Good Results Using Loss of Major Molecular Response as Criterion for Restarting Tyrosine Kinase Inhibitor Therapy in CML


Key Points

  • Loss of major molecular response occurred in 36% of patients at 24 months.
  • All patients re-treated with tyrosine kinase inhibitors regained major molecular response, and 84% regained complete molecular response at 24 months.

Many patients with chronic-phase chronic myelogenous leukemia (CML) in complete molecular response have molecular relapse after discontinuation of imatinib (Gleevec) treatment. In a French multicenter observational study reported in the Journal of Clinical Oncology, Rousselot et al assessed the effects of imatinib discontinuation on major molecular response persistence in patients with chronic-phase CML durable complete molecular response. The investigators also evaluated the effects of using loss of major molecular response as a criterion for resuming tyrosine kinase inhibitor therapy. They found that cumulative loss of major molecular response was 36% at 2 years and that complete molecular response was achieved in most patients after resuming treatment.

Study Details

The study involved 80 patients with chronic-phase CML who had stopped imatinib after prolonged complete molecular response. Patients had a median age at diagnosis of 55 years, and 51% had Sokal low risk; 52% had received interferon alone or interferon plus cytarabine, and 46% had received no treatment prior to imatinib.

Median duration of imatinib treatment was 79 months, and median duration of complete molecular response was 41 months, with 52% of patients having confirmed response with occasional positive values. Median duration of follow-up after imatinib discontinuation was 31 months, with 76% of patients having ≤ 12-month follow-up. Resumption of imatinib treatment was recommended when loss of major molecular response was observed.

Loss of Response

Overall, 29 patients (36%) lost major molecular response after a median of 4 months off therapy (range, 2–17 months). The cumulative rates of major molecular response loss were 35% at 12 months and 36% at 24 months. The overall incidence of loss of complete molecular response was 56% after a median of 4 months off therapy (range, 1–40 months), and cumulative rates were 51% at 12 months and 54% at 24 months.

Fluctuation of BCR-ABL transcript levels below the major molecular response threshold (at least two consecutive positive values) occurred in 31% of patients after discontinuing imatinib. Treatment-free remission rates were 64% at 12 and 24 months and 61% at 36 months. No loss of hematologic response was observed during the discontinuation period.

Resumption of Treatment

Treatment was resumed in 31 patients after loss of major molecular response, with imatinib in 27, nilotinib (Tasigna) in 2, and dasatinib (Sprycel) in 1. Median follow-up after treatment resumption was 17 months (range, 2–83 months). Major molecular response was regained in all retreated patients (100%), with a second complete molecular response rate estimated at 84% at 24 months. Median time to second complete molecular response was 7.3 months.

No patients died during the follow-up period. One patient had lymphoid blast crisis 9 months after restarting imatinib while in major molecular response. This patient achieved complete remission with the combination of nilotinib and chemotherapy after failure of dasatinib and chemotherapy, underwent allogeneic matched unrelated-donor transplantation, and was alive at last follow-up.

The investigators concluded, “[O]ur results show that the probability of losing [major molecular response] after imatinib discontinuation is estimated as 36% in the long term. [Major molecular response] loss could be used as a practical criterion for future discontinuation studies. This criterion has been chosen for analysis in the EURO-SKI (Europe Stop TKI) trial, which is currently in progress.”

Philippe Rousselot, MD, PhD, of H?pital André Mignot, Le Chesnay, France, is the corresponding author for the Journal of Clinical Oncology article.

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