ABSTRACT
Quizartinib is a tyrosine kinase inhibitor with single agent activity in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) and has demonstrated efficacy in first‐line therapy when combined with intensive chemotherapy in both FLT3 ITD‐negative and positive AML. The FLAG‐QUIDA trial was a multicenter phase 1/2 study of quizartinib combined with FLAG‐IDA in adult patients with first R/R AML. The primary objectives were to determine the recommended phase 2 dose (RP2D) in phase 1 and to establish the complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates in phase 2. Nine patients were included in phase 1 and 52 in phase 2. Eighteen out of 61 (30%) patients were FLT3‐ITD‐positive. The RP2D of quizartinib was established at 60 mg/day for 14 days per 28‐day cycle. Overall, the CR/CRi rate was 56% (n = 34), and the CR/CRi plus morphologic leukemia free state (MLFS) rate was 66% (n = 40), without differences across genetic subgroups. Measurable residual disease negativity was achieved in 38% (n = 13) of CR/CRi patients. Thirty‐one patients (51%) were bridged to allogeneic stem cell transplantation after FLAG‐QUIDA, 28 in CR/CRi and 3 in MLFS. Median relapse‐free survival was 17 months as compared to 7.6 months in a cohort of matched patients treated with FLAG‐IDA without quizartinib (p = 0.028), and median overall survival was 15.8 months in the FLAG‐QUIDA cohort and 8.6 months in the matched cohort (p = 0.09). No safety concerns were raised. FLAG‐IDA with quizartinib demonstrated promising efficacy in R/R AML, supporting future investigations.
Trial Registration: EudraCT number: 2019‐001976‐12; ClinicalTrials.gov identifier: NCT04112589
Keywords: acute myeloid leukemia, chemotherapy, quizartinib, relapse
1. Introduction
More than 50% of patients with acute myeloid leukemia (AML) will experience relapse or will not respond to initial therapy [1]. In this setting, achieving a response may help to proceed to allogeneic hematopoietic stem cell transplantation (allo‐SCT), which remains the only therapeutic strategy offering long‐term disease control [2]. Although novel agents targeting specific molecular pathways have emerged, most remain investigational and, when used as monotherapy, rarely induce long‐lasting responses [3, 4, 5, 6]. Moreover, there are no FDA‐ or EMA‐approved drugs indicated for treating relapsed/refractory (R/R) AML patients regardless of their mutational profile or surface antigen expression.
Intensive chemotherapy options for appropriate patients include anthracycline, cytarabine, mitoxantrone, purine antimetabolites/analogs based regimens, with no clear advantages of one scheme over another [7, 8]. The combination of fludarabine, cytarabine, and idarubicin (FLAG‐IDA) is considered one of the most active therapies for fit patients, enabling approximately 35% of them to proceed to transplantation and a median overall survival (OS) of 10.2 months [7]. This reflects the wide margin for improvement.
Quizartinib is a second‐generation, potent and selective tyrosine kinase inhibitor which inhibits FLT3 autophosphorylation both in FLT3‐ITD mutant and wild‐type FLT3 [9, 10]. Notably, it has demonstrated promising activity as a single agent in patients with R/R or AML, irrespective of FLT3 mutational status [10]. It is currently approved for maintenance monotherapy following consolidation chemotherapy in adults with newly diagnosed FLT3‐ITD AML.
This study evaluates the safety and efficacy of combining quizartinib with the FLAG‐IDA regimen, with the aim of leveraging the complementary anti‐leukemic activity of both therapeutic approaches.
2. Methods
2.1. Study Design and Participants
FLAG‐QUIDA (NCT04112589) was a multicenter, open‐label, non‐randomized two‐stage phase 1/2 study of quizartinib combined with FLAG‐IDA in adult patients with R/R AML. Eligible patients were aged ≥ 18 and ≤ 70 years and had a diagnosis of AML in first relapse after intensive first‐line chemotherapy with or without allo‐SCT, or first refractory disease, defined as the failure to achieve at least a partial response (PR) after a first induction cycle and/or failure to achieve CR/CRi after the first 2 cycles. Prior therapy with other FLT3 inhibitors than quizartinib was allowed.
The phase 1 portion, 3 + 3 dose escalation study assessed the recommended phase 2 dose (RP2D) of quizartinib with standard FLAG‐IDA. The starting dose of quizartinib was 40 mg/day × 14 days. If no dose‐limiting toxicity (DLT) was observed, the next cohort would receive 60 mg/day × 14 days. If no DLT was observed, 3 additional patients would receive 60 mg/day × 14 days, establishing this dose as the RP2D if 0–1 DLT events were observed in 6 patients. The study allowed dose reductions to 60 mg/day × 7 days, and 40 mg/day × 7 days based on emerging safety data (details are provided in the Supporting Information Protocol). Strong CYP3A4 inhibitors were not allowed concomitantly with quizartinib. Patients entered this phase irrespective of FLT3‐ITD status.
The phase 2 portion of the study assessed the safety and efficacy of the combination of quizartinib at the RP2D dose. Of 68 planned patients, half were required to be FLT3‐ITD positive (allelic ratio > 0.03). CYP3A4 inhibitors were allowed with appropriate dose adjustments.
The FLAG‐IDA regimen consisted of fludarabine 30 mg/m2/day intravenously (IV) on days 1–4; idarubicin 10 mg/m2/day IV on days 1–3; cytarabine 2 g/m2/day (1 g/m2/day in patients aged 60–70 years) IV on days 1–4; non‐pegylated G‐CSF 300 mg/m2/day subcutaneously (SC) from days −1 to 5. Oral quizartinib started on day 5 for 14 days. Allo‐SCT was recommended at second CR/CRi, followed by maintenance therapy with quizartinib for 12 months, starting between days 60 and 180 after infusion. An optional consolidation regimen included cytarabine (2 cycles at 3 g/m2 every 12 h × 3 days in patients < 60 years; 1.5 g/m2 every 12 h × 3 days in patients ≥ 60 years) starting quizartinib on day 6 for 14 days at RP2D. Quizartinib maintenance could start on day 30–60 after day 1 of consolidation chemotherapy if allo‐SCT was not feasible.
2.2. Endpoints and Analyses
The primary objective of the phase 1 portion of the study was to determine the RP2D of quizartinib in combination with FLAG‐IDA. The primary objective of the phase 2 portion was to evaluate the CR/CRi rate after 1 cycle of FLAG‐IDA plus quizartinib. Secondary endpoints included overall response rate (ORR; CR + CRi + MLFS), OS, early mortality, duration of response (DOR), relapse‐free survival (RFS), centralized negative measurable residual disease (MRD) rate by flow cytometry prior to allo‐SCT (cut‐off < 0.1%), subanalysis of genetic subgroups (centralized NGS for FLT3‐ITD, NPM1, IDH1/2, TP53 mutations) and hematologic and non‐hematologic toxicity. All patients provided written informed consent. Each site's Institutional Review Board approved the study protocol. The study was conducted following the International Council for Harmonization Guideline for Good Clinical Practice and the Declaration of Helsinki. Further details, including statistical analysis, are provided in the Extended Supporting Information.
3. Results
3.1. Study Population and Patient Disposition
This study was conducted between December 2019 and January 2023 and included a total of 61 patients across two phases. Overall, 77 patients were screened, of whom 14 were excluded prior to enrolment in phase 2 due to screening failures. In addition, one patient withdrew from the trial without receiving quizartinib due to a pericardial effusion, and another was withdrawn from the study due to discordant FLT3‐ITD mutational results. Due to slow recruitment of FLT3‐ITD‐positive patients, phase 2 was closed prematurely with 61 patients from 18 different centers included in the trial. Nine patients were included in the phase 1 portion and 52 in the phase 2 portion. Figure 1 shows the flow chart of the study.
FIGURE 1.
Flow chart of the study trial.
The median age of the patients included in the trial was 50 years (range 44–57), of whom 49% were female (n = 30). First‐line treatment consisted of idarubicin plus cytarabine (3 + 7) in 65% of patients (n = 40), 3 + 7 plus midostaurin in 27% (n = 15), CPX‐351 in 6% (n = 4), venetoclax plus azacitidine in 1% (n = 1), and FLAG in 1% (n = 1). Response to first‐line treatment was CR in 62% of patients (n = 38) and resistant disease in 38% (n = 23). Forty‐one percent of patients (n = 25) had AML with recurrent genetic abnormalities at diagnosis according to the 2016 World Health Organization classification [11], while 38% (n = 23) had AML with myelodysplasia‐related changes and 21% (n = 13) had unspecified AML. Most patients (75% [n = 46]) had a score of 0 on the ECOG performance scale, while 21% (n = 13) and 3% (n = 2) had a score of 1 and 2, respectively, at the time of diagnosis. Genetic risk according to the European Leukemia Net 2022 classification (ELN22) [2] was favorable in 13 patients (21%), intermediate in 21 (34%), adverse in 26 (43%), and not available in 1 (1%). Almost one‐third of patients (30% [n = 18]) were positive for the FLT3‐ITD mutation. Table 1 shows the baseline characteristics of the patients included in the trial. Frequency of individual baseline mutations from next‐generation sequencing analysis is shown in Table S1.
TABLE 1.
Baseline characteristics of the patients.
| Characteristics | All patients | Phase 1 | Phase 2 |
|---|---|---|---|
| n (%) | n = 61 | n = 9 | n = 52 |
| Age (years) | 50 | 50 | 55 |
| (44–57) | (46–52) | (48–63) | |
| Sex (male) | 31 (51) | 4 (44) | 27 (52) |
| ECOG performance status | |||
| 0 | 46 (76) | 8 (89) | 38 (73) |
| 1 | 13 (21) | 0 | 13 (25) |
| 2 | 2 (3) | 1 (11) | 1 (2) |
| Hemoglobin | 9.8 | 9.6 | 9.8 |
| (9.1–11.6) | (9.5–11.2) | (9–12) | |
|
WBC (×109 cells/L) |
3.7 | 4.6 | 3.6 |
| (1.7–6.8) | (1.3–6.9) | (1.8–10) | |
|
ANC (×109 cells/L) |
0.87 | 1.4 | 0.8 |
| (0.4–2.1) | (0.8–2.6) | (0.4–2) | |
|
Platelet count (×109 cells/L) |
61 | 77 | 61 |
| (27–120) | (31–186) | (27–111) | |
|
Bone marrow blasts % |
35 | 77 | 33 |
| (22–77) | (55–84) | (20–65) | |
| Cytogenetic category | |||
| Favorable | 7 (12) | 1 (11) | 6 (11) |
| Intermediate | 33 (54) | 5 (56) | 28 (54) |
| Adverse | 16 (26) | 3 (33) | 13 (25) |
| NA | 5 (8) | 0 | 5 (10) |
| ELN 2022 genetic category | |||
| Favorable | 13 (21) | 1 (11) | 12 (23) |
| Intermediate | 21 (34) | 3 (33) | 18 (35) |
| Adverse | 26 (43) | 5 (56) | 21 (40) |
| NA | 1 (1) | 0 | 1 (2) |
| WHO classification | |||
| Recurrent genetic abnormalities | 25 (41) | 5 (56) | 20 (39) |
| MDS‐related | 23 (38) | 2 (22) | 21 (40) |
| NOS | 13 (21) | 2 (22) | 11 (21) |
| FLT3 ITD mutation (%) | 18 (29.5) | 2 (22) | 16 (31) |
| Allelic ratio | 0.7 (0.12–0.96) | 0.83 (0.73–0.93) | 0.7 (0.11–0.94) |
| NPM1 mutation | 13 (21) | 2 (22) | 11 (21) |
| Secondary AML (%) | 7 (11) | 2 (22) | 5 (10) |
Abbreviations: AML, acute myeloid leukemia; ANC, absolute neutrophil count; ECOG, Eastern Cooperative Oncology Group performance status; ELN22, European leukemia Net 2022; MDS, myelodysplastic syndrome; NOS, not otherwise specified; WBC, White Blood Cell Count; WHO, World Health Organization.
In the phase 1 portion of the study (dose escalation), 3 patients received quizartinib at dose level 1 (40 mg/day for a period of 14 days) and as no toxicity was observed, another 3 patients received dose level 2 (60 mg/day for a period of 14 days). One patient experienced treatment‐unrelated grade 4 hyperbilirubinemia. No dose‐limiting toxicity (DLT) was observed in 6 consecutive patients at 60 mg/day. Therefore, the RP2D for the phase 2 portion of the trial was set at 60 mg/day for a period of 14 days. In accordance with the protocol guidelines for quizartinib dosing, 26 patients initiated quizartinib treatment on day 5 of induction with a dose of 30 mg/day due to concomitant administration of a strong CYP3A4 inhibitor (n = 25) for an equivalent exposure of 60 mg/day or due to prolonged baseline QT interval (n = 1). The remaining 24 patients initiated quizartinib with a dose of 60 mg/day.
3.2. Efficacy
The aggregate CR/CRi rate for the phase 1 and 2 cohorts was 56% (n = 34), with a CR rate of 15% (n = 9) and a CRi rate of 41% (n = 25). Six additional patients (10%) achieved a morphologically leukemia‐free state (CR + CRi + MLFS rate: 66%). Among patients in CR/CRi, the MRD‐negativity rate was 38% (n = 13). Table 2 details the responses grouped by study phase. CR/CRi rates were comparable among patients with mutations in FLT3‐ITD (61%, 11 patients), FLT3‐TKD (75%, 3 patients), NPM1 (62%, 8 patients), DNMT3A (65%, 15 patients), IDH1 (56%, 5 patients), IDH2 (100%, 3 patients), and c‐KIT (60%, 3 patients). A CR/CRi was reported in 1 of 5 patients with TP53 mutations (20%). Median duration of response in patients achieving CR/CRi was 16.5 months (95% confidence interval [CI]: 7.7–54.5).
TABLE 2.
Response assessment.
| Response | All patients | Phase 1 | Phase 2 |
|---|---|---|---|
| (n = 61) (%) | (n = 9) (%) | (n = 52) (%) | |
| ORR (CR + CRi + MLFS) | 40 (66) | 5 (55) | 35 (67) |
| CR/CRi | 34 (56) | 5 (55) | 29 (56) |
| CR | |||
| MRD (−) | 1 (2) | 0 | 1 (2) |
| MRD (+) | 7 (11) | 2 (22) | 5 (10) |
| MRD NA | 1 (2) | 0 | 1 (2) |
| CRi | |||
| MRD (−) | 12 (20) | 3 (33) | 9 (17) |
| MRD (+) | 13 (21) | 0 | 13 (25) |
| MLFS | 6 (10) | 0 | 6 (11) |
| PR | 2 (3) | 1 (11) | 1 (2) |
| Resistance | 15 (24) | 3 (33) | 12 (23) |
| Death in aplasia | 4 (6) | 0 | 4 (8) |
Note: Percentage of patients with negative minimal residual disease.
Abbreviations: CR, complete remission; CRi, complete remission with incomplete hematological recovery; MLFS, morphological leukemia free status; MRD, minimal residual disease; NA, not available; ORR, overall response (CR + CRi + MLFS); PR, partial remission.
Four patients with FLT3‐ITD mutations were refractory to FLAG‐IDA. Two of them received gilteritinib, achieved MLFS, but later relapsed; one was treated with high dose cytarabine without response, and one received palliative care. None of the FLT3‐ITD‐positive patients who relapsed received gilteritinib. None of the FLT3‐ITD‐negative patients received gilteritinib after refractoriness to FLAGQUIDA.
Fifty‐one percent of patients (n = 31) in the entire cohort were bridged to allo‐SCT after FLAG‐QUIDA, including 3 after MLFS and 28 after CR/CRi (82% of the patients who achieved CR/CRi). The MRD‐negativity rate in 28 CR/CRi patients bridged to allo‐SCT was 36% (n = 10). The allo‐SCT rate was 55% (n = 10) in FLT3‐ITD‐positive patients and 48% (n = 21) in FLT3‐ITD‐negative patients. Conditioning was myeloablative in 61% of patients (n = 19), while 39% (n = 12) received reduced‐intensity conditioning. The donor was a sibling in 48% of patients (n = 15), an unrelated in 26% (n = 8), and another family member in the remaining 8 patients. HLA‐identical, haploidentical, and non‐compatible transplants were performed in 58% (n = 18), 36% (n = 11), and 6% (n = 2) of patients, respectively.
Maintenance treatment with quizartinib was initiated in 14 patients, 12 of whom had received allo‐SCT. Among the 10 patients with FLT3‐ITD mutation who received allo‐SCT, maintenance was initiated in 5. The median time between infusion and initiation of maintenance was 99 days (75–119). The median number of maintenance cycles received was 8 (2–11). Seven out of 14 patients did not complete the 12‐cycle schedule due to relapse (n = 4), viral infection (n = 1), and pancytopenia (n = 2). Among the 2 patients who proceeded to maintenance without prior allo‐SCT, one is alive in remission at 52 months.
With a median follow‐up of 15.8 months (5–50), the median OS was 15.8 months (95% CI: 10.6–24.2), with 44 deaths reported at the time of data cut‐off (Figure 2A). OS at 1 and 2 years was 60% (95% CI: 49–74) and 36% (95% CI: 26–50), respectively. In responding patients, median OS was 33.3 months (95% CI: 21–NR).
FIGURE 2.
Overall survival (OS) according to genetic mutations. (A) OS in all the patients; (B) OS according to FLT3 ITD mutation status; (C) OS according to NPM1 mutation status; (D) OS according IDH1 to mutation status; (E) OS according to IDH2 mutation; status (F) OS according to c‐KIT mutation status; (G) OS according to DNMT3A mutation status; (H) OS according to TP53 mutation status. [Color figure can be viewed at wileyonlinelibrary.com]
In FLT3 WT patients, median OS was 8 months longer than in FLT3‐ITD patients: 20 months (95% CI: 14–NR) versus 11.5 months (95% CI: 5–41.2), respectively. However, this difference was not statistically significant, probably due to the small number of patients. By contrast, analyses in patients with NPM1 mutations suggested that NPM1 status was not associated with improved OS: median OS was 15.8 months (95% CI: 12.6–32.2) in NPM1‐negative patients, compared with 16.5 months (95% CI: 4.3–NR) in NPM1‐positive patients. OS across genetic subgroups is shown in (Figures 2B–H and Table S2).
Median OS in non‐transplanted patients was 5 months (95% CI: 3.1–12.9), as compared to 34 months (95% CI: 21–NR) in transplanted patients (Figure S1A,B). Among the latter, FLT3‐ITD mutational status did not correlate with differences in OS: patients carrying the FLT3‐ITD mutation: 21.1 months (95% CI: 10.4–NR); non‐carriers: NR (95% CI: 22.8–NR), p = 0.16 (Figure S1C). Similar survival was observed between patients who received maintenance therapy after transplantation (median OS of 28.6 months [95% CI: 19.3–NR]) and those who did not (median OS 41 months [95% CI: 21.3–NR], p = 0.85) (Figure S1D).
The CR/CRi rate was compared between the FLAG‐QUIDA cohort and a historical cohort composed of 1079 patients treated with FLAG‐IDA and reported to the PETHEMA registry [12]. For this comparison, patients were matched by the SALFLAGE score with a 1:2 ratio (see extended methods in the Supporting Information). Table S3 shows the baseline characteristics of the historical cohort before and after matching. After matching, CR/CRi was achieved in 64 of the 122 matched patients treated with FLAG‐IDA (52%) (p = 0.67 for the comparison with the CR/CRi rate observed in patients treated with the FLAG‐QUIDA regimen). Among FLT3‐ITD‐positive patients, CR/CRi rates were 46% (13/28) in patients treated with FLAG‐IDA and 61% (11/18) in those treated with FLAG‐QUIDA (p = 0.33).
The proportion of patients bridged to allo‐SCT in the matched cohort treated with FLAG‐ IDA was 35% (n = 43) compared with 51% (n = 31) in patients treated with FLAG‐QUIDA, p = 0.06. Median OS of patients treated with FLAG‐IDA was 8.6 months (95% CI: 7.5–13.6), p = 0.09 for the comparison with patients treated with FLAG‐QUIDA (Figure 3A). Median relapse‐free survival, defined as time from CR/CRi until relapse or death, was 17 months (95% CI, 12.7–NA) in the FLAGQUIDA cohort and 7.6 months (95% CI: 6.1–15.1) in the FLAG‐IDA cohort (p = 0.028) (Figure 3B). Median duration of response, defined as time from CR/CRi until relapse, with patients dying in remission being censored, was 7.5 months (95% CI, 4–21) in the historical FLAG‐IDA cohort, and 16.5 months in the FLAG‐QUIDA cohort (p = 0.057).
FIGURE 3.
Comparison of (A) overall survival (OS) and (B) relapse free survival (RFS) between patients treated with FLAG‐IDA plus quizartinib and those treated with FLAG‐IDA from a historical cohort. [Color figure can be viewed at wileyonlinelibrary.com]
3.3. Safety
All 61 patients experienced at least one treatment‐related adverse event (AE). Hematological AEs were frequent, with 23 (38%), 29 (47%), and 39 (64%) episodes of anemia, decreased absolute neutrophil count, or decreased platelet counts in the entire cohort. None of these adverse events were grade 5. Bone marrow suppression was transient in patients who achieved CR. In these patients, the median time to absolute recovery with a neutrophil count > 0.5 × 109/L was 35 days (34–43). The median time to recovery with a platelet count > 100 × 109/L was 39 days (35–45).
The most common non‐hematologic AEs were fever (n = 42, 68%), bacteraemia (n = 33, 53%), febrile neutropenia (n = 28, 46%), nausea (n = 25, 40%), diarrhea (n = 24, 39%), infection (n = 23, 37%), rash (n = 22, 35%), oral mucositis (n = 17, 27%), and vomiting (n = 16, 26%). Grade 3 and grade 4 events were observed in 46 (75%) and 32 (52%) patients, respectively. The most frequently reported grade 3–4 non‐hematologic AEs were febrile neutropenia (n = 14, 23%), bacteraemia (n = 11, 17%), pulmonary infection (n = 10, 16%), and sepsis (n = 9, 14%). Ten patients experienced grade 5 AEs. All of these patients were included in the phase 2 portion of the trial. These AEs were: sepsis in 4 pancytopenic patients resulting in death at days 17, 20, 40 and 64 after the first day of induction; one lung infection in the context of progressive disease; invasive aspergillosis in 2 patients who achieved MLFS without hematopoietic recovery; one thrombotic event in a patient with persistent bacteraemia and resistant disease, and a septic event in a patient with resistant disease. None of these deaths were attributed to quizartinib. The cumulative incidence of mortality at 30 and 60 days was 6% (n = 3) and 9% (n = 6), respectively. Ten patients in the phase 2 cohort developed prolonged QT interval during the induction cycle (n = 6), first consolidation (n = 2), or maintenance (n = 2). Of these AEs, seven were considered quizartinib‐related, with eight events classified as grade 1–2 and two events as grade 3. Seven AEs ceased with dose reduction or discontinuation, while 3 resolved spontaneously. Other AEs considered related to quizartinib by investigator assessment were infrequent and mostly single occurrences. These included hepatic events (grade 1 transaminitis [n = 1] and grade 2 liver function test abnormalities [n = 2]); dermatologic events (grade 1 toxicodermia [n = 1] and grade 3 skin rash [n = 1]); cardiac and gastrointestinal events (grade 1 sinus bradycardia [n = 1] and grade 1 abdominal bloating [n = 1]); ocular toxicity (grade 3 dry eye [n = 1]); and hematologic events, including grade 4 neutropenia (n = 1), grade 4 pancytopenia (n = 1) grade 3 thrombocytopenia (n = 1), grade 3 anemia (n = 1), and grade 3 febrile neutropenia (n = 1). All events resolved with quizartinib dose omission (n = 3), dose reduction (n = 1) or spontaneously (n = 9).
Of the 31 patients that received allo‐SCT, 16% (n = 5) developed graft‐versus‐host disease (GVHD). None of the episodes were attributed to quizartinib. Four of these patients completed the planned 12 cycles of maintenance therapy; one patient was unable to initiate quizartinib maintenance. All hematological and most frequent non‐hematological AEs are shown in Table 3. The complete list of AEs observed in more than 10% of patients and all grade 3–5 AEs are shown in Table S4.
TABLE 3.
Hematological and non‐hematological most frequent adverse events.
| Treatment‐emergent adverse events | N of events in phase 1 and 2 | N of events in phase 1 | N of events in phase 2 | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (n = 61) | (n = 9) | (n = 52) | ||||||||||
| G1‐2 | G3 | G4 | G5 | G1‐2 | G3 | G4 | G5 | G1‐2 | G3 | G4 | G5 | |
| Hematologic | ||||||||||||
| Anemia | 16 (26) | 4 (6) | 3 (5) | 0 | 2 (22) | 1 (11) | 1 (11) | 0 | 14 (27) | 3 (5) | 2 (4) | 0 |
| Decreased neutrophil counts | 9 (15) | 5 (8) | 15 (24) | 0 | 6 (66) | 0 | 1 (11) | 0 | 3 (5) | 5 (9) | 14 (27) | 0 |
| Decreased platelet counts | 10 (16) | 11 (18) | 18 (29) | 0 | 2 (22) | 0 | 4 (44) | 0 | 8 (15) | 11 (21) | 14 (27) | 0 |
| Non‐hematologic | ||||||||||||
| Fever | 38 (62) | 3 (5) | 0 | 1 (1) | 6 (66) | 3 (33) | 0 | 0 | 32 (61) | 0 | 0 | 1 (2) |
| Bacteremia | 22 (36) | 10 (16) | 1 (1) | 0 | 1 (1) | 0 | 1 (1) | 0 | 21 (41) | 9 (17) | 1 (2) | 0 |
| Febrile neutropenia | 14 (23) | 9 (15) | 5 (8) | 0 | 3 (33) | 0 | 1 (12) | 0 | 11 (21) | 9 (17) | 4 (7) | 0 |
| Nausea | 24 (39) | 1 | 0 | 0 | 8 (89) | 0 | 0 | 0 | 16 (31) | 1 (2) | 0 | 0 |
| Diarrhea | 24 (39) | 0 | 0 | 0 | 5 (55) | 0 | 0 | 0 | 19 (36) | 0 | 0 | 0 |
| Infection | 20 (33) | 2 (3) | 1 (1) | 0 | 0 | 1 (11) | 0 | 0 | 20 (38) | 1 (2) | 1 (2) | 0 |
| Rash | 21 (34) | 1 (1) | 0 | 0 | 3 (33) | 0 | 0 | 0 | 18 (34) | 1 (2) | 0 | 0 |
| Oral mucositis | 14 (23) | 2 (2) | 1 (1) | 0 | 2 (22) | 0 | 0 | 0 | 12 (23) | 2 (4) | 1 (2) | 0 |
| Vomiting | 16 (26) | 0 | 0 | 0 | 5 (55) | 0 | 0 | 0 | 11 (21) | 0 | 0 | 0 |
| Pulmonary infection | 6 (9) | 10 (16) | 0 | 3 (5) | 0 | 1 (11) | 0 | 0 | 6 (11) | 9 (17) | 0 | 3 (5) |
| Sepsis | 1 (1) | 4 (6) | 5 (8) | 5 (8) | 0 | 1 (11) | 0 | 0 | 1 (2) | 3 (5) | 5 (9) | 5 (9) |
| QT prolongation | 8 (15) | 2 (2) | 0 | 0 | 0 | 0 | 0 | 0 | 8 (17) | 2 (4) | 0 | 0 |
Abbreviation: G, grade.
4. Discussion
This multicenter, phase 1/2 study of quizartinib combined with FLAG‐IDA in adult patients with R/R AML showed promising results. The combination was effective in treating patients with relapsed/refractory disease, achieving high CR/CRi rates and enabling bridging to transplantation. Quizartinib maintenance treatment after allo‐SCT was safe. Based on our historical matched cohort analyses, the FLAG‐QUIDA regimen could lead to improved results compared with FLAG‐IDA through increased CR + CRi + MLFS and allo‐SCT rates, as well as prolonged remission duration. The regimen appeared efficacious in both FLT3‐ITD‐positive and ‐negative patients.
With the exception of midostaurin and lestaurtinib, which have limited activity in the relapsed setting [13, 14], FLT3 inhibitors are widely used to treat relapsed FLT3‐mutated AML, primarily as monotherapy. The phase 3, randomized, placebo‐controlled ADMIRAL trial evaluated the use of gilteritinib versus intensive or less intensive chemotherapy (at the investigator's discretion) in patients with R/R FLT3‐ITD‐mutated AML. ORR was 34%; 25% of patients proceeded to allo‐SCT, and median OS was 9.3 months. In Quantum‐R, a randomized controlled phase 3 trial comparing quizartinib versus intensive or less intensive chemotherapy, median OS was significantly longer in the quizartinib arm, although the benefit was not clinically relevant (6.2 vs. 4.7 months). Approximately one third of the patients treated with quizartinib underwent allo‐SCT, 54% of whom had achieved prior CR/CRi. In this subgroup of patients, median OS was 12.2 months [15]. While these results highlight the efficacy of targeted therapies, they also underscore the need to implement strategies that enable long‐term disease control.
Herein, the median OS of 15.8 months and the CR + CRi + MLFS rate of 66% in the overall population are comparable with outcomes recently reported with FLAG‐IDA plus venetoclax (67% CR + CRi + MLFS rate and mOS of 12 months) in a single institution trial of 61 R/R AML patients (median age of 47 years, 69% of them in first R/R episode), where notably, 57% of them were successfully bridged to allo‐SCT [16]. In our study, the median duration of response was 16.5 months, and the median OS after CR/CRi was 33 months. These outcomes were probably influenced by the high rate of allo‐SCT, especially among responder patients. Undoubtedly, allo‐SCT is the mainstay therapeutic strategy capable of achieving long‐term disease control in the setting of AML relapse, and its results could improve when it is performed in the absence of MRD [17]. In line with this evidence, a key strength of the present study is that over one third of the patients who underwent transplantation achieved a negative pre‐transplant MRD status by centralized flow cytometry.
Interestingly, the median OS in FLT3‐ITD‐positive patients was only 2 months longer than that reported with gilteritinib monotherapy in the ADMIRAL trial, and shorter than the 20 months observed in FLT3‐ITD‐negative patients here. Two factors may explain the finding: first, 40% of FLT3‐ITD‐positive patients did not undergo transplantation, and second, only five out of 10 transplanted FLT3‐ITD‐positive patients initiated maintenance therapy. Maintenance with FLT3 inhibitors is associated with better disease control after allo‐SCT, particularly when there is detectable MRD [18, 19].
The efficacy of FLAG‐IDA combined with quizartinib in terms of both response and survival was observed regardless of mutational status (i.e., FLT3 and other co‐mutations), suggesting that this regimen could be used as a mutation‐agnostic therapeutic approach. AML is a polyclonal disease, whereby mutation‐specific therapies may fail due to the clonal expansion of subpopulations harboring alternative mutations. Consequently, targeting a single molecular event may be insufficient to eradicate the disease. From this perspective, therapeutic strategies that can target multiple biological pathways, irrespective of specific mutational profiles, are of particular interest. In this regard, quizartinib has demonstrated to exhibit antitumor activity as a single agent in FLT3‐ITD‐negative R/R AML. In a phase 2b study evaluating multiple doses of quizartinib in patients with and without FLT3‐ITD mutations, 32% of the FLT3‐ITD‐negative patients responded, with a median response duration of 16 weeks. However, none of these patients proceeded to allo‐SCT [20]. These results contrast with the 60% CR/CRi rate and 20‐month median OS observed in FLT3‐ITD‐negative patients in the present study, indicating that this combination warrants further evaluation in larger studies. Interestingly, the randomized, double‐blind, phase 3 trial of crenolanib versus placebo in combination with intensive chemotherapy (MEC or FLAG‐IDA) [21] in R/R FLT3‐mutated AML patients reported a median OS of 12.4 months in the crenolanib arm.
FLAG‐IDA is one of the most widely used salvage chemotherapy regimens for R/R AML [4, 20]. A recent study from the PETHEMA group indicates improved survival with the use of this regimen in the most recent time period [12]. Potential improvements to the FLAG‐IDA regimen are limited by hematological and extra‐hematological toxicity. Therefore, any enhancement of this strategy should focus on combining it with other agents that do not significantly increase toxicity, such as targeted agents. Of note, we used the validated SALFLAGE score [7] (specifically designed to predict OS after FLAG‐IDA) to select a matched historical cohort from a larger series of 1079 patients with first R/R AML from the PETHEMA epidemiological registry [7]. The comparison between FLAG‐IDA plus quizartinib and FLAG‐IDA in the matched cohort showed a significant advantage in terms of RFS and a numerically longer median OS. This could be driven by higher allo‐SCT rates, probably due to the higher CR + CRi + MLFS rate in the FLAGQUIDA versus historical cohort (66% vs. 57%) but also changes in clinical practice in past decade enabling more patients to undergo a rapid allo‐SCT. Furthermore, the benefits of quizartinib may be driven by improvements in the quality and durability of response, as has been reported in both FLT3‐ITD‐positive and ‐negative de novo AML patients [22, 23].
The most frequent grade AEs were related to the bone marrow suppression that follows intensive chemotherapy, including worsening cytopenias and infectious events. Extrahematological toxicity secondary to chemotherapy was also frequent. Prolongation of the QT interval is a well‐known AE related to quizartinib and other kinase inhibitors [10]. Indeed, seven out of 10 QT prolongation episodes were quizartinib‐related. However, all of them were manageable with dose modifications or even resolved spontaneously. Aside from the AEs on cardiac conduction, other AEs were manageable and resolved with dose modifications or spontaneously. Importantly, there were no deaths attributed to quizartinib. GVHD was infrequent and non‐related to the study drug. Of note, four of the five patients developing GVHD were able to complete the 12 courses of quizartinib maintenance.
Our study has several limitations: first, the proportion of patients who received maintenance therapy was lower than expected. This may have reduced the overall efficacy of the therapeutic strategy. Second, the non‐randomized design of the study limits our ability to draw definite conclusions. Third, the small number of patients analyzed in the various genetic subgroups warrants caution when interpreting the results of efficacy according to genetic profile. Fourth, there is an inherent time‐related bias in comparisons with historical cohorts. In our study, for example, it could be argued that patients who were refractory to, or relapsed after an initial response to FLAGQUIDA may have subsequently been treated with specific FLT3 inhibitors and this option was not available in the early cohort. In this regard, only two patients who were refractory to FLAGQUIDA received gilteritinib, without achieving durable disease control. However, we acknowledge that some improvements in patient selection, transplant access, and supportive care measures may have impacted on differential results between the historical FLAG‐ida cohort and the FLAGQUIDA cohort [12]. Finally, the study was terminated prematurely due to slow recruitment of FLT3‐ITD‐positive patients, maybe due to the commercialization of gilteritinib monotherapy in Spain. Consequently, the results in this subgroup of patients are limited by the relatively small sample size.
In conclusion, these findings suggest that combining quizartinib with FLAG‐IDA potentially achieves a CR + CRi + MLFS rate of 66% without increased toxicity compared with FLAG‐IDA and enables allo‐SCT in half of the patients. Compared with intensive chemotherapy alone, the addition of quizartinib to intensive chemotherapy could prolong the duration of response, potentially improving survival. These preliminary results warrant confirmation in larger studies.
Funding
This study was supported by grants from Daichi Sankyo.
Ethics Statement
The study was approved by the ethics committee of Hospital Universitari La Fe (465/2019).
Consent
All patients gave written informed consent to participate in this trial.
Conflicts of Interest
R.R.‐V. reports lectures fees from Daiichi Sankyo, Jazz Pharma, Servier, Astellas and Pfizer. P.M. reports grants from AbbVie, Astellas, BMS/Celgene, Daiichi Sankyo, Janssen, Karyopharm, Novartis, Pfizer, Teva; consulting fees from Astellas, Agios, Tolero Pharmaceutical, Glycomimetics, Forma Therapeutics, BMS/Celgene, Daiichi Sankyo; lecture fees from AbbVie, Astellas, BMS/Celgene, Daiichi Sankyo, Incyte, Janssen, Novartis, Pfizer, Sanofi, Servier, Teva and support for participation on advisory board from AbbVie, Astellas, BMS/Celgene, Daiichi Sankyo, Incyte, Janssen, Karyopharm, Novartis, Pfizer, Sanofi, Servier, Syndax, Teva. T.B. reports grants from AbbVie; consulting fees from AbbVie, Jazz Pharmaceuticals and Astellas; lectures fees from Otsuka; support for attending meetings from AbbVie and Otsuka.
Supporting information
Table S1: Frequency of individual baseline mutations by next‐generation sequencing.
Table S2: Overall survival according to mutation status.
Table S3: Baseline characteristics of the historical cohort before and after matching.
Table S4: Main treatment emergent adverse events during treatment.
Figure S1: (A) Overall survival in transplanted patients; (B) overall survival according to transplant; (C) overall survival in transplanted patients according to FLT3 ITD mutation status; (D) overall survival in transplanted patients according to receiving maintenance with quizartinib.
Contributor Information
Teresa Bernal, Email: bernalmaria@uniovi.es.
Pau Montesinos, Email: montesinos_pau@gva.es.
Data Availability Statement
Data are available from the corresponding author upon reasonable request.
References
- 1. Schlenk R. F., Müller‐Tidow C., Benner A., and Kieser M., “Relapsed/Refractory Acute Myeloid Leukemia: Any Progress?,” Current Opinion in Oncology 29, no. 6 (2017): 467–473, 10.1097/CCO.0000000000000404. [DOI] [PubMed] [Google Scholar]
- 2. Döhner H., Wei A. H., Appelbaum F. R., et al., “Diagnosis and Management of AML in Adults: 2022 Recommendations From an International Expert Panel on Behalf of the ELN,” Blood 140, no. 12 (2022): 1345–1377, 10.1182/blood.2022016867. [DOI] [PubMed] [Google Scholar]
- 3. CD D. N., Stein E. M., De Botton S., et al., “Mutated Relapsed or Refractory AML,” New England Journal of Medicine 378, no. 25 (2018): 2386–2398, 10.1056/NEJMoa1716984. [DOI] [PubMed] [Google Scholar]
- 4. Perl A. E., Martinelli G., Cortes J. E., et al., “Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3 ‐Mutated AML,” New England Journal of Medicine 381, no. 18 (2019): 1728–1740, 10.1056/NEJMoa1902688. [DOI] [PubMed] [Google Scholar]
- 5. Issa G. C., Aldoss I., Thirman M. J., et al., “Menin Inhibition With Revumenib for KMT2A ‐Rearranged Relapsed or Refractory Acute Leukemia (AUGMENT‐101),” Journal of Clinical Oncology 43, no. 1 (2025): 75–84, 10.1200/JCO.24.00826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Wang E. S., Montesinos P., Foran J., et al., “Ziftomenib in Relapsed or Refractory NPM1 ‐Mutated AML,” Journal of Clinical Oncology 43, no. 31 (2025): 3381–3390, 10.1200/JCO-25-01694. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Bergua J. M., Montesinos P., Martinez‐Cuadrón D., et al., “A Prognostic Model for Survival After Salvage Treatment With FLAG‐Ida +/− Gemtuzumab‐Ozogamicine in Adult Patients With Refractory/Relapsed Acute Myeloid Leukaemia,” British Journal of Haematology 174, no. 5 (2016): 700–710, 10.1111/bjh.14107. [DOI] [PubMed] [Google Scholar]
- 8. Wattad M., Weber D., Döhner K., et al., “Impact of Salvage Regimens on Response and Overall Survival in Acute Myeloid Leukemia With Induction Failure,” Leukemia 31, no. 6 (2017): 1306–1313, 10.1038/leu.2017.23. [DOI] [PubMed] [Google Scholar]
- 9. Zarrinkar P. P., Gunawardane R. N., Cramer M. D., et al., “AC220 Is a Uniquely Potent and Selective Inhibitor of FLT3 for the Treatment of Acute Myeloid Leukemia (AML),” Blood 114, no. 14 (2009): 2984–2992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Cortes J. E., Kantarjian H., Foran J. M., et al., “Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS‐Like Tyrosine Kinase 3–Internal Tandem Duplication Status,” Journal of Clinical Oncology 31, no. 29 (2013): 3681–3687, 10.1200/JCO.2013.48.8783. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Arber D. A., Orazi A., Hasserjian R., et al., “The 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemia,” Blood 127, no. 20 (2016): 2391–2405. [DOI] [PubMed] [Google Scholar]
- 12. Aspas Requena G., Rodríguez‐Veiga R., Gil C., et al., “Real‐World Outcomes of flag ‐Ida Regimen in 1079 Adult Patients With First Relapsed/Refractory aml: A pethema Study,” American Journal of Hematology 101 (2026): 1692–1705, 10.1002/ajh.70340. [DOI] [PubMed] [Google Scholar]
- 13. Fischer T., Stone R. M., DJ D. A., et al., “Phase IIB Trial of Oral Midostaurin (PKC412), the FMS‐Like Tyrosine Kinase 3 Receptor (FLT3) and Multi‐Targeted Kinase Inhibitor, in Patients With Acute Myeloid Leukemia and High‐Risk Myelodysplastic Syndrome With Either Wild‐Type or Mutated FLT3,” Journal of Clinical Oncology 28, no. 28 (2010): 4339–4345, 10.1200/JCO.2010.28.9678. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Levis M., Ravandi F., Wang E. S., et al., “Results From a Randomized Trial of Salvage Chemotherapy Followed by Lestaurtinib for Patients With FLT3 Mutant AML in First Relapse,” Blood 117, no. 12 (2011): 3294–3301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Cortes J. E., Khaled S., Martinelli G., et al., “Quizartinib Versus Salvage Chemotherapy in Relapsed or Refractory FLT3‐ITD Acute Myeloid Leukaemia (QuANTUM‐R): A Multicentre, Randomised, Controlled, Open‐Label, Phase 3 Trial,” Lancet Oncology 20, no. 7 (2019): 984–997, 10.1016/S1470-2045(19)30150-0. [DOI] [PubMed] [Google Scholar]
- 16. CD D. N., Jen W. Y., Takahashi K., et al., “Long Term Results of Venetoclax Combined With FLAG‐IDA Induction and Consolidation for Newly Diagnosed and Relapsed or Refractory Acute Myeloid Leukemia,” Leukemia 39, no. 4 (2025): 854–863, 10.1038/s41375-025-02531-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Short N. J., Zhou S., Fu C., et al., “Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta‐Analysis,” JAMA Oncology 6, no. 12 (2020): 1890–1899, 10.1001/jamaoncol.2020.4600. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Levis M. J., Erba H. P., Montesinos P., et al., “FLT3‐ITD Measurable Residual Disease From the QuANTUM‐First Trial,” Blood Advances 10, no. 3 (2026): 917–928, 10.1182/bloodadvances.2025016444. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Burchert A., Bug G., Fritz L. V., et al., “Sorafenib Maintenance After Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myeloid Leukemia With FLT3‐Internal Tandem Duplication Mutation (SORMAIN),” Journal of Clinical Oncology 38, no. 26 (2020): 2993–3002, 10.1200/JCO.19.03345. [DOI] [PubMed] [Google Scholar]
- 20. Cortes J., Perl A. E., Döhner H., et al., “Quizartinib, an FLT3 Inhibitor, as Monotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukaemia: An Open‐Label, Multicentre, Single‐Arm, Phase 2 Trial,” Lancet Oncology 19, no. 7 (2018): 889–903, 10.1016/S1470-2045(18)30240-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Cluzeau T., Dumas P. Y., Montesinos P., et al., “Crenolanib Plus Salvage Chemotherapy Improves Outcomes in FLT3‐Mutant and NPM1 Co‐Mutated Relapsed/ Refractory (R/R) Acute Myeloid Leukemia (AML): Results From a Randomized, Placebo‐Controlled, Double‐Blind Trial,” Blood 146, no. Supplement 1 (2025): 767, 10.1182/blood-2025-767.40811002 [DOI] [Google Scholar]
- 22. Montesinos P., Rodríguez‐Veiga R., Bergua J. M., et al., “Quizartinib for Newly Diagnosed FLT3‐Internal Tandem Duplication‐Negative AML: The Randomized, Double‐Blind, Placebo‐Controlled, Phase II QUIWI Study,” Journal of Clinical Oncology 44, no. 1 (2026): 42–53, 10.1200/JCO-25-01841. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Erba H. P., Montesinos P., Kim H. J., et al., “Quizartinib Plus Chemotherapy in Newly Diagnosed Patients With FLT3‐Internal‐Tandem‐Duplication‐Positive Acute Myeloid Leukaemia (QuANTUM‐First): A Randomised, Double‐Blind, Placebo‐Controlled, Phase 3 Trial,” Lancet 401, no. 10388 (2023): 1571–1583, 10.1016/S0140-6736(23)00464-6. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Table S1: Frequency of individual baseline mutations by next‐generation sequencing.
Table S2: Overall survival according to mutation status.
Table S3: Baseline characteristics of the historical cohort before and after matching.
Table S4: Main treatment emergent adverse events during treatment.
Figure S1: (A) Overall survival in transplanted patients; (B) overall survival according to transplant; (C) overall survival in transplanted patients according to FLT3 ITD mutation status; (D) overall survival in transplanted patients according to receiving maintenance with quizartinib.
Data Availability Statement
Data are available from the corresponding author upon reasonable request.