Patients with CML with stable molecular response may reduce TKI dose by half

Issue: January 25, 2017

SAN DIEGO — Patients with chronic myeloid leukemia who achieved a certain level of stable molecular response could safely decrease their tyrosine kinase inhibitor dose by half, according to results of the DESTINY study presented at the ASH Annual Meeting and Exposition.

Perspective from Mikkael Sekeres, MD, MS

The ability to safely reduce TKI dose — which also led to an improvement in treatment-related adverse events — suggests that many patients with stable responses are being overtreated for their disease, according to the researchers.

“There are three critical questions at the moment for CML,” Mhairi Copland, MD, PhD, professor of translational hematology at University of Glasgow in the United Kingdom, said during a press conference. “These include how to predict and treat those patients who transform to acute leukemia, how to manage patients with side effects to modern treatment, and how to identify patients with enduring good response to modern TKI treatment who can stop therapy.”

Previous studies of TKI discontinuation in patients with CML have focused on those patients with stable molecular response 4 (MR⁴), defined as a BCR–ABL/ABL ratio that is consistently lower than 0.01%. There have been anecdotal accounts of safe treatment cessation in patients with MR³ — or a BCR–ABL/ABL ratio less than 0.1% — however; these patients have not been the focus of treatment cessation or dose reduction studies. The detection of patients in MR³ has been enabled by the introduction of new, highly sensitive tests.

Copland and colleagues evaluated data from 174 patients (men, n = 98) in the first chronic phase of CML who had received the same TKI since diagnosis and for at least 3 years (median duration, 7 years). All patients had polymerase chain reaction tests in the past 12 months that indicated they were in at least MR³ (MR³, n = 49; MR⁴, n = 125).

TKIs at entry included imatinib (n = 148), nilotinib (Tasigna, Novartis; n = 16) and dasatinib (Sprycel; Bristol-Myers Squibb, Otsuka Pharmaceuticals; n = 10).

Patients decreased their TKI dose by half for the next 12 months.

After 12 months of decreased-dose therapy, three patients (2.4%) with MR⁴ at entry and nine patients (18.4%) with MR³ at entry experienced molecular relapse (P < .001).

Median time to relapse was 4.4 months in the MR³ group and 8.7 months in the MR⁴ group.

All 12 patients who experienced molecular recurrence regained MR³ within 4 months of resuming full-dose TKI therapy.

Age, gender, performance status, prior TKI (imatinib vs. second generation) or duration of TKI therapy did not appear to predict risk for recurrence on de-escalation of therapy.

No patient progressed to advanced-phase disease or lost cytogenetic response.

One death and 15 serious adverse events occurred, none of which were related to CML or TKI therapy.

During the first 3 months of de-escalation, the occurrence of patient-reported adverse events decreased, including lethargy, diarrhea, rash, nausea, periorbital edema and hair thinning. Adverse events did not decrease significantly after that time.

However, 36 patients (21%) experienced 53 new musculoskeletal symptoms, which researchers noted were usually mild and transient.

Researchers calculated that halving treatment would result in a 46.7% monetary savings overall.

“Taken together, these findings might indicate that some patients are being unnecessarily overtreated,” Copland said in a press release. “The other important implication is that patients do not have to have extremely low levels of leukemia on very sensitive tests in order to safely try reducing their TKI dose.” – by Alexandra Todak

Reference:

Clark RE, et al. Abstract 938. Presented at: ASH Annual Meeting and Exposition; Dec. 3-6, 2016; San Diego.

Disclosure: Copland reports honoraria and research funding from, and board of directors or advisory roles with, Amgen, Ariad, Bristol-Myers Squibb, Novartis, Pfizer and Shire. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Perspective

Mikkael Sekeres, MD, MS

These studies advance the management of chronic myeloid leukemia, a cancer of the white blood cells that is generally slower moving than acute myeloid leukemia. Tyrosine kinase inhibitors imatinib, nilotinib (Tasigna, Novartis) and dasatinib are some of the great success stories in the past 4 decades of cancer therapy. They are so effective at controlling CML that some patients seek to avoid the drug side effects and save costs by reducing the dose of these drugs or discontinuing treatment once they have achieved remission. Results of these two new studies suggest that, although it could be safe for many patients to reduce or discontinue drug therapy without a major risk for relapse, particularly in those patients who have been on stable medication doses for years, almost half of patients had leukemia that returned after 2 years. It is still an open question about whether stopping TKI therapy is safe.

Mikkael Sekeres, MD, MS

Cleveland Clinic

Disclosures: Sekeres reports honoraria and research funding from Celgene.