Ponatinib Plus Chemo Records Several ‘Firsts’ in Ph+ ALL and Becomes New SOC


Elias Jabbour, MD, expands on the significance of ponatinib’s approval in Philadelphia chromosome–positive acute lymphoblastic leukemia.



The FDA’s approval of ponatinib (Iclusig) plus reduced-intensity chemotherapy signals a significant shift in the treatment paradigm for patients with newly diagnosed Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), according to Elias Jabbour, MD. Not only does this decision introduce ponatinib as the first and only TKI to be approved for use in the first-line setting of this disease with chemotherapy, it also represents a notable milestone as the first FDA authorization supported by the assessment of minimal residual disease (MRD) after induction.

Findings from the phase 3 PhALLCON trial (NCT03589326) showed that patients treated with first-line ponatinib plus reduced intensity chemotherapy experienced superior response rates vs imatinib (Gleevec) plus reduced-intensity chemotherapy, meeting the study’s primary end point.1 Efficacy-evaluable patients who received the ponatinib combination (n = 164) achieved a MRD­negative complete response (CR) rate of 30% at the end of induction vs 12% in evaluable patients treated with imatinib (Gleevec) plus chemotherapy (n = 81; 95% CI, 0.08-0.28; P = .0004). Furthermore, CRs were achieved in 79% of evaluable patients at the end of induction therapy and in 63% of patients in the imatinib arm.

Based on these data, the FDA granted accelerated approval to ponatinib plus chemotherapy for the treatment of patients in this population on March 19th, 2024. Notably, ponatinib has a boxed warning for arterial occlusive events, venous thromboembolic events, heart failure, and hepatotoxicity.

“This is the first time we have a frontline TKI approved in Ph-positive ALL. From now on, we have a new SOC,” said Jabbour, who is a professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.

In an interview with OncLive®, Jabbour outlined findings from PhALLCON supporting the use of ponatinib in Ph-positive ALL, expanded on the agent’s potency and mechanism of action, and discussed the significance of this approval for both the current paradigm and future research efforts in ALL.

OncLive: What is unique about ponatinib’s mechanism of action and how did this provide a rationale for the agent’s investigation in Ph-positive ALL?

Jabbour: For any new drug to be approved, it should be compared with the SOC. We now have ponatinib [as this] SOC in combination with chemotherapy for the frontline treatment of [patients] with Ph-positive ALL. Ponatinib is a very potent BCR-ABL inhibitor. Compared with other TKIs it is more potent and can suppress the emergence of, or can overcome the problem of, mutations. In particular, [the agent inhibits] the gatekeeper mutation called T315I, which is the driver of resistance to most of the TKIs. In that way, ponatinib can overcome this problem; it can deepen the responses and it can prevent resistance. That was the hypothesis behind [evaluating the agent in] the randomized PhALLCON trial.

Please describe the design of the PhALLCON trial. Why was MRD-negative CR selected as the primary end point?

This was a randomized phase 3 trial. Patients with newly diagnosed Ph-positive ALL were randomly assigned 2:1 to receive either low-dose chemotherapy and ponatinib or low-dose chemotherapy and imatinib. The dose of ponatinib was 30 mg per day and was reduced to 15 mg once an MRD-negative CR was achieved. Imatinib was [administered at] 600 mg per day and was de-escalated if adverse effects were encountered. The treatment included an induction phase that takes about 3 months, consolidation, and maintenance with a single-agent TKI. If at any time [a patient wanted] to go for transplant, they could.

The primary end point was unique; it was the MRD-negative CR at the end of induction [treatment; patients] must have [had] a CR for 4 weeks to be MRD negative. This [end point] was based on data showing that patients who achieved MRD negativity have better survival outcomes. Therefore, the FDA agreed to consider MRD-negative CR as the primary end point for the drug’s approval.

What key efficacy data from the trial supported the approval of ponatinib in this population?

In the study, the rate of MRD-negative CR was doubled with ponatinib compared with imatinib, and that led to the approval of the drug. That said, this superior efficacy was obtained without additional toxicities. There was no difference in AEs and discontinuation [rates] between the 2 arms; therefore, we improved efficacy without [increasing] risk at all.

Key secondary end points are event-free survival [EFS] and overall survival [OS]. These [data] are still not mature enough to report out. I do want to highlight that molecular relapse or resistance of molecular disease was not considered an event as such if a patient [became] MRD positive later on in the imatinib arm, [they] could go on to receive ponatinib, so [the trial has] a crossover design by nature. Despite this crossover design, we know more patients on imatinib did go on to receive subsequent therapy. The EFS is trending in favor of ponatinib, [as] the median [EFS] has not been reached for ponatinib and was with imatinib. We need to wait for longer follow-up data to see how this difference will further mature. That will hopefully lead to [full] approval of the drug.

What should be known about the agent’s safety profile based on this study? Are there any patient populations in which you would hesitate to use this therapy?

The toxicity profile [of ponatinib] is quite favorable. One of the safety concerns with ponatinib was vascular or [arterial] occlusive events. Here, we don’t see an exacerbation of the rate [of these events] compared with [that observed with] imatinib. This has to do with 2 things. One is the dose adjustment of ponatinib. We never used 45 mg; we used 30 mg and reduced it to 15 mg, which is quite acceptable and good. The second is that [we should use this therapy in] patients who [do not] have acute vascular problems at the beginning. In my practice, [for] a patient with acute vascular problems, I would be cautious and not use ponatinib in someone with vascular problems. Otherwise, the drug has been shown to be safe, and should be considered the SOC for all comers.

Are there any planned or ongoing efforts to investigate ponatinib further in ALL?

The approval of ponatinib is the beginning of a new era of research that involves this drug. [At MD Anderson Cancer Center], my colleagues and I are leading [research on a] chemotherapy[-free] approach with blinatumomab [Blincyto] and ponatinib; the results are so far [show] with more than 60 patients treated, [approximately] 9% are on 3 years [of treatment], which is amazing [in the phase 2 study (NCT03263572)]. We’re expanding on that [by examining] low-dose chemotherapy, ponatinib, and blinatumomab for those at higher risk [in a phase 2 study (NCT03147612)].

Besides that, for patients who are younger, in the frontline we’re using immunotherapy up front with blinatumomab, inotuzumab ozogamicin [Besponsa], and hyper-CVAD, and [the estimated 3-year OS rate is 87%], which is quite good [in the phase 2 study (NCT02877303)]. For older patients with ALL, we’re using inotuzumab and blinatumomab—a chemotherapy-free [approach]—or mini-HCVD [plus] inotuzumab and blinatumomab which is a low-intensity chemotherapy [regimen being evaluated in a phase 1/2 study (NCT01371630)]. This represents major progress in ALL.


  1. FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. FDA. March 19, 2024. Accessed March 27, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome
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