Outcome of CML patients with ABL tyrosine kinase mutations after hematological resistance to imatinib

Abstract

6540 Background: Although responses in chronic phase (CP) CML to imatinib have been quite durable, a significant proportion of pts with advanced disease develop resistance after short period of therapy. The mechanisms of resistance are diverse, but in most cases mutations are found that change amino acids within the kinase domain of BCR-ABL. Methods: We analyzed the outcome of 53/117 pts with BCR-ABL mutations (45%) detected by direct sequencing at the time of resistance. Median exposure to imatinib was 12 months (range 1–30). Prior to imatinib therapy, 21 pts were in CP, 18 in accelerated phase (AP), 13 in myeloid and one in lymphoid blast crisis (BC). Mutation specific restriction digests of RT-PCR products (n=129) were employed to track the proportion of mutated clones. Results: Resistance was associated with 22 different mutations affecting 18 amino acids of the P-loop area (n=21), T315I (n=8), the activation loop (n=9), and other sites (n=18). In 3 pts, 2 different mutations were found. Median time to resistance was 0.7 yrs in CP, 1.3 yrs in AP and 1.2 yrs in BC. After relapse, imatinib was continued for 0–30 (median 4) months. Dose was escalated in 18 pts. In 27 pts, imatinib was combined with other drugs, in 22 pts with ara-C. After imatinib withdrawal, treatment was continued with hydroxyurea, n=27; ara-C, n=21; other drugs, n=38, allogeneic stem cell transplantation, n=7. In 4 cases, imatinib was reintroduced leading to a hematologic remission in one patient. Overall survival after resistance was 1.2 yrs (0–3.1). A reduction of mutated BCR-ABL to a level of <2% was seen in 4 pts after imatinib withdrawal. Median survival after resistance was 0.8 yrs for P-loop mutations, 1.5 yrs for others (n.s.). Conclusions: (i) The outcome of CML pts resistant to imatinib is heterogeneous with the most aggressive course in pts with P-loop mutations. (ii) The time course of the onset of mutations suggests both preexistence and new occurence in individual cases. (iii) Approaches to handle resistance include dose escalation and combination therapy leading to a temporary stabilization of the disease. (iv) Withdrawal of imatinib is suggested to stop the clonal selection of resistant cells. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Pharma, Nürnberg, Germany