ASH 2010: Ponatinib Inhibits Mutations That Block Treatment Paths for CML, ALL, and AML

An investigational pan-BCR-ABL inhibitor designed to inhibit the entire spectrum of mutations responsible for resistance to drugs such as imatinib (Gleevec) and its cousins nilotinib (Tasigna) and dasatinib (Sprycel) appears to fulfill its promise. Although data from this phase I trial are preliminary, they show that oral ponatinib (AP24534) inhibits all the mutations—including T315I—able to thwart existing treatments for chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML).

With first- and second-generation BCR-ABL tyrosine kinase inhibi- tors (TKIs), therapy failure persists for some patients even if they switch to another TKI. The T315I mutation is behind most cases of resistance to existing BCR-ABL TKIs. Patients with this mutation do not respond to therapy with imatinib, nilotinib, or dasatinib.

“These results are exciting because it is very difficult to induce responses—particularly at the high rates seen with ponatinib—in heavily refractory patients. While these results need to be confirmed in a larger study, ponatinib may be the next step in coming closer to overcoming and possibly preventing the most difficult mechanisms of resistance in CML and ultimately finding a cure for Philadelphia chro- mosome—positive [Ph ] leukemias,” said lead author Jorge Cortes, MD, deputy chair and professor of medicine, Department of Leukemia, MD Anderson Cancer Center, The University of Texas, Houston.

This multicenter, open-label, phase I trial enrolled 67 patients with various treatment-refractory hematologic malignancies, including CML (n = 57), Ph ALL (n = 3), AML (n = 3), and other types of hema- tologic malignancy (n = 4). Nearly three-quarters (72%) of patients in the trial had BCR-ABL mutations; 38% (23 of 67) had a T315I mutation and 12% (7 of 67) had the less common F317L mutation. Nearly all the patients (96%) had failed on prior imatinib (96%); 89% failed on dasatinib and 55% failed on nilotinib. Overall, 95% failed on ≤2 TKIs and 64% failed on ≤3 TKIs.

Patients received a daily dose of oral ponatinib ≤60 mg. At the time of the press conference discussing these results, 64% of patients (43 of 67) remained on therapy and 36% (24 of 67) had discontinued. Of the 24 discontinuations, 8 were due to progressive disease, 8 were based on the investigator’s decision, 5 were due to deaths unrelated to treat- ment, 2 were patients who withdrew consent, and 1 was due to an adverse event unrelated to therapy (Figure).

Drug-related adverse events (any grade) that occurred in at least 10% of patients included thrombocytopenia, headache, nausea, arthralgia, fatigue, anemia, increased lipase levels, muscle spasms, rash, myalgia, and pancreatitis (Table). Dose-limiting toxicities at 60 mg consisted of elevated pancreatic enzymes and pancreatitis. Of the 22 patients treated with 45-mg dose, 1 had a grade 3 rash, which was considered a dose-limiting toxicity. Cortes said all dose-limiting toxicities were reversible.

Complete hematologic response (CHR) was seen in 30 of 32 evaluable patients with CML (94%). In this cohort, 20 patients (63%) had major cytogenetic responses (MCyRs), consisting of 12 complete cyto- genetic responses (CCyRs)and 8 partial cytogenetic responses (PCyRs). Of the 20 responsive patients in the CML arm who had chronic-phase disease, 18 remain on treatment with no evidence of progression (mean, 326 d). In the CML cohort, 11 patients in the chronic-phase were positive for the T315I mutation, and all these patients experienced CHR. In addition, 9 (82%) achieved MCyR, of which 8 were CCyR. In the subgroup of 16 evaluable patients who had accelerated- or blastic-phase CML or who had Ph ALL, major hematologic response was observed in 5 (31%), 3 (19%) achieved MCyR, and 1 (6%) had minor cytogenetic response. Looking at the 9 patients with a T315I mutation who had accelerated- or blastic-phase CML or Ph ALL, 3 (33%) experienced MHR and 2 (20%) achieved MCyR.

Of the patients treated with ponatinib ≤4 months, 12 had a major molecular response (MMR), including 4 in patients treated ≤2 months. MMR was also observed in patients with the following mutations: M351T, F359C, F317L, M244V, and G250E. Cortes said these responses occurred in heavily treatment-refractory patients; responses were also observed in heavily pretreated patients with no mutations.

The study was initiated with ponatinib capsules, but in April 2010, the company reformulated ponatinib as tablets. In the phase I study, 10 patients received the tablets, and pharmacokinetic and pharmacodynamic data to date suggest that the formulations are equivalent. The 45-mg tablet dose has been identified as the recommended dose for further study.