Cost, adherence as vital as TKI choice for CML

Second-generation tyrosine kinase inhibitors (TKIs) available for frontline and second-line treatment of chronic myeloid leukemia (CML), like nilotinib and dasatinib, clearly show “better, earlier” major molecular responses for patients with CML than earlier drugs such as imatinib (Gleevec), according to Richard A. Larson, MD, director, Hematologic Malignancies Program, The University of Chicago, who spoke Sunday, December 6, at the 57^th American Society of Hematology (ASH) Annual Meeting, in Orlando, Florida.

“There’s no question that second-generation drugs like nilotinib are more potent,” Larson said. It is not yet clear if that translates to longer survival for patients, however.

Dr. LarsonAnd it does not automatically mean that second-generation drugs are the best option for all patients, Larson was quick to point out. It is important that “the treatment fits the patient."

“Discuss benefits and risks - and costs,” he said. “Tolerability is important; non-adherence leads to poor outcomes, so it’s important to minimize early side-effects.” Late toxicities can be avoided by monitoring and managing comorbid conditions.

Second-generation frontline TKIs are an attractive option. For many patients, it is quickly evident who will benefit and who may not, he said. Patients who are “slow responders” to second-generation kinase inhibitors like nilotinib are less likely to benefit as much from those drugs in the long term (to respond “deeply”), as are patients whose cancers respond quickly to treatment, he said.

Early molecular response (EMR, defined as transcript levels of 10% or less BCR/ABL gene transcripts at three or six months) consistently predicts both major molecular response and better long-term outcomes, including patient survival, Larson said. He was quick to add that “the rate of decline, or the ‘halving time’ for blood transcript levels may be more important than absolute percents” in assessing early molecular responses in CML.

“Rapid early responders do seem to have excellent survival over time,” Larson said.

EMR at the three-month mark predicts which patients will have a molecular response six years later, he noted. BCR-ABL levels at three months predicts overall survival as well, among patients taking nilotinib.

NEXT: Side effects

Side effects tend not to be severe, but they “go on and on and on, because these drugs can be lifelong. Patients complain most about chronic fatigue, but also skin rash and nausea," he said.

A more troubling possible side-effect has also emerged over recent years: cardiovascular events.

“This is a warning to know patients’ comorbidities when they walk in the door,” Larson said. “Because these cardiovascular comorbidities may prove to be more life-threatening than their leukemia.”

Dr. Deininger

“TKIs are so good now that comorbidities have become the leading cause of death,” agreed Michael Deininger, MD, PhD, professor and chief of hematology and hematologic malignancies, department of internal medicine, Huntsman Cancer Institute, University of Utah in Salt Lake City. “Good monitoring starts with a complete work-up at diagnosis,” he mentioned in a subsequent presentation.

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Larson cautioned that randomized clinical trials, while rightly considered the ‘gold standard,’ enroll highly-selected patients with fewer comorbidities than the general patient population, and various risk characteristics tend to be underrepresented in these studies. There’s also “rigorous follow-up for patients on-study, emphasizing adherence to both treatment and monitoring,” he noted - things that don’t always happen in routine clinical practice outside of clinical trials.

Larson also urged clinicians not to neglect drugs’ potential “financial toxicity” for patients when they’re weighing first- and second-generation TKIs for CML.

The price of these drugs reflects unsustainable pricing trends for cancer drugs generally, he suggested.

Current formulary prices for TKIs used in frontline or second-line CML treatment all exceed $130,000 a year per patient, he noted - and ponatinib, a second-line TKI for CML, exceeds $160,000 a year.

But for off-patent biosimilars, that will change, Larson said. “Next year, imatinib will go off patent, and the cost will go to perhaps 20% of where it is now.”

Drug costs have clinical implications because patients who cannot afford drug copays are more likely to skip doses or discontinue treatment entirely, Larson said. “We know there’s a correlation between copays and discontinuation,” he said. “When they have to pay more, we see discontinuation rates go up by as much as 70%.”

“Why is non-adherence a problem?” he asked. “Because missing just three or four tablets of these drugs can make it significantly less likely that a patient will achieve a major molecular response.”