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 blasticphase (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-␣ 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.

The BCR-ABLT315I mutation compromises survival in chronic phase chronic myelogenous leukemia patients resistant to tyrosine kinase inhibitors, in a matched pair analysis

“…CP CML patients with a T315I mutation were extracted from a previously described updated international database containing information from 222 T315I + CML patients (all phases and those with Philadelphia chromosome-positive acute lymphoblastic leukemia). 14 In that study, 14 the survival of T315I + patients did not differ between countries (unpublished data). In this study, the comparison group was CML patients in CP at diagnosis and at IM-resistance, previously screened at IM-resistance for BCR-ABL mutations and found to be T315I negative (they could harbor other mutations).…”

“…14 Mutation screening was performed using different techniques (predominantly direct sequencing, but also polymerase chain reaction-restriction fragment length polymorphisms and denaturing high performance liquid chromatography in combination with sequencing) and, for some patients, included assaying frozen material. Patients with any T315I clone levels were included.…”

“…9 These biochemical and cellular in vitro findings are associated with poor survival rates in patients resistant to IM. [10][11][12][13][14] However, it remains unclear whether the presence of the T315I mutation within the cells in CP confers a specific virulence to the disease or whether it is simply a co-factor in a cell that is IM-resistant for other unknown reasons.…”

“…14 We did this by restricting our analyses exclusively to chronic phase CML patients (at diagnosis and at the time the T315I mutation was detected) who were not eligible for allogeneic stem cell transplantation (as this option might have rescued a number of them 15 ) and who had not received ponatinib, and updating the data. Using a matched pair analysis in our three European centers, we matched CP CML T315I + patients with other IM-resistant CP CML patients who did not have a T315I BCR-ABL mutation at resistance, in an effort to demonstrate the negative impact of the presence of this mutation on overall and failure-free survival.…”

Aurora kinase inhibitors: novel small molecules with promising activity in acute myeloid and Philadelphia-positive leukemias

“…16 A recent review of T315I-positive patients has also demonstrated that compared with CML patients in the chronic (CML CP ) or accelerated phase (CML AP ), patients with CML BC and Ph þ ALL have the T315I mutation detected earlier after starting TKI therapy and have lower disease-free and overall survival rates. 17 Aurora kinase inhibitors currently undergoing clinical trial in patients with CML or Ph þ ALL are summarized in Table 1. One of the first reports of the activity of Aurora kinase inhibitors in Ph þ leukemia involved the pan-Aurora kinase inhibitor MK-0457 (previously known as VX-680), which was studied in three adult patients with T315I ABL-mutated CML (n ¼ 2) or Ph þ ALL (n ¼ 1).…”