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Tuesday, March 8, 2016

CML: How Previous TKIs Affect Outcomes with Ponatinib

BY SARAH DIGIULIO

The higher the number of tyrosine kinase inhibitors (TKIs) a patient with chronic myeloid leukemia (CML) receives prior to starting ponatinib, the less the patient benefits from ponatinib. Those were the findings of a study presented at the American Society of Hematology Annual Meeting and published in Blood (2015;126:4025).

"However, even among heavily treated patients, ponatinib was still quite effective," study co-author, Hagop M. Kantarjian, MD, Professor and Chairman of the Department of Leukemia at The University of Texas MD Anderson Cancer Center and OT's Clinical Advisory Editor for Hematology/Oncology, explained in an email.

"Toxicities from ponatinib follow a similar trend, but not as consistently," he added.

Study Details
The study was a post hoc analysis of results for 270 patients with chronic phase-CML who were enrolled in the Phase II PACE trial according to the number of TKIs those patients received prior to enrolling in the trial. Those patients were resistant or intolerant to dasatinib or nilotinib or had the T315I mutation.

The data found rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs:

  • Of the patients who received one prior TKI: 75% had a major cytogenetic response, 75% had a complete cytogenetic response, and 63% had a major molecular response;
  • Of the patients who received two prior TKIs: 70% had a major cytogenetic response, 64% had a complete cytogenetic response, and 42% had a major molecular response;
  • Of the patients who received three prior TKIs: 49% had a major cytogenetic response, 45% had a complete cytogenetic response, and 36% had a major molecular response; and
  • Of the patients who received four prior TKIs: 58% had a major cytogenetic response, 33% had a complete cytogenetic response, and 8% had a major molecular response.


The rates of toxicities did not follow a consistent trend, but the incidence of grade 3 or higher adverse events increased with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively). Grade 3 or higher adverse events occurring in 10 percent or more of the patients with chronic phase-CML were: thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). 

A similar frequency pattern was observed for serious adverse events (which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively). Serious adverse events occurring in five percent or more of the patients with chronic phase-CML were: pancreatitis (7%), angina pectoris (5%), and pneumonia (5%).

The data also found:

  • Both median age and median time from diagnosis increased with number of prior TKIs;
  • Median dose intensity was highest in patients who had received only one prior TKI; and
  • The most common reasons for discontinuation across groups were adverse events and withdrawal by patient request.


Better Defining the Role of Ponatinib
These findings are most likely explained by disease resistance, Kantarjian said. "The higher the number of prior TKI therapies, the more likely there is increased CML resistance. 

"The findings better define the role of ponatinib in CML salvage therapy and indicate that ponatinib is highly active, but has a side-effect profile that needs to be considered. Studies of lower doses of ponatinib (e.g. 15-30 mg daily) may show similar efficacy and considerable less toxicities, and should be investigated," he said.