CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: September 06, 2022
Expiration: September 05, 2023
Stéphane de Botton, MD:
Between 25% and 30% of patients newly diagnosed with AML have an FLT3-ITD or FLT3-TKD mutation.13 FLT3-ITD represents 80% of all FLT3 mutations and is prognostic for poorer outcomes, whereas the prognostic relevance of FLT3-TKD is unclear.
In the phase III RATIFY trial, the FLT3 inhibitor midostaurin significantly improved OS and EFS in newly diagnosed AML with either FLT3-ITD or FLT3-TKD following allogeneic hematopoietic stem cell transplantation (HSCT).14 Patients were younger than 60 years of age and had received no maintenance therapy.
Quizartinib is a potent second-generation FLT3‑ITD inhibitor with high response rates as monotherapy in phase I trials in AML.15 This agent appears to be effective in patients with wild‑type FLT3.
The phase III QuANTUM-First study is a classical and well-done trial in newly diagnosed FLT3-ITD–positive AML, with intensive induction using daunorubicin or idarubicin with cytarabine in both arms.16 Patients were randomized in the induction phase to receive the addition of quizartinib or placebo for 3 weeks on Days 8-21 (N = 539). Consolidation therapy comprised up to 4 courses of continued quizartinib or placebo plus high-dose cytarabine with or without allogeneic HSCT. Patients then received maintenance with continued quizartinib or placebo for up to 36 cycles.
The primary endpoint was OS. Secondary endpoints included EFS, CR rates, and safety. RFS and duration of response also were assessed.
Stéphane de Botton, MD:
The patient population was well balanced between arms, with a median age of 56 years.16 Most patients had an Eastern Cooperative Oncology Group performance status of 0/1, and approximately 70% had intermediate cytogenetic risk.
Stéphane de Botton, MD:
The study met its primary endpoint, demonstrating a median OS of 31.9 months with quizartinib vs 15.1 months with placebo (HR: 0.776; P = .03).16 This is a highly significant difference of nearly 17 months between arms.
Stéphane de Botton, MD:
OS still was strongly in favor of quizartinib when the analysis censored for allogeneic HSCT (HR: 0.752).16
Stéphane de Botton, MD:
Among patients in first CR, OS was superior with quizartinib regardless of whether the patient received allogeneic HSCT.16
Stéphane de Botton, MD:
The secondary endpoint of EFS was not met in the primary analysis, which defined induction treatment failure as no CR by Day 42 of the last induction cycle.16 However, in sensitivity analyses of EFS, which defined induction treatment failure as no CR or composite CR by end of induction, EFS was significantly better in the experimental arm.
Stéphane de Botton, MD:
The composite CR rate was significantly better with quizartinib at 72% vs 65% with placebo.16 However, true CR rates were equivalent between the 2 arms (55%). Of more importance, the median duration of CR was 3 times as long in the quizartinib arm (39 months vs 12 months for placebo).
Stéphane de Botton, MD:
The secondary endpoint of RFS also was significantly improved by adding quizartinib to intensive treatment.16 Median RFS was 39.3 months with quizartinib vs 13.6 months with placebo. Moreover, the cumulative incidence of relapse at 24 months was lower with quizartinib at 31% vs 43% with placebo.
Stéphane de Botton, MD:
TEAEs associated with discontinuation, dose interruption, or dose reduction were much more frequent in the quizartinib arm vs the placebo arm. One fifth of patients receiving quizartinib experienced a TEAE associated with discontinuation vs 9% receiving placebo.
Serious AEs were seen in 54% of the quizartinib arm vs 45% of the placebo arm. There was a slight increase in death rate at Day 30 and Day 60 with quizartinib but no true safety concerns.
Stéphane de Botton, MD:
The quizartinib arm had slightly higher rates of treatment-emergent febrile neutropenia and a notably higher rate of neutropenia vs placebo (all grade: 20% vs 10%; grade 3/4: 18.1% vs 8.6%).16
Rates of nonhematologic TEAEs such as pyrexia, diarrhea, nausea, and rash all were similar between arms.
Stéphane de Botton, MD:
QTc prolongation occurred more frequently in the quizartinib arm, where 34% of patients had a new QTcF interval >450 ms vs 18% with placebo.16 In the quizartinib arm, 10% of patients had a QTcF increase from baseline >60 ms vs 5% with placebo. Of note, 2 patients in the quizartinib arm had cardiac arrest, and 1 patient died in their sleep.
Stéphane de Botton, MD:
In this phase III trial, the addition of quizartinib to standard induction and consolidation therapy followed by quizartinib monotherapy for up to 3 years significantly improved OS vs placebo in patients newly diagnosed with FLT3-ITD–positive AML.16 In addition, clinically meaningful improvements in RFS, reduced cumulative incidence of relapse, and longer duration of CR also were observed with quizartinib vs placebo. The safety profile for quizartinib combined with standard induction and consolidation therapy was generally manageable, with no new safety signals.
It is not clear whether quizartinib or midostaurin is superior in newly diagnosed AML with FLT3-ITD. There are no comparisons between these agents in the first-line setting, and the safety profile of each is slightly different.
Stéphane de Botton, MD:
Solh and colleagues17 in the United Kingdom conducted a retrospective study of 304 patients with AML and nonfavorable risk who received initial treatment with either 7+3 (n = 86) or fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG) with or without idarubicin. Results showed that 3-year postremission OS and disease-free survival were significantly better with FLAG plus idarubicin (FLAG-Ida) than with 7+3.
AML19 is a randomized phase III trial intended to determine whether the combination therapy of CPX-351 (daunorubicin/cytarabine) is superior to FLAG-Ida in a very difficult-to-treat patient population in the frontline setting. This trial enrolled patients with de novo AML, secondary AML, or MDS with >10% blasts who have an adverse karyotype and are high risk (N = 195).18
In the CPX-351 arm, patients received 4 courses, with HSCT after course 2 if feasible. In the chemotherapy arm, patients received FLAG-Ida for 2 courses, then a course of amsacrine, cytarabine, and etoposide, followed by a course of mitoxantrone and cytarabine.
The primary endpoint was OS, and key secondary endpoints included response rates, EFS, and safety. RFS and duration of response also were assessed. At EHA 2022, Russell and colleagues18 presented results from an exploratory analysis of patients with known adverse-risk cytogenetics
Stéphane de Botton, MD:
The baseline characteristics were well balanced between arms, including the proportion of those with de novo AML (~50%), secondary AML (~20%), and high‑risk MDS (~30%).18 In total, 107 patients were included in the CPX-351 arm and 88 in the FLAG‑Ida arm.
Stéphane de Botton, MD:
With regard to hematologic toxicity, during course 1, platelet recovery took slightly longer in the CPX-351 arm, but by course 2, CPX-351 demonstrated better tolerability in terms of both neutrophils and platelet recovery.18 In course 2, those in the CPX-351 arm took 31 days to recover neutrophils and platelets, whereas in the FLAG-Ida arm, the time was 46 days and 36 days, respectively.
Overall, the 30‑day and 60‑day mortality rates were equivalent between the 2 arms, with 60-day mortality at approximately 12%.
Stéphane de Botton, MD:
The ORR was somewhat better in the FLAG‑Ida arm, but the difference was not statistically significant (76% vs 64% with CPX-351).18 A caveat is that more patients had resistant disease in the CPX-351 arm.
Of interest, the median duration of response appeared to favor CPX-351 (510 vs 391 days with FLAG-Ida), but this too was not significant.
Stéphane de Botton, MD:
OS and EFS results were comparable between arms.18 The 3-year OS rate was 32% for CPX-351 and 24% for FLAG-Ida (HR: 0.85). RFS also seemed comparable until adjusted for NPM1 and FLT3 mutations, which revealed a significant improvement with CPX-351 (HR: 0.58; P = .03). Of note, there were no differences in OS, EFS, or RFS when patients with normal-risk or intermediate-risk cytogenetics were excluded, although multivariable RFS results remained significant).
Stéphane de Botton, MD:
The RFS benefit with CPX-351 was more pronounced in patients with high-risk MDS (HR: 0.48) and secondary AML (HR: 0.32) than in those with de novo AML and adverse cytogenetics (HR: 0.95).18
Stéphane de Botton, MD:
Survival following transplantation was similar between treatment arms in an unadjusted analysis.18 Slightly more patients in the CPX-351 arm received a transplant (51% vs 44% in the FLAG-Ida arm).
Stéphane de Botton, MD:
In summary, this exploratory analysis from AML19 showed that treatment with CPX-351 resulted in improved duration of remission and RFS vs FLAG-Ida in patients with AML and known adverse karyotype at diagnosis.18 Responses, OS, and EFS were similar between arms. Of importance, the RFS benefit with CPX-351 was seen in high‑risk MDS and secondary AML, a condition for which the drug is already registered. The investigators surmise that the RFS benefit may be due to a larger number of patients proceeding to transplant with CPX-351 or more intensive dosing with CPX-351 in the second induction course.
Stéphane de Botton, MD:
Even in the absence of a direct comparison between midostaurin and quizartinib, I expect that the results from QuANTUM-First will change how AML is treated in clinical practice.16 In particular, certain subgroups do very well with quizartinib, including patients with a high allelic ratio and patients who attain a CR. The most significant OS benefit was seen in patients with a CR who received allogeneic HSCT (HR: 0.591). I also found the safety profile to be reassuring.
With regard to CPX-351, the safety profile in AML19 is very interesting, because after course 2, the duration of cytopenias was significantly shorter—especially for neutrophils—than with FLAG‑Ida.18 A substantial percentage of these patients received stem cell transplantation, which translated into an RFS benefit mainly in secondary AML and high‑risk MDS, as expected. I hope that the indication for CPX-351 will be expanded to include high‑risk MDS.
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