Despite the recent advances in the treatment of chronic myeloid leukaemia (CML) over the past decade with both first- and second-generation BCR-ABL inhibitors, there are patients who continue to fail two or more of these therapies and/or develop a mutation called T315I, which alters the shape of the ABL enzyme, making these patients unresponsive to current therapies. Currently, there are no effective treatment options for patients who develop a T315I mutation. Pre-clinical research has demonstrated that ponatinib, an investigational pan-BCR-ABL inhibitor, may inhibit the entire spectrum of mutations that cause resistance to other BCR-ABL inhibitors.

Researchers at The University of Texas MD Anderson Cancer Center in Houston, in collaboration with colleagues from other institutions in the United States, initiated an open-label, dose escalation phase I study to assess the safety and investigate the anti-leukemic activity of ponatinib. A total of 67 patients with various refractory hematologic malignancies including CML, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL), and acute myeloid leukaemia (AML), were enrolled in the study to receive a daily oral dose of ponatinib. A large majority of patients with Ph+ CML had previously failed treatment with other BCR-ABL inhibitors (imatinib: 96 percent, dasatinib: 89 percent, nilotinib: 55 percent, more than two previous therapies: 95 percent, and more than three previous therapies: 64 percent). Additionally, 72 percent of all patients enrolled in the study had BCR-ABL mutations, with 38 percent (23 patients) having a T315I mutation and 12 percent (7 patients) having an F317L mutation.

To date, patients enrolled in the study have received up to 60 mg doses of ponatinib with 64 percent (43 patients) remaining on therapy and 36 percent (24 patients) discontinuing therapy. Of 32 evaluable patients with CML in chronic phase, 30 patients (94 percent) had a complete hematologic response (meaning blood cell counts are in the normal range), and 20 patients (63 percent) had a major cytogenetic response (meaning that no cells containing the Philadelphia chromosome were detected in the bone marrow). Of those achieving a major cytogenetic response, 12 patients had a complete cytogenetic response and eight patients had a partial cytogenetic response. Eighteen of these patients remained on ponatinib for a mean duration of 326 days without progression (range 142 to 599 days) with 13 of these patients having a confirmed response at a second assessment.

Of 11 evaluable patients with CML in chronic phase with a T315I mutation, 11 patients (100 percent) achieved a complete hematologic response and nine patients (82 percent) had a major cytogenetic response (eight of these patients had a complete cytogenetic response). Of 16 evaluable patients with either CML in accelerated or blast phase or with Ph+ ALL, five patients (31 percent) had a major hematologic response, three patients (19 percent) had a major cytogenetic response, and one patient (6 percent) had a minor cytogenetic response. Of nine evaluable patients with CML in accelerated or blast phase or patients with Ph+ ALL with a T315I mutation, three patients (33 percent) had a major hematologic response, and two patients (20 percent) had a major cytogenetic response.

Responses also were seen in heavily refractory patients with no mutations as well as in patients with other mutations who were resistant to currently approved tyrosine kinase inhibitors. For example, there was one complete cytogenetic response and one partial cytogenetic response in two patients with an F317L mutation who had previously failed therapy with imatinib, dasatinib, and nilotinib. Another patient with an F359C mutation who failed both imatinib and nilotinib therapy achieved a complete hematologic response and a complete cytogenetic response with ponatinib.

Overall, 13 out of 60 patients (22 percent) with Ph+ disease achieved a major molecular response, including 12 out of 42 patients (28 percent) with CML in chronic phase and six out of 15 patients (40 percent) with T315I mutation confirmed at the start of the study. Twelve major molecular responses occurred in patients who received ponatinib for four months or less. There were four major molecular responses in patients who received ponatinib for only two months or less. Major molecular responses also were seen in patients with the following mutations: M351T, F359C, F317L, M244V, and G250E.

“These results are exciting because it is very difficult to induce responses, particularly at the high rates seen with ponatinib, in heavily refractory patients,” said lead study author Jorge Cortes, MD, Deputy Chair and Professor of Medicine, Department of leukaemia, The University of Texas MD Anderson Cancer Center in Houston. “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 chromosome-positive leukaemias.”