medwireNews: Combining reduced-intensity chemotherapy with ponatinib rather than imatinib achieves a significantly higher rate of minimal residual disease (MRD)-negative complete remission at the end of induction in people with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), suggest phase 3 data published in JAMA.
“This composite end point had more stringent criteria than typically applied in clinical practice, requiring 4-week durable complete remission (excluding incomplete remission) and MRD negativity as determined by the central laboratory at the end of induction,” note the researchers.
And the authors of a related editorial highlight that “[t]his depth and duration of MRD-negative response has been correlated with improved long-term outcomes, and its incorporation into PhALLCON as an early surrogate end point is a triumph for Ph-[positive] ALL and for leukemia clinical trials in general.”
Jacqueline Garcia and colleagues from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, continue: “While questions remain, the PhALLCON trial establishes that ponatinib plus reduced-intensity chemotherapy is a new frontline option for the treatment of Ph-[positive] ALL.”
In the study, 245 patients were randomly assigned to receive either open-label ponatinib 30 mg/day (with the dose reduced to 15 mg/day after achievement of MRD-negative complete remission) or imatinib 600 mg/day alongside a reduced-intensity chemotherapy regimen comprising induction (cycles 1–3), consolidation (cycles 4–9), and maintenance (cycles 10–20) phases. After cycle 20, patients continued to receive single agent ponatinib or imatinib as per the random assignment.
Over a median follow-up of 20.1 months, the rate of MRD-negative complete remission was 34.4% in the ponatinib group and 16.7% in the imatinib group, equating to a significant risk difference of 0.18. The median duration of remission was unreached and 18.0 months, respectively.
Elias Jabbour (The University of Texas MD Anderson Cancer Center, Houston, USA) and co-investigators report that “molecular responses were more durable in the ponatinib arm.” The median time to loss of MRD negativity was not reached among ponatinib-treated patients and was 20.9 months among those given imatinib.
They also note that although “the prespecified number of events for statistical analysis of survival end points had not occurred” at the time of this interim analysis, the trends favored ponatinib. Specifically, the median durations of event-free survival were unreached and 29.0 months in the ponatinib and imatinib arms, respectively, while the corresponding median progression-free survival times were 20.0 and 7.9 months.
The incidence of treatment-emergent and treatment-related adverse events (AEs) of grade 3–4 were comparable between the ponatinib and imatinib arms, at rates of 85.3% versus 87.7%, and 65.6% versus 59.3%, respectively.
Arterial occlusive events are an AE of interest with ponatinib, explain the researchers, but they “were infrequent and comparable between groups,” with any-grade events in 2.5% and 1.2% of ponatinib- and imatinib-treated participants, respectively.
The team points out that these rates “are lower than previously reported,” which “may be driven by multiple factors, including reduced starting dose, prospective dose-reduction strategies […], and more stringent exclusion criteria.”
Garcia and fellow editorialists caution that “[t]hese exclusion criteria may limit ponatinib’s broad applicability,” and they add: “[F]urther follow-up is necessary to confirm that the safety profile remains unchanged, since arterial occlusive events can emerge as late as 5 years after therapy.”
The editorial authors also stress the need for studies comparing ponatinib with second-generation tyrosine kinase inhibitors as well as investigating the impact of regimens incorporating blinatumomab.
And they conclude: “The maturity of data will confirm whether PhALLCON has a smooth landing.”
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JAMA 2024; doi:10.1001/jama.2024.4783
JAMA 2024; doi:10.1001/jama.2024.5871