Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

Abstract

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-alpha in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.

Figure 1

BCR-ABL mutations detected before and concomitantly to the T315I mutation detection. (A) Other BCR-ABL mutations detected before the T315I mutation detection (n = 36; 16%). Two patients had 2 mutations detected in different tests (one with G250E/L273M and one with Y253H/F317L). (B) Other BCR-ABL mutations detected at the time of T315I detection (n = 52; 23%). Five patients had 2 additional mutations detected. *Solid black bars are different types of P-loop mutations.

Figure 2

Survival analysis in patients with T315I BCR-ABL mutation. (A) OS from leukemia diagnosis by disease phases at the time of leukemia diagnosis. (B) OS from TKI treatment start by disease phase at the time of TKI treatment start. (C) OS from first TKI resistance by disease phase at the time of first TKI resistance. (D) OS from first T315I mutation detection by disease phase at the time of T315I mutation detection. (E) OS from first T315I mutation detection by disease phase at the time of T315I mutation detection, where CML LBP were combined with Ph⁺ ALL (n = 214)

Figure 3

Progression-free survival in patients with T315I BCR-ABL mutation. (A) PFS from first TKI resistance by disease phase at the time of first TKI resistance. (B) PFS from T315I mutation detection by disease phase at the time of T315I mutation detection.