ABL1 T315I + ABL1 M351T + ABL1 L387M

However, in the treatment of CML with a Bcr-Abl kinase inhibitor, the T315I gatekeeper mutant disrupts the important contact interaction between the inhibitor and the enzyme, resistant to the first and second generation drugs currently approved, such as imatinib, bosutinib, nilotinib and dasatinib. Some of these molecules are still under development, and some are being studied preclinically, still others are in clinical research. Herein, this review reports some of the major examples of third generation Bcr-Abl inhibitors against the T315I mutation.

Multivariate analysis determined the prognostic impact of the T315I mutation (OS: hazard ratio &lsqb;HR] = 2.19, 95% confidence interval &lsqb;CI]: 1.5-3.3, p < 0.001; RR: HR = 2.51, 95% CI: 1.5-4.2, p < 0.001). This study is the first to report on the prognostic significance of BCR-ABL1 mutations in Ph + ALL.

A 38-year-old male CML patient developed a BCR-ABL1 gene mutation of T315I after 2.5 years of TKI treatment, including imatinib and dasatinib. Two years after the allo-HSCT, the BCR-ABL1 gene was still undetectable. It provided a successful example in treating CML patients carrying BCR-ABL1 T315I mutation via combination of axitinib with conditional TKI.

Eight patients (4.6%) presented with more than one mutation, three (37.5%) of whom harboured T315I coexisting with other mutations, and for nine (5.1%) patients, the results differed between conventional sequencing and UDS, with the mutations being missed by conventional sequencing. The results form this study suggested that programing mutation analysis in patients with chronic myeloid leukaemia timely may guide the choice of TKIs.

While major molecular response were observed in the majority of patients without TKD mutation, resistant to TKI were detected in patients with T315I mutation (n = 9; % mean IS = 8.1510, % median IS = 9.7000), compound/polyclonal mutations with T315I (n = 9; % mean IS = 13.0779, % median IS = 5.404), and other TKD mutations (n = 14; % mean IS = 8.1416, % median IS = 1.060), respectively. Conlusion: These practical laboratory techniques provided a more comprehensive understanding of CML progression during drug therapy and could be of benefit in earlier prognosis.

Four tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, dasatinib, and bosutinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP)...Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease. Even among older patients who have a cytogenetic relapse post failure on all TKIs, they can maintain long-term survival if they continue on a daily most effective/less toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan, others).