Sustained Remissions after Discontinuation of Ibrutinib in Relapsed/Refractory CLL: A Basis for Reducing Drug Toxicity and Treatment Costs?

In contrast to traditional chemotherapy, patients responding to biological or targeted therapies often are treated indefinitely until progression or toxicity. This therapeutic model, however, increases treatment costs, may induce greater toxicity and theoretically could select for earlier emergence of drug resistance. Moreover, little data is available regarding the outcomes of patients who discontinue targeted therapies after achieving remission. In this regard, we report two patients with relapsed/refractory CLL who chose to stop therapy unrelated to toxicity or disease status after the induction of remission by the BTK inhibitor ibrutinib. Patient A started ibrutinib for progressive CLL at an absolute lymphocyte count (ALC) of 137,000mm³ and recurrent hemolytic anemia. After 5 months, the hemolysis had resolved (Hgb 15.6 g/dl) while the ALC had declined to 9200mm³. Treatment was then interrupted due to patient preference. One month after drug discontinuation, the ALC was in the normal range at 1400mm³ and remained within or near the normal range for a total of 12 months. Two months later, the ALC was again markedly elevated at 68,000mm³and anemia recurred. The patient then agreed to restart ibrutinib. Thus far, after 5 months of re-treatment, he has had prompt resolution of the anemia and achieved a partial remission with a slowly decreasing lymphocytosis. Patient B was started on ibrutinib for a rising ALC (26,000mm³) and severe hemolytic anemia. After 9 months of treatment, the hemoglobin was 13 g/dl and the ALC was in the normal range at 3300mm³. Due to unrelated medical problems, ibrutinib therapy was stopped. Currently, 6 months since drug discontinuation, the ALC remains in the normal range and no other signs of CLL are present. These clinical observations suggest that interruption of ibrutinib may be feasible in at least some CLL patients who achieve remission. Even if flow cytometry were performed at monthly intervals to detect early recurrence and ensure prompt re-institution of therapy, the cost savings would still be considerable. Of course, clinical trials will be necessary to confirm equivalent long-term efficacy and overall survival for intermittent versus continuous ibrutinib therapy in CLL.