Treatment Selection for Resistant or Intolerant CML

For High-Definition, Click

For patients with chronic myeloid leukemia (CML) who do not respond to imatinib, dasatinib, and nilotinib there are three drugs available: bosutinib, ponatinib, and omacetaxine mepesuccinate. Unlike the BCR-ABL TKIs, omacetaxine inhibits protein synthesis and is not a direct inhibitor of BCR-ABL. This treatment is administered as a subcutaneous injection twice daily for 2 weeks followed by 1 week of maintenance.

In the final analysis of two trials that explored omacetaxine in patients with CML, the major cytogenetic response (MCyR) rate for patients with chronic phase (CP)-CML (n = 76) was 18%, notes Harry P. Erba, MD, PhD. There were not any MCyRs in patients with accelerated phase (AP)-CML (n = 35) but the major hematologic response (MaHR) rate was 14%.

Ponatinib is a potent pan—BCR-ABL TKI that was granted accelerated approval by the FDA in December 2012 based on results from the phase II PACE trial. In subset analyses from the PACE trial, MCyR rates for patients with CP-CML treated with imatinib, dasatinib, followed by nilotinib (n = 68) were 46% with a complete cytogenetic response (CCyR) rate of 40%. Moreover, the duration of MCyR was 90% at 12 months, notes Erba. For patients who received imatinib, nilotinib, and dasatinib (n = 46), the MCyR rate was 44% and the CCyR rate was 33% with 87% of patients responding at 12 months.

The toxicity profile for ponatinib was updated in a two year follow-up of the PACE trial, which explored treatment with ponatinib in patients with CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) who were resistant to TKIs or harbored the T315I BCR-ABL mutation. In this data, 60% of patients remained in the trial at 2 years, with 20% discontinuing due to progression, 13% as a result of side effects, and 7% for other causes. The investigator-assessed rates of all cause serious cardiovascular, cerebrovascular, and peripheral vascular adverse events were 6%, 3%, and 2%, respectively. Erba notes that prior reports and warnings from the FDA seemed to indicate a higher rate for these events.

In general, Mark J. Levis, MD, PhD, suggests that omacetaxine is best utilized when T359 mutations are present or when the patient has effusions. This drug can stabilize patients, making them eligible for transplants. The main roadblock to the wider use of omacetaxine is the administration route, since it requires two daily injections for two weeks, Elias J. Jabbour, MD, believes. As a result, trials are investigating new schedules and even self-administration. At this point, omacetaxine is a bridge to other treatments, until different schedules or administration routes can be found, believes Ruben A. Mesa, MD.

The benefits gained from treatment with ponatinib are significant, specifically in patients with T315I mutations, notes Jabbour. The side effect profile of ponatinib can be managed by considering risk factors, such as dyslipidemia, smoking, and past cardiovascular events. It is important to remember the patients indicated for treatment with ponatinib are heavily refractory, notes Mesa. The safety concerns raised with this drug are understandable in this advanced patient population and should be addressed with appropriate prophylactic measures. Altogether, ponatinib remains an important treatment in the CML armamentarium, believes Mesa.