Pau Montesinos, MD, PhD, attending physician, hematologist, University Hospital La Fe, Valencia, Spain, discusses preliminary efficacy seen with the addition of quizartinib to standard 7+3 chemotherapy in patients with newly diagnosed 

-ITD wild-type acute myeloid leukemia (AML).

The phase 2 QUIWI trial (NCT04107727) was designed to compare event-free survival (EFS) outcomes with the combination vs placebo. The trial was composed of a safety run-in portion followed by a double-blind randomization phase. Patients with newly diagnosed 

-ITD wild-type AML who were fit for intensive chemotherapy were enrolled on the trial and stratified according to age. Notably, these patients were centrally screened for 

-ITD before being randomized 2:1 to the experimental vs control regimen.

Early efficacy data from the first interim analysis of this trial were reported at the 2023 EHA Congress. At a median follow-up 21 months, the quizartinib combination produced a median EFS of 16.5 months vs 10.6 months with placebo (HR, 0.741; 95% CI, 0.535-1.026; 2-sided 

= .059), Montesinos reports. This indicates a trend towards improved EFS with the combination, he says. Significant improvement in relapse-free survival (RFS) was also observed, Montesinos adds. Median RFS was 18.6 months with placebo and was not reached with quizartinib plus chemotherapy.

Moreover, the 3-year overall survival (OS) rate was approximately 40% in the placebo arm and 60% in the experimental arm, Montesinos continues. Median OS was 20.2 months with placebo and was not reached with the combination (HR, 0.569; 95% CI, 0.385-0.841; 2-sided 

The composite complete response (cCR) rates were comparable in both arms, Montesinos states. After 1 or 2 induction cycles, the cCR rate was 78% in both study arms, while the CR/CR with incomplete hematologic recovery rate with minimal residual disease (MRD) negativity was 44% vs 43% with the combination and placebo, respectively. Although the regimen did not improve cCR rates vs placebo, significant increases in both EFS and RFS indicate its potential long-term benefit in this population, Montesinos concludes.

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Pau Montesinos, MD, PhD, discusses preliminary efficacy seen with the addition of quizartinib to standard 7+3 chemotherapy in patients with newly diagnosed FLT3-ITD wild-type acute myeloid leukemia.
 

Dr Montesinos on Quizartinib Plus Chemotherapy in Newly Diagnosed FLT3-ITD Wild-Type AML

Pau Montesinos, MD discusses key updates from the global phase 3 AGILE study, as presented at the 2022 American Society of Hematology Annual Meeting, and speaks to the clinical implications of these data.

Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m Newly Diagnosed AML Treated with IVO + AZA in the AGILE Study

Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1).

IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival, and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA in patients (pts) with newly diagnosed 

-mutant acute myeloid leukemia (AML) in the phase 3 AGILE trial (NCT03173248).

Pts were randomized 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously for 7 days in 28-day cycles (n = 72) or PBO+AZA (n = 74).

Red blood cell (RBC)/platelet transfusion history were assessed at screening and follow-up.

Bone marrow (BM) and peripheral blood samples were obtained at screening and during weeks 9, 17, 25, 33, 41, and 53; every 24 weeks thereafter; and at end of treatment and during EFS follow up.

Samples were analyzed at each local site according to ICSH guidelines.

In the IVO+AZA and PBO+AZA arms, 4.2% and 5.5% of pts, respectively, received concomitant granulocyte colony-stimulating factor.

Hemoglobin levels steadily increased from baseline at a similar rate in both treatment arms.

Mean platelet count recovered from baseline values in the IVO+AZA and PBO+AZA arms (71.0 and 92.6 x 109/L, respectively) as early as week 9 of treatment (171.1 and 155.1 x 109/L, respectively) and continued to steadily increase thereafter in the treated population.

In pts receiving IVO+AZA, mean neutrophil counts rapidly increased from baseline (0.99 x 109/L) to week 2 (2.05 x 109/L) and week 5 (4.07 x 109/L), and then generally stabilized to within the normal range to study end (last available cycle value; ̃2.0 x 109/L).

Mean neutrophil counts initially declined with PBO+AZA before slowly recovering to near-normal levels after 36-40 weeks.

The increased blood counts were accompanied by a rapid decrease in the mean BM blast percentage from 54.8% at baseline to 12.0% and 7.2% at week 9 and 17, respectively, in IVO+AZA treated patients and were maintained for 149 weeks.

The decline in BM blasts was slower in the PBO+AZA arm (53.7%, 34.6% and 19.6% at baseline, week 9 and week 17, respectively).

Among patients who were RBC/platelet transfusion-dependent at baseline (̃54.0% in both groups), 46.2% in the IVO+AZA group achieved RBC/platelet transfusion independence compared with 17.5% in the PBO+AZA arm (1-sided p = 0.0032).

Additionally, fewer adverse events of febrile neutropenia (28.2% vs 34.2%) and infections (28.2% vs 49.3%) were reported in the IVO+AZA arm compared to the PBO+AZA arm.

IVO+AZA demonstrated a significant clinical benefit compared with PBO+AZA and this sub-analysis demonstrated a rapidly improved recovery of blood counts and a reduced dependence on RBC and/or platelet transfusion.

Moreover, rates of febrile neutropenia and infections were reduced with IVO+AZA. Clinical trial information: NCT03173248.

Dohner H, Montesinos P, Polo SV, et al. Hematologic improvements with ivosidenib + azacitidine compared to placebo + azacitidine in patients with newly diagnosed acute myeloid leukemia. Abstract presented at: 2022 American Society of Clinical Oncology, June 3-7, 2022; Chicago, Illinois, and virtual. Abstract 7042.

Dr. Pau Montesinos reviews the efficacy of ivosidenib and azacitidine in reducing transfusions and improving blood counts in patients with newly diagnosed acute myeloid leukemia.  

Pau Montesinos, MD, PhD

Articles

Dr Montesinos on Quizartinib Plus Chemotherapy in Newly Diagnosed FLT3-ITD Wild-Type AML

Molecular Characterization of Clinical Response and Relapse in Patients with IDH1m Newly Diagnosed AML Treated with IVO + AZA in the AGILE Study

Hematologic Improvements With Ivosidenib + Azacitidine Compared to Placebo + Azacitidine in Patients With Newly Diagnosed Acute Myeloid Leukemia