Early Cytogenetic or Molecular Landmark Response to Ponatinib Predicts Outcomes in CP-CML

Hagop M. Kantarjian, MD

Early cytogenetic and molecular responses achieved with ponatinib (Iclusig) was significantly linked with better long-term progression-free survival (PFS) and overall survival (OS) in patients with highly resistant, pretreated chronic-phase chronic myeloid leukemia (CML), according to data from a post-hoc analysis of the phase 2 PACE trial (NCT01207440) presented at the 2023 SOHO Annual Meeting.¹

At a landmark time point of 3 months, a complete cytogenic response (CCyR) was achieved by 39% of patients who received ponatinib. A molecular response of MR1, defined as a BCR::ABL1 of 10% or less, was achieved by 49% of patients. Additionally, 34% of patients achieved a molecular response of MR2, defined as a BCR::ABL1 of 1% or less. A major molecular response (MMR), defined as a BCR:ABL1 of 0.1% or less, was reached by 14% of patients; the MMR rate at 5 years was 40%.^1,2

Patients who experienced an MMR at the 3-month time point had significantly improved PFS at 4 years vs those without an MMR (P = .0010).¹ “This is a good value in terms of looking at the early outcome of these patients and saying well, ‘This is someone who’s going to do well on ponatinib. I can reduce the dose now to 15 mg and they are going to do very well,’” said Hagop M. Kantarjian, MD, who is a professor and chair of the Department of Leukemia and the Samsung Distinguished Leukemia Chair in Cancer Medicine at The University of Texas MD Anderson Cancer Center.

Those with an MMR at 3 months also had a numerically higher probability of OS after 4 years (P = .884). “The survival is trending that way, but what you see is that ponatinib appears to be a very good treatment in terms of normalizing survival, even if you do not achieve the molecular end points that you want,” Kantarjian said. “You see that the estimated survival [rate] at 4 to 5 years is in the range of 70% to 80%, whether you achieve an MMR or not.”

Lastly, those who had an MMR with ponatinib had significantly higher rates of achieving deeper cumulative responses (MR4.5) than those who did not respond to the agent.

“The patients who achieved an MMR at 3 months are more likely to achieve a deep molecular response. Can you translate this into a treatment-free remission [TFR]? Remember, these patients are in the salvage setting, so the success of a TFR even with a durable deep molecular response will be lower,” Kantarjian said. “So, the correlate of this end point may or may not have a good value in your community practice, but I would say that if someone on ponatinib achieves an MR4.5 at 3 months, which lasts for 3 to 5 years, then you can attempt another TFR. That will be an important thing to consider.”

For patients with CP-CML, poor outcomes are linked with sequential TKI treatment and/or the presence of BCR::ABL1 mutations. Ponatinib inhibits all known native and single resistance mutation variants of BCR::ABL1, including T315I. “There are a lot of data [with BCR::ABL1 TKIs] in [the] frontline [setting], where achievement of early responses, either cytogenetic or molecular, correlates with long-term outcomes, but the data in the setting of salvage therapy [are] not very well known,” Kantarjian noted.

As such, Kantarjian and colleagues set out to perform an analysis of patients with CP-CML who were enrolled in the PACE trial and who achieved landmark cytogenetic and molecular responses at 3, 6, and 12 months to assess the link between early landmark responses achieved at 3 months with longer-term outcomes like PFS, OS, and depth of response (MR4.5).

The single-arm, open-label, multicenter, phase 2 trial enrolled 270 patients with CP-CML who were at least 18 years of age, had resistance or were intolerant to previous treatment with dasatinib (Sprycel) or nilotinib (Tasigna), or who had a T315I mutation following treatment with a BCR::ABL1 TKI. Patients were required to have an ECOG performance status ranging from 0 to 2. If patients were in CCyR at the time that they entered the study, had active central nervous system disease, or substantial or active cardiovascular disease, they were excluded.

Participants were administered ponatinib at a starting dose of 45 mg daily. They were broken into 2 groups: those with CP-CML that was resistant to dasatinib or nilotinib (n = 203) and those with CP-CML who harbored a T315I mutation (n = 64).

The primary end point of the trial was major cytogenetic response (MCyR) by 12 months, and important secondary end points comprised MMR, time to response, duration of response, PFS, OS, and safety/tolerability.

When comparing baseline characteristics by whether a patient achieved an MMR at 3 months (n = 33) or did not (n = 200), “pretreatment characteristics are [similar],” Kantarjian said. “They have the same incidence of BCR::ABL1 and number of TKIs prior to starting therapy. If anything, we show that patients who achieved an early molecular response had, at the start, a higher level of BCR, and a higher incidence of a T315I mutation.”

At the time of the final analysis, which had a median follow-up of 56.8 months, 55% of 267 patients achieved the primary end point of MCyR at 12 months.² The Kaplan-Meier–estimated PFS rate at 5 years was 53%; the 5-year OS rate was 73%. “The long-term data show that ponatinib is an excellent drug in terms of controlling the disease,” Kantarjian said.

Additional data presented from the post-hoc analysis showed that when utilizing older response criteria, patients who achieved a MCyR (P < .0001) or CCyR (P = .0004) at 3 months experienced significantly improved PFS at 4 years vs those who did not.¹ Additionally, those who reached MCyR (P = .0006) or CCyR (P = .0117) at 3 months were also significantly more likely to experience improved OS at 4 years vs those who did not achieve a cytogenetic response.

“Assessing cytogenetic and molecular response at early time points [such as] 3 months may help outcome prediction and treatment decisions,” Kantarjian concluded.

References

1. Muller MC, Cortes J, Chuah C, et al. Achieving early cytogenetic or molecular landmark response is predictive of outcomes in heavily pretreated patients with chronic-phase chronic myeloid leukemia treated with ponatinib in the phase 2 PACE trial: 5-year data. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.
2. Cortes JE, Kim D-W, Pinilla-Ibarz J, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404. doi:10.1182/blood-2016-09-739086