Quizartinib Triplet Shows Activity in Heavily Pretreated, FLT3-ITD–Mutated AML

The triplet combination regimen comprised of quizartinib, decitabine, and venetoclax elicited encouraging responses in heavily pretreated patients with relapsed/refractory FLT3-ITD–mutated acute myeloid leukemia who were previously exposed to a FLT3 inhibitor.

The triplet combination regimen comprised of quizartinib, decitabine, and venetoclax (Venclexta) elicited encouraging responses in heavily pretreated patients with relapsed/refractory FLT3-ITD–mutated acute myeloid leukemia (AML) who were previously exposed to a FLT3 inhibitor, according to findings from a phase 1/2 trial (NCT03661307).1

At the 2022 EHA Congress, investigators reported safety and efficacy data from the relapsed/refractory and frontline cohorts who received treatment on the trial. In the relapsed/refractory cohort (n = 28), the triplet elicited a composite complete response (CRc) rate of 82%, with a CR rate of 11% and a complete remission with incomplete count recovery (CRi) rate of 28%. Moreover, the morphologic leukemia-free state (MLFS) rate was 43%. Additionally, 46% of patients had bone marrow blasts of 5% or less at day 14.

Additionally, the FLT3 minimal residual disease (MRD) negativity rate in this cohort was 25% per flow cytometry, and the FLT3 PCR negativity after 1 cycle was 33%. The 60-day mortality rate in these patients was 11%, and 43% were able to proceed with allogeneic stem cell transplant (ASCT).

In the frontline cohort (n = 7), all patients who received the triplet regimen achieved a CRc and day 14 bone marrow of less than 5%. The best MRD negativity rate was 66% for flow cytometry and the FLT3 PCR-negative rate was 86%. No early mortality has been observed, and 3 of these patients (43%) were able to proceed with ASCT.

“The triplet regimen of decitabine, venetoclax, and quizartinib is effective in heavily pretreated patients with FLT3-ITD–mutated patients, and about one-quarter of the patients are alive in this study,” Musa Yilmaz, MD, lead study author and assistant professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a presentation on the data. “We show that 30 mg is the recommended phase 2 dose [RP2D] for [quizartinib]. Moreover, delayed ANC is a problem with triplet regimens, and this requires significant attention. Limiting venetoclax to 14 days, even limiting the FLT3 inhibitor to 14 days, [may help] the ANC to recover faster.”

Approximately one-third of patients with AML have tumors that harbor FLT3 mutations, according to Yilmaz, and this mutation is linked with an increased risk of relapse and worse overall survival (OS). In the past decade, FLT3 inhibitors like midostaurin (Rydapt), sorafenib (Nexavar), and gilteritinib (Xospata) have emerged in the treatment landscape, and regimens comprised of a FLT3 inhibitor and intensive chemotherapy has served to improve outcomes for younger patients.

However, older patients are often unable to receive intensive chemotherapy; the patients are typically administered a hypomethylating agent (HMA) and venetoclax or a FLT3 inhibitor, and the expected median OS is poor for these patients, ranging from 8 months to 12 months. Moreover, those with relapsed or refractory disease who are exposed to several lines of FLT3 inhibitors can experience a median OS that can be as short as 2 months.

In this phase 1 portion of the study presented during the meeting, investigators examined the second-generation FLT3 inhibitor quizartinib, which has been shown to produce responses even when used as a monotherapy. Preclinical data have also suggested that there may be synergy between this agent and venetoclax. In this study, investigators sought to explore this combination further.

The study enrolled patients into 2 cohorts: those with relapsed/refractory, FLT3-mutated AML or high-risk myelodysplastic syndrome and 10% or higher blasts, or those with newly diagnosed, FLT3-mutated AML who were not candidates to receive intensive chemotherapy. Those with FLT3-ITD with or without TKD mutations were permitted.

In the induction phase of treatment, intravenous (IV) decitabine was given at 20 mg/m2 on days 1 through 10, plus venetoclax at a daily dose of 400 mg on days 1 to 21 (with a bone marrow biopsy performed on day 14), and quizartinib at a daily dose ranging from 30 mg to 40 mg on days 1 through 28. Venetoclax was discontinued on day 14 in patients with bone marrow blasts of at least 5% or those with hypoplastic bone marrow.

In the consolidation phase, decitabine was given at 20 mg/m2 on days 1 to 5, plus venetoclax at 400 mg daily on days 1 to 14, and quizartinib at 30 mg to 40 mg daily on days 1 to 14 for up to 12 cycles. Venetoclax duration was reduced in subsequent cycles for those who were in CR based on count recovery durations. Quizartinib was dose reduced to 14 days in those with prolonged count recovery.

The primary end point of the trial was to determine the RP2D of quizartinib in combination with decitabine and venetoclax in those with AML harboring a FLT3 mutation. The secondary objective of the research was to identify CR, CRi, MRD, and OS experienced with the regimen.

Among the 35 patients, the median age ranged from 57 years (range, 23-86) in the relapsed/refractory cohort to 70 years (range, 65-85) in the frontline cohort; 32% and 14% of patients, respectively, were male.

“In the relapsed/refractory cohort, I would like to pull your attention to the median number of prior therapies, which was 3,” Yilmaz noted. “As such, this [was a] heavily pretreated patient population—82% received at least 1 FLT3 inhibitor and 75% already received gilteritinib.”

In the frontline cohort, most of the patients were high risk with an adverse (43%) karyotype and had secondary (72%) or therapy-related (14%) AML.

All patients were required to have FLT3-ITD, and only a few patients had FLT3-TKD mutations in the relapsed/refractory cohort, according to Yilmaz. In the frontline cohort, all patients had FLT3-ITD–mutated disease, and the median FLT3-ITD allelic ratio was 0.47 (range, 0.21-0.85).

As part of the first phase of the research, 9 patients with FLT3-ITD–mutated AML received treatment. Quizartinib was administered at a 30-mg daily dose in 7 patients, and 2 patients received the agent at a daily dose of 40 mg. At the lower dose level, no dose-limiting toxicities (DLTs) were observed. However, 2 DLTs were experienced by those who received the agent at 40 mg and both were grade 4 myelosuppression. “As such, we stopped further enrollment to the 40-mg dose, and we chose 30 mg daily as the RP2D for quizartinib,” Yilmaz said.

When looking at patient subgroups within the relapsed/refractory cohort (n = 28), previous receipt of gilteritinib or HMA/venetoclax did not appear to impact response rates with the triplet regimen. The CRc rate reported in those who previously received gilteritinib was 80% vs 85% in those who had no prior gilteritinib; in those who previously received a HMA in combination with venetoclax, the CRc rate was 80% vs 85% in those who did not.

Moreover, the triplet induced a CRc rate of 62% in those who were RAS/MAPK positive vs 95% in those who were negative; in those who were positive for DNMT3A, the CRc rate was 73% vs 100% who were negative. The regimen produced a CRc rate of 80% in those with NPM1 positivity vs 88% in those with NPM1 negativity.

The most common grade 3 to 5 adverse effects experienced with the combination regimen were febrile neutropenia (39%), lung infection (39%), other infections (29%), and sepsis (16%). Frequently experienced grade 1 or 2 toxicities were hypocalcemia (81%), hypokalemia (76%), dyspnea (53%), diarrhea (50%), hypophosphatemia (47%), and increased creatinine level (47%).

“In this patient population, we have seen only 1 grade 3 QTc prolongation in 1 patient. Prolonged myelosuppression was an important hassle when we first launched this study and enrolled the first cohorts of our phase 1 group,” Yilmaz said.

In the relapsed/refractory cohort, when quizartinib was given continuously, the median time to ANC recovery was prolonged, at 51 days (range, 26-138). Then, the protocol was amended, and investigators limited quizartinib to 28 days and venetoclax to day 14. An improvement in ANC recovery time was observed in those who achieved a response, at 26 days (range, 13-53).

At last follow-up, 12 of the 28 patients in the relapsed/refractory cohort achieved a CRc and went on to ASCT; 4 of these patients were alive and in CRc, 4 died in CRc, and 6 relapsed and died. Of 11 patients who achieved CRc with the regimen but did not go on to ASCT, 2 achieved CRc and were alive, 2 died in CRc, and 7 relapsed and died. All 5 patients who did not respond to the combination died of disease progression.

“In the relapsed/refractory cohort, the median OS was 6.9 months, and patients who achieved deeper responses had better OS of 19.0 months or 11.1 months,” Yilmaz said. “Also, patients who did not receive prior HMA/venetoclax or those who did not receive prior gilteritinib, had better OS at a median of 11.1 months [and 11.5 months, respectively].”

At last follow-up, 3 of the 7 patients in the newly diagnosed cohort had a CRc with ASCT; 1 patient was alive in CRc, 1 patient died in CRc, and the last patient relapsed after transplant and died; this patient had TP53-mutated disease and complex karyotype. Four of the patients in this cohort had a CRc without ASCT; of these patients, 3 had CRc and were alive, and the last patient relapsed and died; this patient had INV at baseline, and at the time of relapse, was FLT3 negative. In this cohort, the median OS with the triplet regimen was 14.5 months.

Investigators also examined next-generation sequencing, and they found that that RAS/MAPK mutations drove both primary and secondary resistance. Specifically, those who did not have these mutations were found to be the ones who experienced prolonged, durable remissions, according to Yilmaz. Those who had underlying RAS/MAPK at the time of treatment initiation, either did not respond or experienced a short response and rapid relapse.

“RAS/MAPK pathway mutations or FLT3-F691L mutations are still associated with resistance even after the triplet,” Yilmaz concluded. “This clinical trial continues to enroll.”


  1. Yilmaz M, Muftuoglu M, Kantarjian H, et al. Quizartinib with decitabine and venetoclax (triplet) is active in patients with FLT3-ITD mutated acute myeloid leukemia – a phase I/II study. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract S127.