Imatinib discontinuation does not increase long-term molecular recurrence risk

Patients with chronic myeloid leukemia who achieve a sustained deep molecular response can discontinue imatinib without an increased risk for late molecular recurrence, according to long-term results from the French Stop Imatinib Study.

Prior study results have shown that imatinib (Gleevec, Novartis) can be discontinued in patients with CML who maintain undetectable minimal residual disease levels for at least 2 years.

François -Xavier Mahon, MD, PhD, professor of hematology at University of Bordeaux in France, and colleagues prospectively discontinued imatinib treatment in 100 patients (median age, 59.4 years; range, 29-81; 52% women) who received treatment at any dose for at least 3 years and had undetectable minimal residual disease for at least 2 years.

Mahon and colleagues conducted molecular follow-up every month for the first year after treatment cessation, then every 2 months in the second year. From the third year onward, molecular follow-up occurred every 3 months.

The researchers defined molecular recurrence as a minimum of two positive reverse transcriptase polymerase chain reaction assays showing a significant increase, or the loss of major molecular response at any one time.

The median follow-up after imatinib cessation was 77 months (range, 9-95).

Sixty-one patients (61%) experienced a molecular recurrence after a median of 2.5 months (range, 0.9-2223). One patient with undetectable minimal residual disease died 10 months after discontinuing imatinib.

The majority of recurrences occurred within 6 months of imatinib cessation, and 80% (n = 49) occurred in the first 3 months. No molecular recurrences were reported from 22 months after discontinuation.

The cohort had a molecular recurrence–free survival rate of 43% (95% CI, 33-52) at 6 months and 40% (95% CI, 30-49) at 18 months. At 5 years, the molecular recurrence–free survival was 38% (95% CI, 29-47).

Fifty-seven patients with molecular recurrence restarted treatment. The majority of patients (n = 56) reinitiated imatinib; one patient received dasatinib (Sprycel, Bristol-Myers Squibb).

The median time to treatment resumption was 2.1 months (range, 0.7-15.6).

Four patients did not restart treatment with tyrosine kinase inhibitors, due to patient refusal (n = 3) or chemotherapy for a concomitant second neoplasm (n = 1).

All but two patients who restarted therapy achieved a second undetectable minimal residual disease after a median of 4.3 months (range, 1.5-21).

No patient with a molecular recurrence experienced disease progression after a median follow-up of 73 months. Four patients died due to unrelated causes, including second malignancies (n = 2), renal failure (n = 1) or cerebral hemorrhage (n = 1).

Thirty-nine patients remained free of molecular recurrence and further TKI therapy at final follow-up, 37 of whom continually achieved undetectable minimal residual disease. One patient in this cohort died of a myocardial infarction.

Sokal risk score (P = .024) and duration of imatinib (P = .024) served as independent prognostic factors for molecular recurrence.

“We hypothesize that a careful selection of patients on the basis of a sustained deep molecular response before imatinib may partially explain the success of imatinib discontinuation,” Mahon and colleagues wrote. “Whether patients who do not achieve such sustained deep molecular responses are not good candidates from imatinib discontinuation remains debatable. ... With respect to the heterogeneous characteristics of the patients, Sokal risk score and imatinib duration before treatment discontinuation have to be considered from the perspective of imatinib discontinuation.” – by Cameron Kelsall

Disclosure: Mahon reports research funding and travel expenses from, as well as consultant roles with, Bristol-Myers Squibb and Novartis. Please see the full study for a list of all other researchers’ relevant financial disclosures.