizartinib (Quiz) to intensive chemotherapy (IQ) has proved to be superior as compared to IQ alone in newly diagnosed AML patients with FLT3 ITD mutation (Quantum-first trial). Moreover, OS was also superior when Quiz was added to IQ in newly diagnosed FLT ITD negative AML. We designed a phase I/II to assess the efficacy and safety of the combination of oral Quiz and FLAG-IDA chemotherapy schedule (FLAG-QUIDA regimen) in first R/R AML patients (NCT identifier: NCT04112589).
Methods
This is a multicenter, prospective, non-randomized, Phase I-II trial enrolling in 20 PETHEMA sites between 26/12/2019 and 18/2/2022. Patients were included in the phase I part irrespective of the FLT3 status, whereas 50% patients included in the phase II should carry the FLT3 ITD mutation. All patients received FLAGQUIDA followed by an allogeneic Stem Cell Transplant (alloSCT) when possible, with up to 3 High-Dose-AraC (HiDAC) consolidation cycles. All patients were aimed to received one year maintenance with Quiz after the end of chemotherapy or allo. The primary end point was CR and CR with incomplete peripheral blood counts (CRi) rate after 1 cycle of FLAG-QUIDA. Secondary endpoints were CR/CRi with minimal residual disease (MRD) negativity by flow centralized flow cytometry after one cycle of induction and OS after 1 and 2 years. Data are presented as median and Interquartile Rank or number and proportion. Statistics were done with R.
Results
Seventy-seven patients were screened with 62 finally meeting the inclusion/exclusion criteria. Nine patients were included in the phase I and 53 in the phase II. The recommend phase 2 dose of Quiz was stablished at 60 mg/day from day 1 to day 14. Thirty of 62 patients (48%) were female. Median age was 53 years (47-63). ECOG Performance Status was 0, 1 and 2 in 47/62 (76%), 13/62 (21%) and 2/62 (3%), respectively. WHO 2016 classification was AML with recurrent genetic abnormalities in 19/62 (31%) patients, AML with myelodysplastic related changes in 15/62 (24%), AML not otherwise specified in 24/62 (39%), myeloid sarcoma in 1/62 (1%) and AML therapy related in 3/62 (5%). Hematopoietic Cell Transplantation-Specific Comorbidity Index was 0-1 in 35/62 (57%) patients, 2 in 17/62 (27%) and ³3 in 10/62 (16%). European Leukemia Net 2022 (ELN22) genetic risk was favorable in 14/62 (23%), intermediate in 13/62 (21%), adverse in 30/62 (48%) and not available in 5/62 (8%) patients. FLT3-ITD mutation was present in 18/62 (29%) patients with a median ratio of 0.7 (0.12-1). At the end of induction, 32/62 patients (52%) achieved CR/CRi (61% CR/CRi in FLT3-ITD positive and 49% in FLT3-ITD negative patients). MRD was negative in 14/32 (44%) of them. Death in induction occurred in 5 (8%) patients due to infection. A subsequent alloSCT was performed in 30/62 (48%) patients, with 7 receiving a previous consolidation cycle. Maintenance was administered to 14/62 patients, of whom 12 had received an alloSCT. With a median follow-up of 1.1 year (0.3-1.7), median OS was 15 months (95%CI: 10.3-21), with no differences between FLT3-ITD mutated (11.5 months, 95%CI: 5-NA) and negative patients (15.8 months, 95%CI: 10.5-30), P=0.3. Patients receiving an alloSCT in CR/CRi after FLAGQUIDA had prolonged OS as compared to those not transplanted (HR: 0.31 [ 95%CI: 0.15-0.63] P=0.001).
Conclusion: FLAG-QUIDA followed by maintenance with Quiz is a promising regimen, equally effective for FLT3-ITD mutated and negative patients. Longer follow up is needed to stablish its long-term efficacy.