Characteristics and Outcome of Chronic Myeloid Leukemia (CML) Patients with E255K and E255V BCR-ABL Kinase Domain Mutations.

Mutations in the kinase domain (KD) of Abl represent the most common mechanism of resistance to tyrosine kinase inhibitors (TKI) in CML. T315I is recognized as the most resistant mutant as no available TKI has activity against it. Historically, P-loop mutations have also been recognized as conferring a poor prognosis. Among them, mutations in codon 255 represent one of the most resistant mutations, with the next highest (after T315I) IC50 to most TKI, and in some instances, higher even than for T315I (eg, for AP24534, DCC-2036). However, the outcome for patients with mutations in codon 255 has not been previously described.

To describe the incidence, prognosis and response to treatment in patients with E255K/V.

We evaluated a total of 500 CML patients by DNA sequencing for BCR-ABL KD mutations after failure of therapy with tyrosine kinase inhibitor/s (TKIs). The characteristics of patients found to have the E255K and E255V mutations were reviewed. These included the stage of the disease when the mutation was first detected, prior treatment with interferon and TKIs, as well as treatment following detection of mutation with outcome of the treatment. Survival was calculated by the Kaplan-Meier method.

Of the 500 patients evaluated, 184 patients had KD Mutations. Of those, 29 had mutations in codon 255. Twenty-two patients had E255K and 8 had E255V. Composite mutations occurred in 6 patients; 5 with E255K and 1 with E255V, with the following additional mutations: E459K, M351T, F359V, V299L, T315I and Y253F. Median follow-up time from diagnosis of CML to death or last follow-up was 62 months (range 8 – 249) and median time from diagnosis of CML to mutation detection was 36 months (range 4 – 216). At the time of E255K/V detection, 13 patients were in chronic (CP), 6 in accelerated (AP), and 10 in blast phase (BP). Among the 13 pts in CP at the time of mutation detection, only 2 pts continued therapy unchanged, for 5 (then transformed to BP) and 19 months (then died of sepsis); 9 patients changed therapy after detection of E255K/V (2 to nilotinib, 2 to dasatinib, 1 to bosutinib and 4 to other investigational agents); one pt was lost to follow-up and one received supportive care only (due to cardiac co-morbidities). The best response to therapy in CP pts after mutation detection was complete major molecular response (MMR) in 2 pts, cytogenetic response (CCyR) in 1, minor CyR (mCyR) in 1, complete hematological response (CHR) in 4, no response in 2 patients, and 1 lost to follow-up. Out of these 13 pts in CP at mutation detection, 4 progressed to BP, 1 progressed to AP, 5 pts remained in CP, 2 were lost to follow-up and 1 went to hospice. Subsequent treatment for pts in AP after mutation detection included nilotinib (2 pts), stem cell transplant (SCT) (1 pt), other investigational agents (2 pts), and 1 received supportive care only. The best response to therapy in these patients was a CHR in one pt treated with nilotinib while 4 patients showed no response to treatment. Pts in AP, 4 transformed to BP, and 2 showed no progression. For the 10 pts in BP at the time of mutation detection, treatment included bosutinib (1 pt), nilotinib (1 pt), imatinib plus decitabine (1 pt), hyper CVAD plus dasatinib (1 pt), and investigational agents (3 pts), 2 supportive care only, and 1 lost to follow-up. Only one patient in BP who received bosutinib, responded (mCyR); this pt subsequently underwent SCT but relapsed with extramedullary disease and died 8 months later. No response was observed in all others BP pts. The overall median time from mutation detection to transformation was 3 months (range1 – 20). A total of 23 (79%) patients have died, a median of 8 months after detection of the mutation (range 1–37). The overall median survival was 11 months.

Patients with E255K/V mutations in CML have a poor prognosis. These patients tend to have a low response to treatment, a higher risk of transformation to BP and death. Alternative treatment options are required for this patient population.

Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Research Funding; Chemgenex: Consultancy, Research Funding.