Eight of 18 patients with BCR-ABLT315I-mutated chronic myelogenous leukemia (44%) had hematologic responses and one of three patients (33%) with Philadelphia chromosome-positive acute lymphoblastic leukemia obtained complete remission.
Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Separated into Two Subgroups Associated with Survival by BCR-ABL Fluorescence in situ Hybridization of Segmented Cell Nuclei: Report from a Single Institution.
Established leukemia-specific predictive biomarkers for precision medicine include those genetic lesions such as BCR-ABL1 for Philadelphia-positive acute lymphoblastic leukemia and PML-RARα for acute promyelocytic leukemia.
We conclude that molecular studies are useful in detecting BCR-ABL-positive disease in a subset of patients with Ph-positive ALL who are not identified by cytogenetic analysis because of insufficient metaphases.
A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy.
The latter two losses have been shown to be part of 'hot spot' genome imbalances associated with BCR/ABL1 positive pre-B lymphoid phenotype in CML and Ph(+)ALL.
In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML.
ABL KD mutations, especially at codons 315 and 253, emerged at the time of disease recurrence in the vast majority of patients who had Ph-positive ALL and received maintenance KI therapy.
Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia.
BCR-ABL1-positive (Ph+) ALL has historically had a very poor outcome, but recent studies have demonstrated the impressive improvements in treatment outcome with the use of tyrosine kinase inhibitors (TKIs).
The efficacy of this approach on the leukemogenic potential of BCR/ABL was studied in Ba/F3 cells, primary murine bone marrow cells, and untransformed Rat-1 fibroblasts expressing BCR/ABL or BCR/ABL-T315I as well as in patient-derived long-term cultures (PDLTC) from Ph + ALL-patients.
Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) into frontline therapeutic regimens has improved outcomes for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL).
VX-680 is a pan-Aurora kinase inhibitor active against all Bcr/Abl proteins but has not been extensively examined in preclinical models of Ph-positive ALL.
Despite the clinical efficacy achieved with frontline therapies for BCR-ABL-positive disease, such as imatinib and second-generation ABL inhibitors like nilotinib or dasatinib that were originally designed to override insensitivity to imatinib, drug resistance still remains a challenge, especially for patients with advanced-stage chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.
ABL1 kinase mutations were found in 2.6% of patients with chronic-phase chronic myelogenous leukemia (CML), 25.0% of accelerated-phase CML, 66.7% of blast-phase CML, and in 58.3% with Ph+ acute lymphoblastic leukemia.
Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).
We describe a childhood refractory Ph + ALL patient in whom progressive resistance to imatinib was correlated with the appearance of a mutation in the BCR-ABL kinase domain and in vitro drug resistance to imatinib as determined by the methyl-thiazol-tetrazolium (MTT) assay.