TKI Ponatinib Plus Chemotherapy Effective in Ph-Positive ALL

The combination of chemotherapy with the novel tyrosine kinase inhibitor (TKI) ponatinib was an effective treatment for patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL), according to the early results of a phase II trial published in Lancet Oncology.

“The regimen is effective in achieving early sustained responses, with a median follow-up of 26 months,” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues. “New strategies, including dose titration of ponatinib, optimum control of vascular risk factors, and the addition of new monoclonal antibodies, might help to further improve outcomes.”

According to the study, the standard of care for patients with Ph-positive ALL is TKIs combined with chemotherapy; however, many patients will ultimately relapse due to TKI resistance developed through the T315I mutation in the BCR-ABL1 fusion protein. Because of this resistance, researchers are actively trying to find new TKIs that can target the T315I-mutant disease.

This study evaluated ponatinib, a potent BCR-ABL1 inhibitor. It included 37 patients with treatment-naïve Ph-positive ALL (92%) or those who had fewer than two courses of previous chemotherapy with or without TKIs.

Study treatment was 8 cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine every 21 days. In addition, patients received ponatinib 45 mg given daily for the first 14 days of cycle 1 then continuously for the remaining cycles. Maintenance therapy was given to patients in remission.

Patients received a median of 6 cycles of therapy. Major molecular response occurred in 100% of patients (37 of 37), complete cytogenetic response occurred in 100% (32 of 32), and complete molecular response in 78% (29 of 37).

“After follow-up of over 2 years, only two patients have relapsed, and no T315I mutations have been detected, a significant improvement compared with first-generation and second-generation tyrosine kinase inhibitors,” the researchers wrote.

At the median follow-up of 26 months, 78% of patients were in complete remission, with an estimated 2-year event-free survival rate of 81% and 2-year overall survival of 80%. As of September, 13 patients were currently taking maintenance therapy and in complete remission with this treatment regimen.

Safety analysis showed that more than half of patients experienced grade 3 or higher infections during induction. Grade 3 or higher adverse events also included increased aspartate aminotransferase and alanine aminotransferase concentration (38%), thrombotic events (8%), myocardial infarction (8%), hypertension (16%), skin rash (22%), and pancreatitis (16%).

“Apart from the increased rates of vascular events encountered, a post-hoc analysis comparing the adverse events encountered with hyper-CVAD and ponatinib to similar trials using hyper-CVAD in combination with other tyrosine kinase inhibitors showed similar rates of other grade 3 and above adverse events,” the researchers wrote.

Two patients died from myocardial infarction that was possibly related to the study treatment, according to the study. Another patient died from myocardial infarction due to sepsis.

In an editorial that accompanied the study, Xavier Thomas, MD, of Lyon-Sud Hospital in Lyon, France, wrote that the results seen in this phase II trial are “a significant improvement compared with those from first-generation and second-generation tyrosine kinase inhibitors combined with chemotherapy.”