In CML, Assess Response to First-Line TKI at 3 Months

Wayne Kuznar

May 2015, Vol 6, No 4 - NCCN 2015 Updates


Hollywood, FL—Switching therapy in patients with chronic myelogenous leukemia (CML) should be considered in those who have a suboptimal response to a first-line tyrosine kinase inhibitor (TKI) at 3 months, said Jerald P. Radich, MD, Director of the Molecular Oncology Laboratory, Fred Hutchinson Cancer Research Center, Seattle, WA, and Vice Chair of the National Comprehensive Cancer Network (NCCN) guideline panel on CML. He discussed the management of patients with CML at the 2015 NCCN conference.

In patients with CML, response to therapy should be assessed at 3 months, and if a molecular response is not achieved, first consider poor adherence.

“The NCCN recommends evaluating compliance whenever a milestone is not achieved,” said Dr Radich. In the Adherence Assessment with Glivec: Indicators and Outcomes (ADAGIO) study, the adherence of patients with CML to imatinib as prescribed was only 14.2% as assessed by pill count, with 71% of patients taking less than the prescribed dose.

Dr Radich noted that the likelihood of achieving a major molecular response (MMR) or maintaining a complete cytogenetic response (CCyR) hinges on adherence of more than 90%.

After ruling out nonadherence, if patients still have more than 10% of BCR-ABL1 transcripts, or have not had a partial cytogenetic response at 3 months after the initiation of imatinib (Gleevec) or nilotinib (Tasigna), the NCCN guidelines recommend evaluating for drug–drug interactions and considering mutational analysis, with a switch to a different primary TKI if necessary.

Early Molecular Response Is Important

Achieving an early molecular response is important, because it predicts a higher probability of achieving an MMR, which is associated with a long­er duration of CCyR and higher rates of event-free survival and progression-­free survival.

An early MMR “is a good place to get to,” said Dr Radich. Not achieving, or losing, MMR is associated with shortened progression-free survival.

The rationale to switch therapy when the patient’s BCR-ABL1 transcript level is >10% at 3 months comes from a study in which patients with <9.8% of BCR-ABL transcripts after 3 months of im­atinib had an 8-year overall survival­rate of 93.3% compared with 57% for patients with >9.8% of BCR-ABL transcripts. The same effect is true for second-­line therapy.

If a patient is having a poor response at 3 months, “it should set off a bell that this may be a patient who’s going to need something more than a TKI in the future,” Dr Radich said. Consideration of human leukocyte antigen typing for a potential stem-cell transplant in the future may be prudent at this point.

Data to support that an early change in therapy improves prognosis in poor responders are lacking. The TIDEL II trial in Australia and New Zealand “suggests that maybe you can salvage some people” by switching from imatinib to nilotinib, said Dr Radich.

In addition, the Evaluating Nilotinib Efficacy and Safety in Clinical Trials (ENEST)cmr study suggests that switching from imatinib to a second-generation TKI if BCR-ABL is detectable after 2 years of treatment “may push your molecular response further,” he said.

When to Consider Mutation Analysis

The analysis of mutations status may provide additional information in patients with CML who have inadequate response. “For chronic-phase patients upfront, there’s really no need to do it, because the sensitivity of the molecular assays we have for sequencing aren’t there,” Dr Radich said.

“If people do not reach their milestones, or if they reach their milestones and lost those milestones, that’s when you test.”

Once patients progress with therapy, switching to a second-generation TKI is associated with CCyR in 20% to 50% of patients, at which point, a transplant search should be started.

“A really good toggle point in looking for response to second-generation drugs is really at 3 months,” Dr Radich said. “If they haven’t had a major cytogenetic response at 3 months with new therapy, then it’s clear their disease-free survival is really poor.”

In the setting of chronic-phase CML that progresses after treatment with any single approved TKI, ponatinib (Iclusig) is a “remarkably effective drug,” said Dr Radich. Approximately 50% to 70% of heavily pretreated patients will get a CCyR with ponatinib.

The key in treatment is keeping patients from going into accelerated-phase or blast-crisis phase disease, Dr Radich said. The median survival once patients progress to accelerated-phase or blast-crisis phase disease is only 10 months. Most accelerated-phase or blast-crisis phase disease progression occurs early, usually in the first year of treatment with first-line imatinib.