In Chronic Myeloid Leukemia, Selection of Tyrosine Kinase Inhibitors Depends on Variables Other Than Survival

August 2017, Vol 10, Special Issue: Payers’ Perspectives in Oncology: ASCO 2017 Highlights - Leukemia
Wayne Kuznar

Chicago, IL—Survival with the use of a tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia (CML) in the chronic phase is comparable among the available drugs, so other variables should come into play when selecting a specific TKI. In some instances, a treatment-free remission is possible, said CML experts at the 2017 ASCO annual meeting.

Comorbidities, adverse-event profiles, and patient preferences should be considered in the selection of a TKI, said Rüdiger Hehlmann, MD, PhD, Professor of Medicine, Heidelberg University, Mannheim, Germany. For example, nilotinib should not be used in patients with preexisting vascular disease, and dasatinib should be avoided in those with lung disease or a history of pleural effusion.

Cost is another variable, according to Dr Hehlmann. The annual price estimates for TKIs range from $92,000 to $348,000. Imatinib represents a rational first-line TKI choice, because it is now available as a generic, and its efficacy and safety profiles are favorable.

Response milestones should be monitored in patients with CML who are receiving a TKI. If response milestones are not reached, check adherence first.

“Nonadherence is the most frequent cause of resistance or failure of treatment. Those patients who adhere to their drugs have a better survival than those who do not,” Dr Hehlmann said.

Mutations are responsible for 30% to 40% of resistance to a TKI.

“If you encounter resistance, and you switch drugs to a second-generation TKI, do a mutation analysis to make sure you did the right thing,” he advised. Additional cytogenetic aberrations while receiving therapy are a sign of resistance and require a change in therapy, preferably to stem-cell transplantation.

Bosutinib as First-Line Option?

In new data released at the meeting, a 400-mg dose of bosutinib was associated with higher rates of major molecular response and complete cytogenetic response (CCyR) than imatinib in patients with newly diagnosed chronic-phase CML.

In the multinational, open-label, randomized phase 3 study known as BFORE, which examined bosutinib in the first-line setting, the major molecular response rate at 12 months in the modified intent-to-treat population was 47.2% with bosutinib versus 36.9% with imatinib (odds ratio, 1.55; P = .02), reported Jorge E. Cortes, MD, Deputy Department Chair, Department of Leukemia, M.D. Anderson Cancer Center, Houston. The rate of CCyR by 12 months was also significantly higher with bosutinib (77.2% vs 66.4%, respectively; hazard ratio [HR], 1.74; P <.01), and the time to CCyR was shorter with bosutinib (HR, 1.34; P <.02).

“With these results, I believe that bosutinib could become a very welcome new treatment option for frontline therapy of chronic-phase CML,” said Dr Cortes.

TKI Discontinuation Is Possible

Although outcomes are excellent with long-term oral TKI therapy and most side effects are manageable, reduced quality of life (QOL) and high financial burden are reasons that patients may discontinue TKI therapy after achieving a sustained deep molecular remission, said Ehab L. Atallah, MD, Associate Professor of Medicine, Medical College of Wisconsin, Milwaukee.

Up to 40% of patients experience low-grade but substantial adverse reactions that affect QOL and adherence, he noted.

Patients who can consider stopping a TKI are those who have been receiving a TKI for ≥3 years and have a duration of low-level BCR-ABL by PCR of 1 to 2 years and a depth of response of at least MR4, which is achieved by 40% to 60% of patients with chronic-phase CML who are using a TKI.

Predictors of relapse after discontinuation are (1) TKI use of ≤5.8 years and (2) younger age. Patients with a higher natural killer–cell count are less likely to have a relapse or experience disease progression, said Dr Atallah.

Approximately 30% of patients experience a TKI withdrawal syndrome, which is characterized by musculoskeletal or joint pain. The duration is typically 6 months, and it can be managed effectively with nonsteroidal anti-inflammatory drugs and prednisone, he said. Patients who experience this withdrawal syndrome are less likely to have a relapse.

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