Switching Therapy Following Suboptimal Response in Chronic Myelogenous Leukemia

Neil P. Shah, MD

Now that several effective agents are FDA-approved for the treatment of chronic myelogenous leukemia (CML), it is important to ascertain whether a treatment is working, and if not, how to respond in terms of switching treatment, explained Neil P. Shah, MD, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center.

Imatinib, a tyrosine kinase inhibitor (TKI), was the first drug to be approved for frontline therapy of CML; secondgeneration TKIs dasatinib and nilotinib were subsequently approved by the FDA in the front-line setting; most recently, bosutinib (Bosulif) gained FDA approval as second-line therapy, and ponatinib is expected to gain approval early in 2013, Shah told attendees at the NCCN 7th Annual Congress on Hematologic Malignancies.

A change in the 2012 NCCN CML Guidelines is the incorporation of suboptimal response to guide therapy at treatment milestones. “The term suboptimal response evolved from the European Leukemia Network guidelines,” Shah explained. “Suboptimal response means that patients may still have a substantial long-term benefit from continuing treatment, but have reduced chances of optimal outcomes; suboptimal responders are eligible for alternative approaches.”

Response at 3 Months

Lack of any cytogenetic response after 3 months of imatinib is considered suboptimal response and is associated with a low likelihood of achieving complete cytogenetic response (CCyR). Bone marrow cytogenetics can provide useful information to guide therapy at this milestone, but most patients with CML do not want to undergo another invasive bone marrow biopsy. In the United States, performing biopsies at 3 months is uncommon and thus, suboptimal response is frequently not recognized, Shah noted.

PCR tests showing a BCR-ABL level <10% at 3 months can distinguish patients who will do well on imatinib or dasatinib from those who will have a poor outcome. Shah said that this criterion has not yet been incorporated into the NCCN CML Guidelines, but he expects that it will be soon.

If a patient fails to meet the threshold of <10% BCRABL at 3 months, then physicians should evaluate compliance, test for mutations, consider obtaining bone marrow cytogenetics, consider allogeneic stem cell transplant, and consider a clinical trial, Shah advised. Continuing such a patient on imatinib is not recommended; rather, the patient should be switched to dasatinib (100 mg daily) or nilotinib (300-400 mg/twice daily). The guidelines have not yet incorporated bosutinib, another second-line option. The guidelines do not consider strategies for failure on second-generation TKIs.

At 6 months, at least a partial cytogenetic response is considered an optimal response by the guidelines. Patients with a suboptimal response should not be continued on the same treatment; however, the NCCN CML Guidelines do not include the 6-month time point as a milestone.

12-Month Milestone

Failure to achieve CCyR at 12 months is associated with risk of progression or death. Patients who fail to achieve CCyR at this time point need other therapies, as do patients considered treatment failures.

For suboptimal response, physicians should consider changing therapy to an alternate secondgeneration TKI. Patients should be continued on higher-dose imatinib only if they are not candidates for a second-generation TKI. Patients who do not respond to a second-generation TKI should be considered for allogeneic stem cell transplant or a clinical trial.

18-Month Milestone

At 18 months, patients with less than CCyR are deemed failures in the NCCN Guidelines, while patients with less than a major cytogenetic response are considered suboptimal responders. At this time point, bone marrow cytogenetic testing should be done in patients who are not in major molecular response and who lacked CCyR at 12 months. Those in CCyR should be continued on the same dose of imatinib, nilotinib, or dasatinib.

Suboptimal response due to mutations is an emerging issue with TKI treatment. T315I mutations are associated with resistance to imatinib, nilotinib, and dasatinib, but studies suggest that ponatinib can overcome resistance to this mutation (See Below).

According to Shah, mutational testing should not be done at baseline because drug-resistant mutations develop on treatment. “Mutational testing should be done on any patient who fails to meet a treatment milestone,” he said.

Javier Pinilla-Ibarz, MD

Overcoming the T315I Mutation in Chronic Myelogenous Leukemia

The T315I mutation inhibits tyrosine kinase inhibitor (TKI) treatment in patients with chronic myelogenous leukemia (CML). This mutation is not overcome by the TKIs currently approved to treat CML, imatinib, dasatinib, nilotinib, and bosutinib. Results from the phase II PACE trial suggest that the third-generation TKI ponatinib could provide hope for heavily pretreated patients with T315I-positive CML (J Clin Oncol. 2012;30[suppl;abstr 6503]).

The PACE trial enrolled 449 patients with refractory CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation. Patients were separated into three main cohorts: CML in chronic phase (CP), CML in accelerated phase (AP), and CML in blast phase (BP) combined with patients with Ph+ALL. All patients received 45 mg of ponatinib daily.

Overall, ponatinib generated significant responses in more than 50% of the patients with CML. Further, in T315I-positive patients in the CP-CML group, 70% (45/64) achieved major cytogenic response and 66% (42/64) had a complete cytogenic response. In the AP-CML group, 50% (9/18) of patients with a T315I mutation had a major hematologic response (MaHR), with 33% (15/46) of T315I-positive patients achieving a MaHR in the BP-CML and Ph+ALL cohort.

Ariad Pharmaceuticals, which is developing ponatinib, announced in September that it had completed its FDA submission for the drug. The company anticipates approval in early 2013 and physicians were already discussing the drug’s use at the recent 7th Annual NCCN Congress on Hematologic Malignancies. Javier Pinilla- Ibarz, MD, director of Immunotherapy at the H. Lee Moffitt Cancer Center in Tampa, Florida, suggested that in T315I-positive CML patients with imatinib failure in the accelerated phase or blast phase, ponatinib could be used as a bridge to achieve minimal residual disease before going on to an allogeneic stem cell transplant.

Earlier use of ponatinib also continues to be explored. In July, Ariad announced the initiation of the phase III EPIC trial comparing ponatinib against imatinib in previously untreated patients with CML.