Spontaneous recovery of severe nilotinib-induced bone marrow aplasia and successful retreatment with dasatinib in a patient with Chronic Phase Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm of the pluripotent bone marrow (BM) stem cells and is consistently associated with the breakpoint cluster region – Abelson (BCR – ABL1) fusion gene caused by the Philadelphia chromosome [t(9;22)(q34;q11.2)]. Th is genetic fusion results in persistent tyrosine kinase activation leading to unrestrained cell proliferation and suppression of apoptosis in malignant cells. Tyrosine kinase inhibitors (TKIs) target the BCR – ABL1 protein, which is overexpressed in the hematopoietic progenitor and stem cells of patients with CML. Th ere are currently fi ve US Food and Drug Administration (FDA) approved TKIs for the management of CML: the prototype TKI (imatinib) and four second-generation TKIs (nilotinib, dasatinib, bosutinib and ponatinib). Nilotinib, an orally bioavailable derivative of imatinib, binds to the inactive conformation of ABL1 kinase with higher affi nity than imatinib, and therefore inhibits its catalytic activity with 20 – 30-fold higher potency than imatinib [1,2]. Nilotinib 400 mg twice daily is FDA approved for the treatment of patients with CML in chronic phase (CP) or accelerated phase (AP) who failed treatment with imatinib due to resistance/intolerance, based on a phase II study of 321 patients with CML-CP who failed imatinib [3]. Nilotinib is also approved as a front-line treatment of patients with CML-CP, based on the phase III study called the ENESTnd (Evaluating Nilotinib Effi cacy and Safety in Clinical Trials – Newly Diagnosed Patients) trial [4 – 6]. BM toxicities associated with TKIs aff ect all cell lineages, but are usually dose-dependent and reversible with drug cessation or dose reduction. Th e ENESTnd study showed that nilotinib is well tolerated with an acceptable safety profi le [4]. However, it is recommended that nilotinib treatment should be held for any grade 3 – 4 toxicity and can be resumed with the same dose if recovery occurs within 2 weeks, otherwise dose reduction should be considered [3]. Although myelosuppression is a common adverse event seen in patients