Ponatinib Boosts MRD-Negative Complete Remission Rates in Patients With Ph+ ALL

Elias Jabbour, MD

Patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) achieved higher rates of minimal residual disease (MRD)-negative complete remission when the TKI ponatinib (Iclusig) was added to reduced-intensity chemotherapy, compared with imatinib (Gleevec), according to findings from the phase 3 PhALLCON trial (NCT03589326) presented during the 2023 SOHO Annual Meeting.

At the August 12, 2022, data cutoff, patients who received ponatinib (n = 154) experienced an MRD-negative CR at the end of induction, defined as a hematologic CR for at least 4 weeks with MR4 MRD negativity (BCR::ABL1 ≤ .01%) at a rate of 34.4% compared with 16.7% in the imatinib arm (n = 78; relative risk [RR], 2.06; 95% CI, 1.19-3.56; P = .0021). Additionally, the MR4 MRD negativity rates at the end of induction regardless of CR assessment were 41.6% vs 20.5%, respectively (RR, 1.94; 95% CI, 1.19-3.17; P = .0017). The median follow-up was 20.0 months (range, 18-24) in the ponatinib arm and 18 months (range, 14-24) in the imatinib arm.

“Today, TKIs and chemotherapy or steroids are the standard of care in Ph-positive ALL,” Elias Jabbour, MD, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said during the presentation. “We know that the remission is not long lasting. And we know that complete molecular response matters a lot [as] resistance is driven by the acquisition of the T315I mutation.”

PhALLCON enrolled adult patients with newly diagnosed Ph-positive or BCR::ABL1-positive ALL. Eligible patients needed to have an ECOG performance status of 2 or less, no history or current diagnosis of chronic, accelerated, or blastic phase chronic myeloid leukemia, and an absence of clinically significant of uncontrolled cardiovascular disease.

Patients were randomly assigned 2:1 to reduced-intensity chemotherapy in combination with ponatinib 30 mg once daily with dose reduction to 15 mg once daily (n = 164) after MRD-negative CR in the induction phase or reduced intensity chemotherapy with imatinib at a starting dose of 600 mg once daily (n = 81). During the induction phase, patients received the TKI plus vincristine and dexamethasone in three 28-day cycles, after which the primary end point was assessed, then they proceeded to the consolidation phase which consisted of the TKI plus methotrexate and cytarabine in six 28-day cycles, followed by maintenance therapy with the TKI plus vincristine and prednisone in eleven 28-day cycles, and finally treatment with TKI monotherapy until the completion of the study. Additionally, during the first 6 cycles, intrathecal therapy was given twice per month to mitigate central nervous system disease prophylaxis.

The primary end point was MRD-negative CR, and a key secondary end point was event-free survival (EFS). Molecular response rates, duration of MRD-negative CR, overall survival (OS), and safety represented other secondary end points.

The baseline patient characteristics were well balanced between the 2 arms; the median age was 54 years (range, 19-82) in the ponatinib arm and 52 years (range, 19-75) in the imatinib arm. Most patients in both arms were female (55% vs 53%), had an ECOG performance status of 1 or less (96% vs 94%), had p190 as the dominant BCR::ABL1 variant (70% vs 65%), and had at least 1 cardiovascular comorbidity (56% vs 64%). The median leukocyte counts were 4.4 × 10⁹/L (range, 0.4-198) vs 3.2 × 10⁹/L (range, 0.2-81), respectively, and the median leukemic blasts were 80% (range, 0%-100%) vs 75% (range, 0%-100%).

Additional findings from the study revealed that the duration of MRD negativity was not estimable (NE; 95% CI, 17.0-NE) vs 20.9 months (95% CI, 10.9-NE) among patients who achieved MRD negativity in the ponatinib (n = 62) and imatinib arms (n = 15), respectively. In the overall populations, the times to treatment failure were NE (95% CI, NE-NE) vs 21.9 months (95% CI, 12.3-NE), respectively.

Patients in both the ponatinib and imatinib arms went on to receive a subsequent anticancer therapy (35% vs 57%). Subsequent anticancer therapies included first-generation BCR::ABL1 TKIs (10% vs 9%), second- or third-generation BCR::ABL1 TKIs and/or immunotherapy (19% vs 37%), and ponatinib-based treatments (8% vs 16%).

In PhALLCON, EFS was defined as death due to any cause, failure to achieve CR by the end of induction, or relapse from CR. There were 34 EFS events in the ponatinib arm compared with 24 in the imatinib arm; the median EFS was NE (95% CI, NE-NE) vs 29.0 months (95% CI, 22.9-NE), respectively (HR, 0.65; 95% CI, 0.39-1.10).

Progression-free survival (PFS) was analyzed in a post hoc analysis. The median PFS was 20.0 months (95% CI, 11.8-NE) compared with 7.9 months (95% CI, 6.2-12.4) in the ponatinib and imatinib arms, respectively (HR, 0.58; 95% CI, 0.41-0.83). The median OS was NE (95% CI, NE-NE) vs NE (95% CI, 29.0-NE), respectively (HR, 0.76; 95% CI, 0.38-1.52).

Patients with MR4 MRD negativity in the ponatinib and imatinib achieved molecular responses in cycle 3 at rates of 43% (n = 61 of 142) vs 22% (n = 15 of 68). In cycle 5 these rates were 63% (n = 57of 90) vs 52% (n = 17 of 33), respectively, 70% (n = 41 of 59) vs 40% (n = 8 of 20) in cycle 7, and 92% (n = 44 of 48) vs 47% (n = 7 of 15) in cycle 9.

In the ponatinib and imatinib arms, respectively, patients with MR4.5 MRD negativity (BCR::ABL1 ≤ .0032%) had molecular response rates of 27% (n = 38 or 142) vs 15% (n = 10 of 68) in cycle 3, 40% (n = 36 of 90) vs 30% (n = 10 of 33) in cycle 5, 48% (n = 28 of 59) vs 25% (n = 5 of 20) in cycle 7, and 63% (n = 30 of 48) vs 27 (n = 4 of 15) in cycle 9.

Safety findings showed similar adverse effect profiles for ponatinib and imatinib. Treatment-emergent adverse effects (TEAEs) were reported in both the ponatinib arm (n = 163) and the imatinib arms (n = 81) at a rate of 99%. These includes serious TEAEs (60% vs 56%), grade 3/4 TEAEs (90% vs 93%), grade 5 TEAEs (5% vs 5%), treatment-emergent arterial occlusive events (2% vs 1%), and treatment-emergent venous thromboembolic events (12% vs 12%). Dose discontinuation (10% vs 9%), reduction (20% vs 22%), and interruptions (68% vs 40%) occurred in both arms.

In the ponatinib and imatinib arms, the most common grade 3/4 hematological TEAEs were decreased platelet count (63% vs 58%), decreased white blood cell count (53% vs 49%), and decreased neutrophil count (49% vs 46%). Grade 3/4 nonhematological TEAEs included increased alanine transaminase levels (19% vs 9%), hypokalemia (6% vs 19%), and hypertension (12% vs 6%).

At the data cutoff, 41% of patients in the ponatinib arm remained on study treatment compared with 12% in the imatinib arm. Patients discontinued study treatment at rates of 58% vs 86%, respectively, due to lack of efficacy (7% vs 26%), AEs (12% vs 12%), progressive disease (4% vs 6%), hematopoietic stem cell transplantation (HSCT; 30% vs 37%), and other reasons (4% vs 5%). Patients discontinued study at respective rates of 18% and 22%, with death (13% vs 16%), withdrawal (4% vs 5%), being lost to follow-up (0% vs 1%), and other reasons (1% vs 0%) being the reported causes. Patients in both arms received HSCT at any time at rates of 34% vs 48%, respectively.

“This study has established ponatinib as the standard of care for Ph-positive ALL,” Jabbour said. “It is superior to imatinib in inducing a higher rate of MRD negativity at 12 weeks. This superiority was associated with a better PFS and improvement the long-term EFS. [Although] we see an advantage in efficacy, we did not see an increase in AEs. Therefore, based on these data, we hope that ponatinib will be approved.”

Reference

Jabbour E, Kantarjian H, Aldoss I, et al. First report of PhALLCON: a phase 3 study comparing ponatinib versus imatinib in newly diagnosed Philadelphia chromosome-positive acute lymphocytic leukemia. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.