Ponatinib Plus Low-Dose Chemotherapy Improves MRD– CR Rates in Newly Diagnosed Ph+ ALL

Elias Jabbour, MD

The efficacy and safety displayed by the combination of ponatinib (Iclusig) plus reduced intensity chemotherapy could alter the treatment paradigm for patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to Elias Jabbour, MD.

Findings from the phase 3 PhALLCON trial (NCT03589326) presented at the 2023 EHA Congress showed that first-line treatment with ponatinib plus reduced intensity chemotherapy resulted in superior efficacy vs imatinib (Gleevec) plus reduced-intensity chemotherapy in this patient population.

At the August 2022 data cutoff, efficacy-evaluable patients who received ponatinib plus reduced intensity chemotherapy (n = 154) achieved a minimal residual disease (MRD)­–negative complete response (CR) for at least 4 weeks at the end of induction at a rate of 34.4% compared with 16.7% among patients who received imatinib plus chemotherapy (n = 78; relative risk, 2.06; 95% CI, 1.19-3.56; P = .0021). Moreover, the MRD negativity rates regardless of CR at the end of induction were 41.6% vs 20.5%, respectively (relative risk, 1.94; 95% CI, 1.19-3.17; P = .0017).

Patients in the ponatinib (n = 163) and imatinib (n = 81) safety populations experienced treatment-emergent adverse effects (TEAEs) that were serious (60% vs 56%), grade 3 to 4 (90% vs 93%), and grade 5 (5% vs 5%), respectively. The most common grade 3 to 4 hematological TEAEs included decreased platelet count (63% vs 58%), decreased white blood cell count (53% vs 49%), and decreased neutrophil count (49% vs 46%), respectively.

“The primary end point was met, with a twofold increase of MRD negativity with CR or MRD overall,” Jabbour said. “Based on the efficacy and safety, ponatinib should be considered the standard of care in frontline Ph-positive ALL.”

In an interview with OncLive, Jabbour a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, outlined additional findings from PhALLCON and their clinical implications.

OncLive: What was the rationale behind conducting the PhALLCON trial?

Jabbour: The combination of a TKI and chemotherapy is the standard of care in Ph-positive ALL. In the past, we have used imatinib or dasatinib [Sprycel] and then [sent patients] for allogeneic transplantation. We’ve seen throughout treatment that patients are relapsing, and when they relapse, they develop a T315I mutation. Yet with all chemotherapies given with first- and second-generation TKIs, the complete molecular response [CMR] rate at the end of induction was down to [approximately] 20% to 30%.

Therefore, we hypothesized that if we want to improve outcomes, we need to deepen the responses, and we need to prevent the emergence of T315I mutations. Ponatinib was a good fit because it does overcome the mutation and it deepens the CMR rate because it’s a more potent TKI.

Studies were done combining ponatinib and chemotherapy, and the long-term follow-up has shown robust results. Therefore, to make this drug available to everybody, we moved it into a randomized trial. The PhALLCON trial evaluated the efficacy and safety of ponatinib in combination chemotherapy in a frontline [population of those with] newly diagnosed ALL.

How was the study conducted?

Patients in good shape without major cardiovascular problems and no history of chronic myeloid leukemia were randomly assigned 2:1 to either of low-dose chemotherapy and ponatinib at the dose of 30 mg per day, [then] reduced to 15 mg once CMR was obtained, or low-dose chemotherapy and imatinib [at a dose of] 600 mg per day. The imatinib dose did not change.

The primary end point of the study was very original and very specific: MRD-negative CR at the end of induction, which has never been done in ALL. To meet the end point [patients] needed to have a CR for at least 4 weeks and be MRD negative at a 10-4 [sensitivity] at the end of induction. After that, the patient got consolidation, maintenance, and then single-agent TKI therapy. Secondary end points included event-free survival [EFS], defined as death, loss of CR, or primary refractory [disease], as well as progression-free survival [PFS] and others.

What efficacy findings were presented during the 2023 EHA Congress?

The primary end point of the study was met. Ponatinib was associated with a twofold increase in MRD-negative CR [rate]. Not only were responses obtained, across time, ponatinib was associated with deeper responses. At the MR4 time point or MR4.5, which is even deeper, the responders to ponatinib had more sustained remission compared with [those treated with] imatinib, and time to treatment failure was in favor of ponatinib.

When it comes to subsequent therapy, we noticed with ponatinib that more patients were staying on the medication compared with imatinib. [Many patients treated with] imatinib went on to receive subsequent therapy, mainly with ponatinib and blinatumomab [Blincyto], making the trial a crossover by design, and that affected the EFS. [In terms of] EFS, despite a short follow-up and the crossover design, the trend was in favor of ponatinib. The median [EFS] has been reached for imatinib [29.0 months] but had not been reached for ponatinib.

The PFS was by far in favor of ponatinib. Of course, this is short follow-up for [overall] survival [OS], and we don’t have mature enough [data] for OS, but it’s very important to note that the imatinib arm performed well. The OS rate at 2 years was around 87% [for ponatinib], which we had never seen with imatinib.

What was observed regarding safety?

There was nothing significant from a safety point of view. When you look at the safety in general, we saw an increased in liver function tests and more hypertension with ponatinib, but these were mainly grade 1 and 2. It’s very important [to note] that for grade 3 and 4 treatment-emergent adverse effects, there was [little] difference between the two arms [90% for ponatinib vs 93% for imatinib]. When you look at treatment-emergent arterial occlusive, the rates were 2% [for ponatinib] vs 1% [for imatinib].

We know imatinib is very well-tolerated regimen, and there was no [significant] increase in discontinuation rate between ponatinib [10%] and imatinib [9%].

Reference

Jabbour E, Kantarjian HM, Aldoss I, et al. First report of PhALLCON: a phase 3 study comparing ponatinib vs imatinib in newly diagnosed Ph+ALL. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S110.