Advent of Ponatinib for Ph+ ALL Expected to Influence New Guidelines

Earlier this year, the dual therapy of ponatinib (Iclusig; Takeda) plus chemotherapy received an accelerated FDA approval as a primary treatment for patients with newly-diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). With the advent of this medication, updates to the current guidelines for Ph+ ALL can be expected in the coming year.

The randomized, multicenter, active-controlled, open-label, phase 3 PhALLCON (NCT03589326) trial showcased the efficacy of ponatinib, with 30% of patients receiving ponatinib achieving minimal residual disease (MRD)-negative complete remission (CR). For this study, patients were randomized to either the ponatinib arm, which took ponatinib—a tyrosine kinase inhibitor (TKI)—orally at a dose of 30 mg per day, or the imatinib arm, which took imatinib orally at a dose of 600 mg per day. The risk difference for participants, in favor of ponatinib, was 0.18 (95% CI, 0.08-0.28; P = .0004).¹

stethoscope | image credit: Kanisorn - stock.adobe.com

“Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline,” Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center and lead investigator of the PhALLCON trial, commented in a news release this past spring.²

Throughout the study period, both groups underwent 3 cycles of induction chemotherapy with dexamethasone and vincristine, 6 consolidation cycles alternating between cytarabine and methotrexate, as well as an additional 11 maintenance cycles with prednisone and vincristine. Following MRD-negative CR, it is recommended to reduce ponatinib to 15 mg daily.¹

The guidelines for PH+ ALL remain similar for both adolescent and youth adults (AYA; aged 15-39 years), as well as adults aged 40 years and beyond.³ Patients with ALL are recommended to pursue different courses of treatment depending on their Ph status. First-line treatment options recommend a dual therapy of chemotherapy plus TKI. Furthermore, the guidelines state that allogeneic stem cell transplant, pending a suitable donor, should be sought out for AYA patients. Adults should consider this option as well, so long as the donor possesses a good performance status and carries little-to-no comorbidities.

Other TKIs such as dasatinib and imatinib are approved by the FDA for the treatment of Ph+ ALL. These TKIs are best administered in combination with chemotherapy regimens, such as hyper-CVAD. Prior studies have shown that adding hyper-CVAD to imatinib interventions can benefit 3-year CR rates in Ph+ ALL compared to treating the disease without the addition of hyper-CVAD (68% vs 24%).⁴ Furthermore, interventions that administer hyper-CVAD alongside dasatinib have contributed to 94% CR rates in patients with Ph+ ALL.⁵

Notably, ponatinib has demonstrated a major hematologic response in 41% of cases of Ph+ ALL when patients have grown intolerant or failed to respond to other TKIs such as dasatinib. It should be known, however, that ponatinib can lead to an increased risk of thromboembolic events and for this reason is often only administered as a monotherapy for patients with T3151 mutations or those who have not benefited from other TKIs.³

“We are thrilled that the FDA has recognized the potential of Iclusig to fill a large gap in care for these patients and look forward to seeing the impact this can have on people with this rare and aggressive form of cancer," Awny Farajallah, MD, chief medical officer, oncology at Takeda, noted.²

References

1. FDA grants accelerated approval to ponatinib with chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. News release. FDA. March 19, 2024. Accessed November 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-ponatinib-chemotherapy-newly-diagnosed-philadelphia-chromosome

2. Takeda announces U.S. FDA approval of supplemental new drug application (sNDA for iclusig® (ponatinib) in adult patients with newly diagnosed Ph+ ALL. News release. Takeda. March 19, 2024. Accessed November 25, 2024. https://www.takeda.com/newsroom/newsreleases/2024/takeda-announces-us-fda-approval-of-drug-for-iclusig-ponatinib-in-adult-patients/

3. Seiter K. Acute lymphoblastic leukemia (ALL) treatment protocols. Medscape. Updated November 15, 2024. Accessed November 25, 2024. https://emedicine.medscape.com/article/2004705-overview#:~:text=Ph%2B%20ALL%20in%20the%20older,multiagent%20chemotherapy%20and%20a%20TKI

4. Thomas DA, Faderl S, Cortes J, et al. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004;103(12):4396-407. doi:10.1182/blood-2003-08-2958

5. Ravandi F, O'Brien S, Thomas D, et al. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010;116(12):2070-7. doi:10.1182/blood-2009-12-261586