Ponatinib Plus Reduced-Intensity Chemotherapy Outperforms Imatinib in Newly Diagnosed Ph+ ALL

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Frontline ponatinib plus reduced-intensity chemotherapy yielded a higher minimal residual disease-negative complete remission rate than imatinib in the phase 3 PhALLCON study.

Elias J. Jabbour, MD

Elias J. Jabbour, MD

First-line ponatinib (Iclusig) plus reduced-intensity chemotherapy led to more efficacious results than imatinib (Gleevec) among patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to findings from the phase 3 PhALLCON study (NCT03589326), which were presented during the 2023 American Society of Clinical Oncology (ASCO) Plenary Session.1

The trial met its primary end point. Minimal residual disease (MRD)-negative complete remission (CR) at the end of induction was achieved in 34.4% of patients who received ponatinib (n = 154) vs 16.7% of patients who received imatinib (n = 78; RR, 2.06; 95% CI, 1.19-3.56; P = .0021). This end point was described as having a hematologic CR for at least 4 weeks plus MRD negativity defined as no greater than 0.01% BCR::ABL1 (MR4). Median follow-up was 20.4 months (range, 18.4-23.9) in the ponatinib arm and 18.1 months (range, 13.9-24.3) in the imatinib arm.1

Overall, the MRD negativity rate at the end of induction was 41.6% with ponatinib vs 20.5% with imatinib (RR, 1.94; 95% CI, 1.19-3.17; P = .0017). The median duration of MRD negativity—defined as time from first documented MRD negativity to first documented loss of MRD negativity—was not estimable (NE; 95% CI, 17.0-NE) in the ponatinib arm compared with 20.9 months (95% CI, 10.9-NE) in the imatinib arm. The median time to treatment failure was NE with ponatinib vs 21.9 months with imatinib.1

“Ponatinib is a very potent BCR::ABL1 inhibitor with activity against wild-type and BCR::ABL1 [mutated disease] including T315I mutations,” Elias J. Jabbour, MD, said during a presentation of the data. “The combination of ponatinib with steroid, chemotherapy, or immunotherapy has [been shown] very promising [and] with propensity score matching was thought to be superior to dasatinib [Sprycel] and imatinib,” added Jabbour, who is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston. “The PhALLCON trial shows the superior efficacy of ponatinib compared with imatinib in combination with low-dose chemotherapy in patients Ph-positive ALL with a significantly higher and clinically meaningful MRD-negativity CR rate at the end of induction.”

“The combination of [tyrosine kinase inhibitor] TKI and chemotherapy or steroids is the SOC for patients with Ph-positive ALL [and] cross-trial comparison of low-chemotherapy with first- or second-generation TKIs reported a 12-week CMR rate of approximately 14% to 40%, [but] despite the high rate of initial response, resistance is often observed and frequently driven by the acquisition of the T315I kinase domain mutation.”

The secondary end point of the study was event-free survival (EFS), which was assessed among the intention-to-treat population of 164 patients who received ponatinib and 81 patients who received imatinib. The median was NE with ponatinib vs 29.0 months with imatinib (HR, 0.65; 95% CI, 0.39-1.10). Events for this analysis included death from any cause, failure to achieve CR at the end of induction, or relapse from CR.1

Progression-free and overall survival (PFS, OS) findings were also reported. The median PFS was 20.0 months (95% CI, 11.8-NE) vs 7.9 months (95% CI, 6.2-12.4) with ponatinib and imatinib, respectively (HR, 0.58; 95% CI, 0.41-0.83). The median OS was NE in both arms but showed a trend toward a benefit with ponatinib vs imatinib (HR, 0.76; 95% CI, 0.38-1.52).1

PhALLCON was designed to assess the primary end point after the induction phase, which was followed by a consolidation, postconsolidation, and single agent use phase per study protocol.

Adult patients with Ph-positive ALL or BCR::ABL1-positive ALL were randomly assigned to ponatinib at a starting dose of 30 mg once daily with a dose reduction to 15 mg if MRD-negative CR was achieved after the induction phase or imatinib 600 mg once daily. Both TKIs were given in combination with low-dose vincristine plus dexamethasone during the induction phase of three 28-day cycles, followed by low-dose methotrexate plus cytarabine for six 28-day cycles, and then low-dose vincristine plus prednisone for eleven 28-day cycles during the postconsolidation stage. Single-agent TKI was administered thereafter until the end of treatment.

Enrollment criteria also included ECOG performance status 0 to 2, no history or current diagnosis of chronic-phase, accelerated-phase, or blast-crisis chronic myeloid leukemia, and no clinically significant or uncontrolled cardiovascular disease. The median age in the ponatinib arm was 54 years (range, 19-82) and 52 years (range, 19-75) in the imatinib arm. Men accounted for just under half of the study population—45% and 47% of the ponatinib and imatinib arms, respectively—and most patients (96% and 94%) had an ECOG performance status of 0 or 1.1

At enrollment the median leukocyte count was 4.4 × 109/L (range, 0.4-198) in the ponatinib arm compared with a median of 3.2 × 109/L (range, 0.2-81) in the imatinib arm. The median blast count was slightly higher in the ponatinib arm at baseline, Jabbour noted, with a median of 80% (range, 0%-100%) vs 75% (range, 0%-100%) in the imatinib arm.

The dominant BCR::ABL1 variants identified were p190 (70% vs 65%) and p210 (24% vs 31%).1

MRD negativity was assessed during treatment cycles 3, 5, 7, and 9. Using the MR4 cutoff, the MRD-negativity response rate for ponatinib during each cycle was 43% (n = 61/142), 63% (n = 57/90), 70% (n = 41/59), and 92% (n = 44/48), respectively. These rates in the imatinib arm were 22% (n = 15/68), 52% (n = 17/33), 40% (n = 8/20), and 47% (n = 7/15), respectively.

Using a threshold of BCR::ABL1 no greater than 0.0032% (MR4.5), ponatinib outperformed imatinib in each cycle. The rates of MRD negativity with ponatinib vs imatinib were 27% vs 15%, 40% vs 30%, 48% vs 25%, and 63% vs 27%, for cycles 3, 5, 7, and 9, respectively.1

At the time of data cutoff more patients in the ponatinib arm were receiving study treatment vs the imatinib arm (41% vs 12%, respectively). Reasons for treatment discontinuation among the 95 patients in the ponatinib arm included hematopoietic stem cell transplant (HSCT; 30%), lack of efficacy (7%), adverse effect (AE; 12%), progressive disease (4%), or other (4%). In the imatinib arm, these reasons were cited among the 70 patients who discontinued treatment at rates of 37% for HSCT, 26% for lack of efficacy, 12% for AEs, 6% for progressive disease, and 5% citing other reasons. Twenty-one patients died in the ponatinib arm, and 13 patients died in the imatinib arm.

Subsequent anticancer treatment was received by 35% of patients available for follow-up after ponatinib (n = 163) and 57% of patients who received imatinib (n = 81). Second- or third-generation BCR::ABL1 TKIs and/or immunotherapy were received by 19% and 37% of patients, respectively. Of note, 13 patients went on to receive ponatinib-based treatment following imatinib on study.

“Ponatinib had a safety profile comparable to imatinib, which is known to be a very well-tolerated TKI,” Jabbour said. The safety-evaluable population included 163 patients in the ponatinib arm and 81 in the imatinib arm. Serious treatment-emergent AEs (TEAEs) were comparable with 60% of patients in the ponatinib arm and 56% of patients in the imatinib arm experiencing these events. Grade 3/4 TEAEs occurred in 90% and 93% of patients in each arm, respectively. Grade 5 TEAEs were reported for 5% of patients in each arm.

Of interest, treatment-emergent arterial occlusive events were reported among 4 patients in the ponatinib arm and 1 patient in the imatinib arm. Treatment-emergent venous thromboembolic events were reported in 12% of patients in each arm. Dose modifications, reductions, and interruptions due to TEAEs were reported in 10% vs 9%, 20% vs 22%, and 68% vs 40% of patients in the ponatinib vs imatinib arms, respectively.

The most common grade 3/4 nonhematologic TEAEs in the ponatinib and imatinib arms, respectively, included alanine aminotransferase increase (19% vs 9%), lipase increase (13% vs 19%), hypokalemia (6% vs 19%), hypertension (12% vs 6%), and nausea (3% vs 7%). The most common grade 3/4 hematologic TEAEs were decrease in platelet count (63% vs 58%), white blood cell count decrease (53% vs 49%), neutrophil count decrease (49% vs 46%), lymphocyte count decrease (38% vs 47%), anemia (31% vs 36%), and febrile neutropenia (23% vs 19%).

Clinical Implications of PhALLCON

In a discussion of the data, Anjali Advani, MD, provided perspective on how these data would impact clinical practice in the United States. “The strength of this trial [is that] this is the only prospective randomized trial comparing TKIs in this patient population in combination with chemotherapy,” she said. “This is a large number of patients in a relatively rare population, this was an international study, and finally, results were encouraging with no increased risk of TEAEs.”

Advani, who is a staff physician in the Department of Hematologic Oncology and Blood Disorders and director of the Inpatient Leukemia Program at Taussig Cancer Institute in Cleveland, Ohio, noted that the trial did have some caveats. “This was a relatively young patient population, with a median age of 54 years and Ph-positive ALL is typically a disease of the elderly. This population also had a low incidence of cardiovascular risk factors and so the question is whether we can generalize these results to the larger population who may be older and have comorbidities,” Advani said.

“There was a trend toward improved EFS with ponatinib; however, with the new treatments we have such as antibody-based therapies, [or chimeric antigen receptor] CAR T cells, we are now able to salvage these patients,” Advani added. “There was no difference in OS between the 2 arms, although follow-up is short, and the results are not mature yet.”

“Although imatinib was a reasonable comparison to ponatinib in the United States, typically most clinicians are using dasatinib and so it would have been nice to have this comparison,” Advani, an associate professor at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, said. “The landscape is changing with the use of blinatumomab [Blincyto] plus TKIs either dasatinib or ponatinib in the upfront setting and there are data now published from various groups showing excellent results, although longer follow-up is needed on all of these studies.”1-3

Advani noted that despite the changing landscape, the PhALLCON regimen is an exciting treatment option for patients with Ph-positive ALL.

In a discussion for the European perspective, Nicolas Boissel, MD, PhD, who is head of Hematology Adolescent and Young Adult Unit at the Saint-Louis Hospital, and a professor of Medicine at Université de Paris in France, noted that there may be other insights gleaned from the ongoing studies in the European Union and United States assessing ponatinib plus blinatumomab.

“It is expected that the access to ponatinib will be delayed in Europe compared to the United States, so that meanwhile clinical trials remain a good option to gain access to ponatinib in the frontline,” Boissel said. He also cited similar concerns to Advani including disparities for patients with comorbidities and the role of other second-generation TKIs.

Boissel concluded by highlighting some questions to address in next steps with these investigations: “Can you get rid of chemotherapy and allogeneic HSCT in some patients [with Ph-positive ALL] and how can we identify these patients with MRD monitoring, or by identifying additional abnormalities?”

References

  1. Jabbour EJ, Kantarjian HM, Aldoss I, et al. First report of PhALLCON: a phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). J Clin Oncol. 2023;41(suppl 36):398868. doi:10.1200/JCO.2023.41.36_suppl.398868
  2. Foà R, Bassan R, Vitale A; GIMEMA Investigators. Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623. doi:10.1056/NEJMoa2016272
  3. Advani AS, Moseley A, O’Dwyer KM, et al. Dasatinib/prednisone induction followed by blinatumomab/dasatinib in Ph+ acute lymphoblastic leukemia. Blood Adv. Online ahead of print November 2, 2022. doi:10.1182/bloodadvances.2022008216

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