Combination of axitinib with dasatinib improves the outcome of a chronic myeloid leukemia patient with BCR-ABL1 T315I mutation / 中南大学学报(医学版)

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and characterized by the formation of Philadelphia (Ph) chromosome. Recently, tyrosine kinase inhibitors (TKI) treatment greatly improved the prognosis of CML. However, the options may be limited when a patient develops traditional TKI resistance or gene mutation. Herein, we reported a case. 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. We adjusted the treatment with the combined application of dasatinib and axitinib. BCR-ABL1 gene copies dropped down and achieved an early molecular response at 2 months later. Subsequently, he received hematopoietic stem cell transplantation. Axitinib and dasatinib were applied for another half year after the allogeneic hematopoietic stem cell transplantation (allo-HSCT). 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.

Clinical characteristics of chronic myeloid leukemia with T315I mutation and the efficacy of ponatinib / 南方医科大学学报

OBJECTIVE@#To analyze the clinical features of chronic myeloid leukemia (CML) with T315 I mutation (CML-T315I) and compare the effectiveness of different treatments.@*METHODS@#We retrospectively analyzed the clinical data and outcomes of 19 patients with CML-T315I receiving different treatments. The T315 I mutations in these patients were detected by examination of BCR-ABL kinase domain (KD) mutation by RTQ-PCR and Sanger sequencing. The relapse following the treatments, defined as hematological, cytogenetic and molecular biological recurrences, were analyzed in these patients.@*RESULTS@#Of the 19 patients with CML-T315I, 14 (73.7%) were in CML-CP stage at the initial diagnosis, and 13 (81.2%) were high-risk patients based on the Sokal scores. All the 19 patients were treated with TKI after the initial diagnosis, and during the treatment, 15 (78.9%) patients were found to have additional chromosomal aberrations, and 10 (52.6%) had multiple mutations; 13 (68.4%) of the patients experienced disease progression (accelerated phase/blast crisis) before the detection of T315I mutation, with a median time of 40 months (5-120 months) from the initial diagnosis to the mutation detection. After detection of the mutation, 12 patients were treated with ponatinib and 7 were managed with the conventional chemotherapy regimen, and their overall survival rates at 3 years were 83.3% and 14.2%, respectively ( < 0.001).@*CONCLUSIONS@#CML patients resistant to TKI are more likely to have T315I mutations, whose detection rate is significantly higher in the progressive phase than in the chronic phase. These patients often have additional chromosomal aberrations and multiple gene mutations with poor prognoses and a high recurrence rate even after hematopoietic stem cell transplantation. Long-term maintenance therapy with ponatinib may improve the prognosis and prolong the survival time of the patients.

Detection of BCR-ABL T315i Mutation in Imatinib Resistant Chronic Myeloid Leukemia Patients

@#Chronic myeloid leukemia (CML) patients who have BCR-ABL T315I mutation, usually present in the advance phase of the disease with overall survival (OS) shorter than those without the mutation. This study aimed to determine the prevalence of T315I mutation amongst imatinib mesylate (IM) resistant CML patients and to compare the OS between T315I-mutated and non-T315I-mutated patients. Sixty consecutive CML patients who were treated with IM for at least 18 months and their treatment responses, were recorded. The mutation analysis was done using allele-specific oligonucleotide reverse transcriptase-polymerase chain reaction (RT-PCR) assay followed by direct sequencing technique. Forty-two patients (70%) were found to have IM-resistance. Five out of 42 patients had detectable T315I mutation. Median OS of IM-resistant T315I-mutated patients was 96 months (95% CI:54-138) compared to 84 months (95% CI:48-120) in non T315I-mutated patients, although this was found to be statistically insignificant (p = 0.43). The present study showed a higher prevalence of T315I mutation as compared to a few local studies. Median OS of T315I-mutated patients were observed to be longer than non-T315-mutated patients. Further studies encompassing larger cohort of patients are required to confirm this finding

Treatment efficacy of ponatinib as salvage therapy in relapse chronic myeloid leukemia with T315I mutation after allogeneic stem cell transplantation: report of 12 cases / 中华器官移植杂志

Objective To analyze the efficacy of ponatinib as salvage therapy in relapse chronic myeloid leukemia with T315I mutation (CML-T315D after allogeneic stem cell transplantation (allo-HSCT).Methods Twelve patients with CML-T315I (10 cases of T315I mutation before transplantation and 2 cases of T315I mutation at the time of relapse after transplantation) were included in this retrospective analysis.Ponatinib was used as single agent or combined with chemotherapy and/or donor lymphocyte infusion.The samples obtained for RTQ-PCR were also analyzed for the BCR ABL1 mutation by direct sequencing.Scanning of the ABL KD (amino acids 219-506) for the presence of mutations was sequenced by Sanger.Results In 12 patients with relapse after transplantation,2 patients with molecular relapse were treated with only single-agent ponatinib,and among 10 patients with hematologic relapse,1 patient was treated with single-agent ponatinib and 3 patients were given ponatinib combined with donor lymphocyte infusion (DLI),the remaining 6 patients were treated with ponatinib combined with chemotherapy and DLI.After the treatment with ponatinib,11 patients had a good response,10 patients obtained complete hematologic remission (CHR),1 patient obtained partial hematologic remission (PHR) and 1 patient had no response (NR).For cytogenetic response,10 patients obtained complete cytogenetic response (CCyR),1 patient obtained partial cytogenetic response (PCyR) and one patient had no cytogenetic response.For the molecular biological response,9 patients obtained complete molecular response (CMR),1 patient obtained majore molecular response (MMR) and 2 patients had no molecular biological response.The median time to obtain CHR was 36 days (29-96 days),the median time to obtain CCyR was 63 days (32-127 days),and the median time to obtain CMR was 89 days (27-152 days).The median follow-up time after treatment with ponatinib was 598 (range,93-1470) days,9 patients survived and 3 died.Causes of deaths included leukemia relapse (n =2)and ineffective treatment (n =1).The 2-year overall and disease-free survival rate after relapse in 12 patients was 75.0％ ± 12.5％ and 31.7％ ± 14.9％,respectively.Conclusion This small sample data suggested that ponatinib as salvage therapy had a good response to the relapse CML-T315I after allo-HSCT.

Ponatinib: a miracle or a disaster in chronic myeloid leukemia.

Chronic myeloid leukemia (CML), the most common myeloproliferative disorder, occurring due to balanced reciprocal translocation between chromosome 9 and 22 and resulting in a chimeric oncogene called breakpoint cluster region-abelson (BCR-ABL) whose protein product has tyrosine kinase activity, causes uncontrolled proliferation of the myeloid cells. Although, imatinib, the first-generation tyrosine kinase inhibitor (TKI) achieved an extremely high response rate, some patients developed resistance to it. Thus, second-generation TKIs such as nilotinib, dasatinib, bosutinib were developed which proved very useful, till the emergence of T315I point mutation which occurs in the BCR-ABL gene and renders CML resistant to previous TKIs. Ponatinib, a third generation TKI approved by the United States Food and Drug Administration (FDA), showed great promise as it was effective even against T315I point mutation. However, a recent increase in the incidence of blood clots observed in patients taking ponatinib has resulted in FDA temporarily suspending all trials, marketing and distribution of the drug. Hence, whether ponatinib evolves as a miracle or disaster for the patients of CML is yet to be answered.