Abstract
PURPOSE
Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML.
METHODS
This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II).
RESULTS
Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10–5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia–free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort.
CONCLUSION
The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.
INTRODUCTION
Fms-like tyrosine kinase 3 (FLT3) is the most commonly mutated gene in AML.1 FLT3-internal tandem duplication (ITD) mutations are identified in 20%-25% of newly diagnosed AML, whereas point mutations in the tyrosine kinase domain (TKD) are identified in 5%-10%.2,3 For patients who are unsuitable for intensive chemotherapy, there is not an established role for a FLT3 inhibitor in the frontline setting. The current standard of care is the combination of azacitidine plus venetoclax; however, FLT3-driven relapses are common.4 FLT3 mutations also lead to overexpression of BCL-xL and MCL-1, both of which are key mechanisms of resistance to venetoclax.5-11 Outcomes are particularly poor for patients with AML harboring an FLT3-ITD mutation, where a median overall survival (OS) of 9.9 months has been reported with azacitidine plus venetoclax, compared with 14.7 months for those who are FLT3 wild-type.12
CONTEXT
Key Objective
To determine the safety and efficacy of the triplet combination of azacitidine, venetoclax, and gilteritinib—a potent, oral FLT3 inhibitor—in patients with FLT3-mutated AML.
Knowledge Generated
In this phase I/II study, this regimen could be delivered safely although most patients required dose modifications. Outcomes were particularly promising in older patients with newly diagnosed FLT3-mutated AML, where the regimen resulted in high rates of complete remission (CR) and measurable residual disease negativity. The high rate of deep responses translated to encouraging survival, which compares favorably with historical expectations with azacitidine and venetoclax in a similar population.
Relevance (C.F. Craddock)
-
The triplet of azacitidine, venetoclax and gilteritinib results in high CR rates, with acceptable toxicity, in adults with FLT3- mutated AML and represents a potentially important new treatment strategy in both fit and unfit adults with FLT3+ AML justifying further examination in randomized trials.*
*Relevance section written by JCO Associate Editor Charles F. Craddock, MD.
Gilteritinib is an oral, potent FLT3 inhibitor that is active against both FLT3-ITD and FLT3-TKD mutations.13 In the randomized phase III ADMIRAL study comparing gilteritinib versus investigator-choice salvage therapy in patients with relapsed/refractory FLT3-mutated AML, gilteritinib improved OS (median OS, 9.3 months v 5.6 months with chemotherapy; P < .001).14 Preclinically, gilteritinib synergizes with venetoclax to increase BCL-2 dependence and reduce expression of BCL-xL and MCL-1.6,10,11 In a phase Ib clinical trial of gilteritinib plus venetoclax in patients with relapsed/refractory FLT3-mutated AML, the combination achieved a modified composite complete remission (mCRc; defined as complete remission [CR] + complete remission with incomplete hematologic recovery [CRi] + morphological leukemia–free state [MLFS]) rate of 75% and a median OS of 10.0 months.15 These results compare favorably with gilteritinib monotherapy in the ADMIRAL study—where the mCRc rate was 54%14—despite patients in the gilteritinib plus venetoclax study being more heavily pretreated.
The combination of azacitidine and gilteritinib has been evaluated in older adults with newly diagnosed FLT3-mutated AML but did not improve survival in this population, as compared with azacitidine monotherapy16; however, gilteritinib has not been prospectively studied in combination with azacitidine and venetoclax. Given the integral role of FLT3 mutations in mediating resistance to the azacitidine plus venetoclax regimen and the established preclinical and clinical synergy of venetoclax and gilteritinib in FLT3-mutated AML, we designed a phase I/II study to evaluate azacitidine, venetoclax, and gilteritinib in patients with FLT3-mutated AML.
METHODS
Study Design and Participants
This was a single-center, phase I/II study to evaluate azacitidine, venetoclax, and gilteritinib in FLT3-mutated AML. The phase I portion of the study was performed in relapsed/refractory FLT3-mutated AML. This was followed by phase II dose expansion cohorts for (1) patients with relapsed/refractory FLT3-mutated AML or other myeloid diseases and (2) patients with newly diagnosed FLT3-mutated AML who were unsuitable for intensive chemotherapy on the basis of the treating physician's assessment and/or who declined intensive therapy. Patients with either FLT3-ITD or FLT3 D835 mutations were eligible. Additional eligibility criteria are presented in the protocol (Data Supplement, online only). This study was approved by the Institutional Review Board of University of Texas MD Anderson Cancer Center. All patients provided informed consent according to the Declaration of Helsinki.
Treatment Regimen
Treatment in cycle 1 consisted of azacitidine 75 mg/m2 once daily intravenously (IV) or subcutaneously (SC) on days 1-7, venetoclax with ramp-up to 400 mg once daily orally on days 1-28, and gilteritinib once daily orally on days 1-28 (dose of 80 or 120 mg in phase I; 80 mg in phase II). A bone marrow was performed on cycle 1, day 14. In both cohorts, venetoclax was held if bone marrow blasts <5% or if aplastic/insufficient; in the frontline cohort alone, gilteritinib was also held. For cycle 2 and beyond, patients received azacitidine 75 mg/m2 once daily IV or SC on days 1-5, venetoclax 400 mg once daily orally on days 1-7, and gilteritinib once daily orally on days 1-28 (dose of 80 or 120 mg in phase I; 80 mg in phase II). All patients received triazole fungal prophylaxis after the venetoclax ramp-up. The venetoclax dose was decreased to 200 mg with moderate CYP3A4 inhibitors and to 100 mg with strong CYP3A4 inhibitors (except for posaconazole, in which 70 mg was given); no dose adjustments were made for concomitant p-glycoprotein inhibitors. Two doses of prophylactic intrathecal cytarabine were recommended on cycle 1, day 21 and again during cycle 2. In both cohorts, the regimen consisted of up to 24 cycles of azacitidine, venetoclax, and gilteritinib, with each cycle anticipated to be 28 days in duration.
Outcomes
The primary end point of the phase I portion was the maximum tolerated dose (MTD) of gilteritinib in the combination regimen. The primary end point of the phase II portion was the combined CR and CRi rate within two cycles of therapy. Secondary end points included the CR rate, measurable residual disease (MRD) negativity rate by flow cytometry, relapse-free survival (RFS), OS, and safety of the regimen. All patients who received at least one dose of the study regimen were evaluable for efficacy and safety.
AML responses were defined according to the European LeukemiaNet 2017 guidelines.17 RFS was calculated from the time of response until relapse or death from any cause, censored if alive at last follow-up. OS was calculated from the time of treatment initiation until death from any cause, censored if alive at last follow-up. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.03.18
Mutation analysis was performed on bone marrow specimens using the 81-gene targeted next-generation sequencing (NGS) panel as previously described, with a sensitivity of 1%.19,20 Flow cytometric MRD assessment was performed on fresh bone marrow aspiration samples using eight-color multiparameter flow cytometry as described previously, with a sensitivity of 0.01%.21 Multiplex polymerase chain reaction (PCR) for FLT3-ITD or the FLT3 kinase domain (D835) MRD was also performed in remission samples as previously published, with a sensitivity of 1%.20 In the frontline cohort, NGS-based MRD assessment for FLT3-ITD and NPM1 was performed, with a sensitivity of 5 × 10−5 (Invivoscribe, San Diego, CA).
Statistical Analysis
The phase I portion was conducted using a standard 3 + 3 design and evaluated gilteritinib at 80 mg once daily (dose level 0) and 120 mg once daily (dose level +1). After completion of phase I, up to 15 additional relapsed/refractory patients and 30 newly diagnosed patients were to be enrolled in phase II. Interim monitoring rules for efficacy and toxicity were used throughout phase II, and the study was continuously monitored for efficacy and treatment-related toxicities using a Bayesian design.22,23 For the relapsed/refractory cohort, the goal CR/CRi rate was ≥50%. For the newly diagnosed cohort, the goal CR/CRi rate was ≥75%.
Remission duration, RFS, and OS were calculated with Kaplan-Meier estimates, and survival estimates were compared with the log-rank test. The data cutoff for this analysis was July 15, 2023. Data analyses were performed using GraphPad Prism 9 (GraphPad Software Inc, Boston, MA).
RESULTS
Phase I Results
Ten patients with relapsed/refractory FLT3-mutated AML were enrolled into the phase I portion of the study (six with gilteritinib 80 mg once daily and four with gilteritinib 120 mg once daily). No DLTs were observed at the 80-mg dose. In the 120-mg cohort, one patient had prolonged grade 4 myelosuppression that met DLT criteria. An MTD was not formally established. Three of four patients (75%) in the 120-mg cohort achieved MLFS as best response. Because of good clinical activity and superior count recovery observed with the 80-mg dosing (with three of six patients [50%] achieving CR/CRi) and concern for myelosuppression with the 120-mg dose on the basis of previous off-label experience at our institution,24,25 80 mg once daily of gilteritinib was chosen as the phase II dose.
Patient Characteristics of the Frontline Cohort
Between October 2020 and January 2023, 30 patients with newly diagnosed FLT3-mutated AML were treated (Fig 1). The baseline characteristics are shown in Table 1. The median age was 71 years (range, 18-86 years). Twenty-two patients (73%) had an FLT3-ITD mutation alone, and eight patients (27%) had an FLT3-TKD mutation alone. The median FLT3-ITD variant allelic frequency (VAF) was 0.17 (range, 0.02-0.77), and the median FLT3-TKD VAF was 0.39 (range, 0.03-0.57). Twenty-six patients (87%) received intrathecal prophylaxis.
FIG 1.
CONSORT diagram. PR, partial remission.
TABLE 1.
Baseline Characteristics of the Study Population
| Characteristic | Frontline Cohort (n = 30) | Relapsed/Refractory Cohort (n = 22) |
|---|---|---|
| Age, years | ||
| Median (range) | 71 (18-86) | 68 (19-90) |
| ≥60 years, No. (%) | 29 (97) | 16 (73) |
| ≥75 years, No. (%) | 8 (30) | 4 (18) |
| Diagnosis, No. (%) | ||
| AML | 30 (100) | 21 (95) |
| CMML | 0 | 1 (5) |
| ECOG performance status, No. (%) | ||
| 0 | 5 (17) | 2 (9) |
| 1 | 10 (33) | 13 (59) |
| 2 | 15 (50) | 7 (32) |
| Cytogenetics, No. (%) | ||
| Diploid | 20 (67) | 8 (36) |
| Adverse risk | 3 (10) | 8 (36) |
| Others | 7 (23) | 6 (26) |
| ELN 2022 risk, No. (%) | ||
| Favorable | 3 (10) | 1 (5) |
| Intermediate | 12 (40) | 6 (27) |
| Adverse | 15 (50) | 15 (68) |
| FLT3 mutation type, No. (%) | ||
| ITD | 22 (73) | 10 (45) |
| TKD | 8 (27) | 7 (32) |
| ITD + TKD | 0 | 5 (23) |
| FLT3 variant allelic frequency, median (range) | ||
| ITD | 0.17 (0.02-0.77) | 0.26 (0.03-0.94) |
| TKD | 0.39 (0.03-0.57) | 0.37 (0.01-0.64) |
| Mutations,a No. (%) | ||
| NPM1 | 13 (43) | 8 (36) |
| DNMT3A | 11 (37) | 8 (36) |
| TET2 | 6 (23) | 5 (23) |
| RUNX1 | 5 (17) | 5 (23) |
| WT1 | 5 (17) | 7 (32) |
| KRAS/NRAS | 3 (10) | 2 (9) |
| BCOR | 3 (10) | 0 |
| GATA2 | 1 (3) | 2 (9) |
| TP53 | 1 (3) | 2 (9) |
| ASXL1 | 1 (3) | 4 (18) |
| No. of previous therapies, median (range) | — | 2 (1-5) |
| Previous FLT3 inhibitor, No. (%) | — | 8 (36) |
| Previous gilteritinib, No. (%) | — | 3 (14) |
| Previous HMA + venetoclax, No. (%) | — | 10 (45) |
| Previous allogeneic HSCT, No. (%) | — | 6 (27) |
Abbreviations: CMML, chronic myelomonocytic leukemia; ECOG, Eastern Cooperative Oncology Group; ELN, European LeukemiaNet; HMA, hypomethylating agent; HSCT, hematopoietic stem-cell transplantation; ITD, internal tandem duplication; TKD, tyrosine kinase domain.
Mutations detected in ≥3 patients.
Response and Survival Outcomes in the Frontline Cohort
Twenty-seven patients (90%) achieved CR and two patients (6%) achieved CRi for a composite CR/CRi rate of 96% (Table 2). An additional patient achieved MLFS, and the mCRc (CR + CRi + MLFS) rate was 100%. On the cycle 1, day 14 bone marrow assessment, 21 patients (70%) achieved morphological remission, seven patients (24%) were aplastic, and two patients (6%) had persistent morphological disease. All but one patient (96%) achieved morphological remission by the end of cycle 1. This patient achieved CR after cycle 2.
TABLE 2.
Hematologic and MRD Responses
| Hematologic Response | Frontline Cohort (n = 30) | Relapsed/Refractory Cohort (n = 22) |
|---|---|---|
| mCRc (CR/CRi/MLFS), No. (%) | 30 (100) | 15 (68) |
| CR | 27 (90) | 4 (18) |
| CRi | 2 (6) | 2 (9) |
| MLFS | 1 (4) | 9 (41)a |
| PR | 0 | 1 (5)b |
| No response | 0 | 6 (27) |
| MRD Responsec | Frontline Cohort (n = 30) | Relapsed/Refractory Cohort (n = 22) |
| MRD by flow cytometry (after cycle 1), No. (%) | ||
| Negative | 9/16 (56) | 1/9 (11) |
| Positive | 7/16 (44) | 8/9 (89) |
| MRD by flow cytometry (best response), No. (%) | ||
| Negative | 25/27 (93) | 5/11 (45) |
| Positive | 2/27 (7) | 6/11 (55) |
| MRD by PCR for FLT3 (after cycle 1), No. (%) | ||
| Negative | 11/30 (37) | 3/11 (27) |
| Positive | 19/30 (63) | 8/11 (73) |
| MRD by PCR for FLT3 (best response), No. (%) | ||
| Negative | 27/30 (90) | 6/14 (43) |
| Positive | 3/30 (10) | 8/14 (57) |
Abbreviations: CMML, chronic myelomonocytic leukemia; CR, complete remission; CRi, CR with incomplete hematologic recovery; mCRc, modified composite complete remission; MLFS, morphologic leukemia–free state; MRD, measurable residual disease; PCR, polymerase chain reaction; PET, positron emission tomography; PR, partial remission.
Includes one patient with CMML who achieved mCR and is included as MLFS for this analysis.
PR in one patient with extramedullary-only disease (assessed by PET scan).
Denominator includes patients who achieved mCRc with adequate MRD assessment.
Twenty-five of 27 evaluable patients (93%) achieved MRD negativity by multiparameter flow cytometry (Table 2). Twenty-seven patients (90%) achieved MRD negativity by FLT3 PCR with a sensitivity of 1%. Among FLT3-ITD-mutated patients, FLT3-ITD <5 × 10−5 by NGS was achieved in 13 of 20 (65%) by the end of cycle 4 (Figs 2A and 2B). Among patients with at least one FLT3-ITD NGS assessment in cycles 2 or later, 76% (13 of 17) achieved FLT3-ITD <5 × 10−5. Among NPM1-mutated patients, NPM1 <5 × 10−5 by NGS was achieved in 4 of 9 (44%) by the end of cycle 4 (Data Supplement, Fig S1).
FIG 2.
NGS MRD for FLT3-ITD in the frontline cohort: (A) MRD for FLT3-ITD after cycles 1-4 and (B) cumulative rates of MRD for FLT3-ITD <5 × 10–5. ITD, internal tandem duplication; MRD, measurable residual disease; NGS, next-generation sequencing.
The median number of cycles received was three (range, 1-31 cycles). Nine patients (30%) received at least six cycles, and six patients (20%) received at least 12 cycles. The disposition for the 30 frontline patients is shown in the Data Supplement (Fig S2). Thirteen patients (43%) underwent allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission after a median of 4.8 months (range, 2.7-8.0 months). Six transplanted patients (46%) received post–HSCT FLT3 inhibitor maintenance (gilteritinib [n = 5] and sorafenib [n = 1]). Overall, five patients (17%) relapsed (one after HSCT and four in the absence of HSCT), with a median time to relapse of 7.2 months (range, 6.2-19.9 months). Among the five relapses, four had an FLT3-ITD mutation and one had an FLT3-TKD mutation at the time of study enrollment. Two patients had FLT3-positive relapse, two were FLT3-negative, and one was extramedullary-only (FLT3 mutation status could not be assessed). Overall, seven patients (23%) have died (two from HSCT-related complications, three from disease relapse, and two while in remission in the absence of HSCT). One patient who achieved CR died in cycle 1 (day 64) because of sepsis, and one patient who achieved CRi after cycle 1 elected not to receive any further therapy and died 4.5 months later.
The median duration of follow-up in the frontline cohort is 19.3 months (range, 2.1-31.8 months). Eight patients (27%) are still receiving protocol therapy. The median RFS has not been reached, and the 12-month and 18-month RFS rates are 75% and 71%, respectively (Fig 3A). The median OS has not been reached, and the 12-month and 18-month OS rates are 83% and 72%, respectively (Fig 3B). The 60-day mortality rate was 0%. In a post hoc landmark analysis, the 18-month OS for patients who underwent HSCT was 63% and for patients who did not undergo HSCT, it was 79% (Data Supplement, Fig S3). The 18-month OS for patients with FLT3-ITD and FLT3-TKD mutations was 61% and 100%, respectively (Data Supplement, Fig S4), and the 18-month OS for patients younger than 75 years and 75 years and older was 63% and 100%, respectively (Data Supplement, Fig S5). Outcomes by flow MRD response are shown in the Data Supplement (Fig S6).
FIG 3.
Outcomes of the frontline cohort: (A) RFS and (B) OS. OS, overall survival; RFS, relapse-free survival.
Patient Characteristics and Outcomes in the Relapsed/Refractory Cohort
Between December 2019 and December 2022, 22 patients with relapsed/refractory FLT3-mutated AML or chronic myelomonocytic leukemia were treated (Table 1; Fig 1). Ten patients (45%) had an FLT3-ITD mutation alone, eight patients (32%) had an FLT3-TKD mutation alone, and five patients (23%) had both mutations. The median number of previous therapies was two (range, 1-5), including eight patients (36%) with a previous FLT3 inhibitor and 10 (45%) with a previous hypomethylating agent plus venetoclax.
Four patients (18%) achieved CR and two patients (9%) achieved CRi for a composite CR/CRi rate of 27% (Table 2). The mCRC rate was 73%. Best responses by subgroups are shown in the Data Supplement (Table S1).
The median number of cycles received was two (range, 1-9 cycles). The disposition for the 22 relapsed/refractory patients is shown in the Data Supplement (Fig S7). Five patients (23% overall and 33% of patients achieving mCRc) underwent allogeneic HSCT in first remission. With a median duration of follow-up of 30.7 months (range, 1.1-41.8 months), the median RFS was 4.3 months (Data Supplement, Fig S8A) and the median OS was 5.8 months (Data Supplement, Fig S8B). The 30-day and 60-day mortality rates were 0% and 14%, respectively. In a post hoc analysis, the outcomes of patients stratified by type of FLT3 mutation were similar (Data Supplement, Fig S9). There was a trend toward superior OS in patients who had not previously received a hypomethylating agent plus venetoclax and/or gilteritinib (median OS, 10.5 months v 4.2 months in others; P = .095; Data Supplement, Fig S10).
Safety
Grade 3 or higher nonhematologic adverse events are shown in Table 3. Across both cohorts, the most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%). In the frontline cohort, grade 3 or higher infection occurred in 53% of patients and febrile neutropenia occurred in 33%. In the relapsed/refractory cohort, grade 3 or higher infection occurred in 73% of patients, febrile neutropenia in 45%, and sepsis in 23%. Rates of febrile neutropenia, infection, and sepsis in induction versus consolidation are shown in the Data Supplement (Table S2). Five patients in the relapsed/refractory cohort experienced grade 5 events, all in the setting of persistent AML.
TABLE 3.
Grade 3 or Higher Nonhematologic Adverse Events, Regardless of Causality
| Adverse Event | Frontline Cohort (n = 30), No. (%) | Refractory/Relapsed Cohort (n = 22), No. (%) | ||||
|---|---|---|---|---|---|---|
| Grade 3 | Grade 4 | Grade 5 | Grade 3 | Grade 4 | Grade 5 | |
| Acute kidney injury | 2 (7) | 0 | 0 | 0 | 0 | 0 |
| Altered mental status | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Atrial fibrillation | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Cardiac enzyme elevation | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Disseminated intravascular coagulopathy | 0 | 0 | 0 | 0 | 0 | 1 (5) |
| Epistaxis | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Febrile neutropenia | 10 (33) | 0 | 0 | 10 (45) | 0 | 0 |
| GI bleeding | 0 | 0 | 0 | 0 | 1 (5) | 0 |
| Genitourinary bleeding | 0 | 0 | 0 | 2 (9) | 0 | 0 |
| Hyponatremia | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Hypotension | 0 | 0 | 0 | 2 (9) | 1 (5) | 0 |
| Hypoxia | 1 (3) | 0 | 0 | 0 | 0 | 0 |
| Infection | 15 (50) | 0 | 1 (3) | 13 (59) | 1 (5) | 2 (9) |
| Intracranial hemorrhage | 0 | 0 | 0 | 0 | 0 | 1 (5) |
| Multiorgan failure | 0 | 0 | 0 | 0 | 0 | 1 (5) |
| Muscle weakness (generalized) | 0 | 0 | 0 | 1 (5) | 0 | 0 |
| Nausea/vomiting | 1 (3) | 0 | 0 | 0 | 0 | 0 |
| Pain | 2 (7) | 0 | 0 | 1 (5) | 0 | 0 |
| QTc prolongation | 1 (3) | 0 | 0 | 0 | 0 | 0 |
| Sepsis | 2 (7) | 1 (3) | 0 | 4 (18) | 1 (5) | 0 |
| Small bowel obstruction | 1 (3) | 0 | 0 | 0 | 0 | 0 |
| Tumor lysis syndrome | 1 (3) | 0 | 0 | 1 (5) | 0 | 0 |
In the newly diagnosed cohort, the median time to absolute neutrophil count and platelet recovery are shown in the Data Supplement (Figs S11A-S11D). Fifteen patients (50%) in the frontline cohort received PEGylated granulocyte colony stimulating factor in cycle 1 once blast clearance was confirmed on the day 14 bone marrow. Seventeen of 25 patients (68%) in the frontline cohort who received at least one consolidation cycle had a dose reduction of one or more drugs (azacitidine in 44%, venetoclax in 48%, and gilteritinib in 28%). The types and timing of dose reductions in the frontline cohort are shown in the Data Supplement (Fig S12). Four of 16 patients (25%) in the relapsed/refractory cohort had a dose reduction of one or more drugs (azacitidine in 19%, venetoclax in 19%, and gilteritinib in 6%).
DISCUSSION
In this study of the triplet combination of azacitidine, venetoclax, and gilteritinib, a mCRc rate of 75% was achieved in patients with relapsed/refractory FLT3-mutated AML although survival was modest. By contrast, in older adults with newly diagnosed FLT3-mutated AML, high rates of response translated to an encouraging 18-month OS rate of 72%, which compares favorably with expectations of FLT3-mutated AML with azacitidine plus venetoclax or with doublet regimens of low-dose chemotherapy plus an FLT3 inhibitor.12,16,26-28 The regimen could be delivered safely along with appropriate dosing modifications to avoid excessive myelosuppression.
In the frontline setting, all patients achieved morphological remission, with 90% achieving CR and 96% achieving CR/CRi. These remissions were deep, with 93% of patients achieving MRD negativity by flow cytometry and 65% achieving reduction in FLT3-ITD to <5 × 10−5 within four cycles of therapy. Responses were also durable—with only five of the 30 patients relapsing to date—and the 18-month OS rate was 72%, which compares favorably with the reported outcomes with azacitidine plus venetoclax in FLT3-mutated AML (median OS of 12.5 months).12 While our study population was generally younger than the VIALE-A FLT3–mutated population (median age, 71 v 75 years, respectively), encouraging outcomes were observed even in patients 75 years and older (18-month OS of 100%) and in those who did not undergo subsequent HSCT (18-month OS of 79%). These outcomes are encouraging although they should be interpreted with caution given the modest duration of follow-up of our study.
While previous studies have suggested that the combination of venetoclax and FLT3 inhibitors such as gilteritinib is myelosuppressive,15,24,25 our study instituted dosing strategies to mitigate the risk of myelosuppression (eg, use of gilteritinib at 80 mg once daily, a day 14 bone marrow to decide on the duration of venetoclax and gilteritinib, and attenuated dosing of azacitidine and venetoclax in consolidation cycles). With these measures, hematologic recovery was similar to expectations with conventional azacitidine and venetoclax and the 60-day mortality in the frontline cohort was 0%. Given the limitations of our study, including its single-center nature and the lack of rigorous dose-finding in the frontline population (who may tolerate different dosing than patients with relapsed/refractory disease), an additional dose-ranging and expansion study of this triplet regimen in newly diagnosed FLT3-mutated AML is ongoing (ClinicalTrials.gov identifier: NCT05520567). Once an optimized dose is determined, a randomized study comparing this triplet regimen with standard azacitidine and venetoclax in older, unfit patients with newly diagnosed FLT3-mutated AML is warranted.
The promising OS observed with this regimen in newly diagnosed AML raises the question of whether it could be considered even in older adults who are fit for intensive chemotherapy. The AMLSG 16-10 study of 7 + 3 chemotherapy plus midostaurin and the QuANTUM-First study of 7 + 3 chemotherapy plus quizartinib both enrolled patients with FLT3-ITD-mutated AML who were 60 years and older.29,30 In the AMLSG 16-10 trial, the CR/CRi rate in patients older than 60 years was 72.4% and the 1-year OS rate was 59%, and in the QuANTUM-First study, the median OS was 17.5 months. Considering the deep and durable remissions observed in our study, a randomized comparison of this regimen and intensive chemotherapy plus an FLT3 inhibitor in older, HSCT-eligible patients with FLT3-mutated AML may also be considered as the triplet regimen could offer a safer yet effective bridge to HSCT in this population.
Despite encouraging data in the frontline setting, the outcomes in the relapsed/refractory cohort did not appear to improve upon expectations with gilteritinib monotherapy or with gilteritinib plus venetoclax, where the median OS was 9.3 months and 10.0 months, respectively.14,15 However, it is notable that our population was enriched with patients who had received previous hypomethylating agent plus venetoclax and/or gilteritinib (making up 45% of this cohort)—patients who were either excluded or significantly less represented in these other studies. The triplet regimen may be a reasonable option for patients with no previous exposure to any of these agents—where the median OS was 10.3 months—although it remains unclear whether the use of azacitidine provides additional efficacy, beyond what could be achieved with a gilteritinib and venetoclax doublet regimen.
In summary, a triplet regimen of azacitidine, venetoclax, and gilteritinib was safe and effective in patients with newly diagnosed FLT3-mutated AML, resulting in a CR rate of 90% and an 18-month OS rate of 72%, although dose reductions were still required in most patients because of myelosuppression. These data support further development of gilteritinib and other FLT3 inhibitors in combination with azacitidine and venetoclax in older adults with FLT3-mutated AML.
Nicholas J. Short
Honoraria: Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer Inc, Astellas Pharma Inc, Sanofi, BeiGene
Consulting or Advisory Role: Pfizer Inc, GSK, NKARTA, Sanofi
Research Funding: Takeda Oncology, Astellas Pharma Inc, Xencor, Stemline Therapeutics, NextCure
Naval Daver
Consulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics, Gilead Sciences, Arog, Shattuck Labs, Kite, a Gilead company, Stemline/Menarini
Research Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Immunogen (Inst), Genentech (Inst), AbbVie (Inst), Astellas Pharma (Inst), Servier (Inst), Daiichi Sankyo (Inst), Gilead Sciences (Inst), Amgen (Inst), Trillium Therapeutics (Inst), Hanmi (Inst), Trovagene (Inst), Fate Therapeutics (Inst), Novimmune (Inst), Glycomimetics (Inst), Kite, a Gilead company (Inst)
Courtney D. Dinardo
Honoraria: AbbVie, Jazz Pharmaceuticals, Novartis, Foghorn Therapeutics, GlaxoSmithKline, Genmab, Servier, Genentech/AbbVie, Astellas Pharma, Bristol Myers Squibb Foundation, Cleave Biosciences, Gilead Sciences, Schrodinger
Consulting or Advisory Role: Celgene, Agios, AbbVie, GlaxoSmithKline
Research Funding: AbbVie, Celgene, Cleave Therapeutics, Foghorn Therapeutics, Immune-Onc Therapeutics, Jazz Pharmaceuticals, Servier, Loxo/Lilly, Astex Pharmaceuticals
Tapan Kadia
Honoraria: Cure
Consulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, Agios, Daiichi Sankyo/UCB Japan, Liberum, Sanofi, Servier, Pinot Bio
Research Funding: Bristol Myers Squibb, Celgene, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet Therapeutics, Cyclacel, Pulmotech, Cellenkos, Glycomimetics, Astex Pharmaceuticals, Iterion Therapeutics, Delta-Fly Pharma, Regeneron (Inst)
Musa Yilmaz
Research Funding: Daiichi Sankyo, Pfizer
Gautam Borthakur
Consulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, Takeda, AbbVie
Research Funding: Incyte (Inst), GlaxoSmithKline (Inst), Cyclacel (Inst), BiolineRx (Inst), MedImmune (Inst), Lilly (Inst), Oncoceutics (Inst), Ryvu Therapeutics (Inst), Janssen Scientific Affairs (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Novartis (Inst), AstraZeneca (Inst), Mundipharma Research (Inst), PTC Therapeutics (Inst), BioTheryX (Inst), XBiotech (Inst), Arvinas (Inst), Astex Pharmaceuticals (Inst), TCR2 Therapeutics (Inst), Nkarta (Inst), Treadwell Therapeutics (Inst), Cellestia Biotech (Inst)
Guillermo Montalban-Bravo
Research Funding: IFM Therapeutics (Inst), Takeda
Guillermo Garcia-Manero
Honoraria: Astex Pharmaceuticals, Acceleron Pharma, AbbVie, Novartis, Gilead Sciences, Curis, Genentech, Bristol Myers Squibb/Celgene
Consulting or Advisory Role: Astex Pharmaceuticals, Acceleron Pharma, Bristol Myers Squibb
Research Funding: Astex Pharmaceuticals, Novartis, AbbVie, Bristol Myers Squibb, Genentech, Aprea Therapeutics, Curis, Gilead Sciences
Ghayas C. Issa
Consulting or Advisory Role: Novartis, Kura Oncology, Syndax, NuProbe, AbbVie
Research Funding: Novartis (Inst), Syndax (Inst), Kura Oncology (Inst), Merck, Cullinan Oncology
Elias Jabbour
Consulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Astellas Pharma, Genentech
Research Funding: Pfizer, AbbVie, Amgen, Takeda, Adaptive Biotechnologies, Ascentage Pharma Group
Christopher J. Stojanik
Employment: MD Anderson Cancer Center
Keyur P. Patel
Consulting or Advisory Role: Astellas Pharma, Syros Pharmaceuticals
Marina Konopleva
Honoraria: AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, Forty Seven
Consulting or Advisory Role: AbbVie, Genentech/Roche, Stemline Therapeutics, Amgen, Forty Seven, Roche, Janssen, AstraZeneca, Gilead/Forty Seven, MEI Pharma, Sanofi/Aventis, Vincerx Pharma
Research Funding: AbbVie (Inst), Genentech (Inst), Cellectis (Inst), Ablynx (Inst), AstraZeneca (Inst), Sanofi (Inst), Forty Seven (Inst), Allogene Therapeutics, Daiichi Sankyo/Lilly, Gilead/Forty Seven, Immunogen, MEI Pharma, Precision Biosciences, Rafael Pharmaceuticals, Stemline Therapeutics
Patents, Royalties, Other Intellectual Property: Reata pharmaceutical—Research Funding (Issued, Licensed, Royalities)
Hagop Kantarjian
Honoraria: AbbVie, Amgen, Pfizer, Ascentage Pharma Group, Astellas Pharma, AstraZeneca/MedImmune, Ipsen, KAHR Medical, Novartis, Precision Biosciences, Shenzhen Target Rx, Taiho Pharmaceutical, Daiichi-Sankyo (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst)
Consulting or Advisory Role: AbbVie
Research Funding: Amgen (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), AbbVie (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst), Ascentage Pharma (Inst), Daiichi Sankyo/Lilly (Inst)
Farhad Ravandi
Honoraria: Amgen, Pfizer, Astellas Pharma, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, Novartis, Syros Pharmaceuticals, Taiho Pharmaceutical
Consulting or Advisory Role: Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara Inc
Research Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant, Astex Pharmaceuticals, Taiho Oncology, Syros Pharmaceuticals, Prelude Therapeutics, Biomea Fusion, Astellas Pharma (Inst)
No other potential conflicts of interest were reported.
SUPPORT
Supported in part by the MD Anderson Cancer Center Leukemia SPORE CA100632 and the NIH/NCI Cancer Center Support Grant P30 CA016672. Astellas provided research funding and gilteritinib drug support.
CLINICAL TRIAL INFORMATION
DATA SHARING STATEMENT
Qualified researchers may request access to individual patient-level data reported in this article after print publication of the current article. No identifying data will be provided. All requests for data must include a description of the research proposal and be submitted to the corresponding author. The study protocol, including the statistical analysis plan, is included in the Data Supplement.
AUTHOR CONTRIBUTIONS
Conception and design: Nicholas J. Short, Naval Daver, Musa Yilmaz, Elias Jabbour, Wei Qiao, Marina Konopleva, Hagop Kantarjian, Farhad Ravandi
Financial support: Nicholas J. Short, Farhad Ravandi
Administrative support: Nicholas J. Short, Farhad Ravandi
Provision of study materials or patients: Nicholas J. Short, Courtney D. Dinardo, Tapan Kadia, Musa Yilmaz, Ghayas C. Issa, Kelly S. Chien, Keyur P. Patel, Jennifer Thankachan, Marina Konopleva, Farhad Ravandi
Collection and assembly of data: Nicholas J. Short, Naval Daver, Courtney D. Dinardo, Tapan Kadia, Lewis F. Nasr, Walid Macaron, Musa Yilmaz, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia-Manero, Kelly S. Chien, Elias Jabbour, Jairo Matthews, Keyur P. Patel, Regina Abramova, Jennifer Thankachan, Marina Konopleva, Farhad Ravandi
Data analysis and interpretation: Nicholas J. Short, Naval Daver, Courtney D. Dinardo, Tapan Kadia, Lewis F. Nasr, Walid Macaron, Musa Yilmaz, Guillermo Montalban-Bravo, Ghayas C. Issa, Elias Jabbour, Cedric Nasnas, Xuelin Huang, Wei Qiao, Keyur P. Patel, Hagop Kantarjian, Farhad Ravandi
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Nicholas J. Short
Honoraria: Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer Inc, Astellas Pharma Inc, Sanofi, BeiGene
Consulting or Advisory Role: Pfizer Inc, GSK, NKARTA, Sanofi
Research Funding: Takeda Oncology, Astellas Pharma Inc, Xencor, Stemline Therapeutics, NextCure
Naval Daver
Consulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics, Gilead Sciences, Arog, Shattuck Labs, Kite, a Gilead company, Stemline/Menarini
Research Funding: Bristol Myers Squibb (Inst), Pfizer (Inst), Immunogen (Inst), Genentech (Inst), AbbVie (Inst), Astellas Pharma (Inst), Servier (Inst), Daiichi Sankyo (Inst), Gilead Sciences (Inst), Amgen (Inst), Trillium Therapeutics (Inst), Hanmi (Inst), Trovagene (Inst), Fate Therapeutics (Inst), Novimmune (Inst), Glycomimetics (Inst), Kite, a Gilead company (Inst)
Courtney D. Dinardo
Honoraria: AbbVie, Jazz Pharmaceuticals, Novartis, Foghorn Therapeutics, GlaxoSmithKline, Genmab, Servier, Genentech/AbbVie, Astellas Pharma, Bristol Myers Squibb Foundation, Cleave Biosciences, Gilead Sciences, Schrodinger
Consulting or Advisory Role: Celgene, Agios, AbbVie, GlaxoSmithKline
Research Funding: AbbVie, Celgene, Cleave Therapeutics, Foghorn Therapeutics, Immune-Onc Therapeutics, Jazz Pharmaceuticals, Servier, Loxo/Lilly, Astex Pharmaceuticals
Tapan Kadia
Honoraria: Cure
Consulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, Agios, Daiichi Sankyo/UCB Japan, Liberum, Sanofi, Servier, Pinot Bio
Research Funding: Bristol Myers Squibb, Celgene, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet Therapeutics, Cyclacel, Pulmotech, Cellenkos, Glycomimetics, Astex Pharmaceuticals, Iterion Therapeutics, Delta-Fly Pharma, Regeneron (Inst)
Musa Yilmaz
Research Funding: Daiichi Sankyo, Pfizer
Gautam Borthakur
Consulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, Takeda, AbbVie
Research Funding: Incyte (Inst), GlaxoSmithKline (Inst), Cyclacel (Inst), BiolineRx (Inst), MedImmune (Inst), Lilly (Inst), Oncoceutics (Inst), Ryvu Therapeutics (Inst), Janssen Scientific Affairs (Inst), Bristol Myers Squibb (Inst), AbbVie (Inst), Novartis (Inst), AstraZeneca (Inst), Mundipharma Research (Inst), PTC Therapeutics (Inst), BioTheryX (Inst), XBiotech (Inst), Arvinas (Inst), Astex Pharmaceuticals (Inst), TCR2 Therapeutics (Inst), Nkarta (Inst), Treadwell Therapeutics (Inst), Cellestia Biotech (Inst)
Guillermo Montalban-Bravo
Research Funding: IFM Therapeutics (Inst), Takeda
Guillermo Garcia-Manero
Honoraria: Astex Pharmaceuticals, Acceleron Pharma, AbbVie, Novartis, Gilead Sciences, Curis, Genentech, Bristol Myers Squibb/Celgene
Consulting or Advisory Role: Astex Pharmaceuticals, Acceleron Pharma, Bristol Myers Squibb
Research Funding: Astex Pharmaceuticals, Novartis, AbbVie, Bristol Myers Squibb, Genentech, Aprea Therapeutics, Curis, Gilead Sciences
Ghayas C. Issa
Consulting or Advisory Role: Novartis, Kura Oncology, Syndax, NuProbe, AbbVie
Research Funding: Novartis (Inst), Syndax (Inst), Kura Oncology (Inst), Merck, Cullinan Oncology
Elias Jabbour
Consulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Astellas Pharma, Genentech
Research Funding: Pfizer, AbbVie, Amgen, Takeda, Adaptive Biotechnologies, Ascentage Pharma Group
Christopher J. Stojanik
Employment: MD Anderson Cancer Center
Keyur P. Patel
Consulting or Advisory Role: Astellas Pharma, Syros Pharmaceuticals
Marina Konopleva
Honoraria: AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, Forty Seven
Consulting or Advisory Role: AbbVie, Genentech/Roche, Stemline Therapeutics, Amgen, Forty Seven, Roche, Janssen, AstraZeneca, Gilead/Forty Seven, MEI Pharma, Sanofi/Aventis, Vincerx Pharma
Research Funding: AbbVie (Inst), Genentech (Inst), Cellectis (Inst), Ablynx (Inst), AstraZeneca (Inst), Sanofi (Inst), Forty Seven (Inst), Allogene Therapeutics, Daiichi Sankyo/Lilly, Gilead/Forty Seven, Immunogen, MEI Pharma, Precision Biosciences, Rafael Pharmaceuticals, Stemline Therapeutics
Patents, Royalties, Other Intellectual Property: Reata pharmaceutical—Research Funding (Issued, Licensed, Royalities)
Hagop Kantarjian
Honoraria: AbbVie, Amgen, Pfizer, Ascentage Pharma Group, Astellas Pharma, AstraZeneca/MedImmune, Ipsen, KAHR Medical, Novartis, Precision Biosciences, Shenzhen Target Rx, Taiho Pharmaceutical, Daiichi-Sankyo (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst)
Consulting or Advisory Role: AbbVie
Research Funding: Amgen (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), AbbVie (Inst), Immunogen (Inst), Jazz Pharmaceuticals (Inst), Ascentage Pharma (Inst), Daiichi Sankyo/Lilly (Inst)
Farhad Ravandi
Honoraria: Amgen, Pfizer, Astellas Pharma, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, Novartis, Syros Pharmaceuticals, Taiho Pharmaceutical
Consulting or Advisory Role: Amgen, Astellas Pharma, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara Inc
Research Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant, Astex Pharmaceuticals, Taiho Oncology, Syros Pharmaceuticals, Prelude Therapeutics, Biomea Fusion, Astellas Pharma (Inst)
No other potential conflicts of interest were reported.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Qualified researchers may request access to individual patient-level data reported in this article after print publication of the current article. No identifying data will be provided. All requests for data must include a description of the research proposal and be submitted to the corresponding author. The study protocol, including the statistical analysis plan, is included in the Data Supplement.