Tyrosine Kinase Inhibitors May Improve Treatment Outcomes in Children With Philadelphia Chromosome–Like ALL
Using genomic profiling and next-generation sequencing of patients with BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (B-cell ALL) and Philadelphia chromosome–like ALL, researchers recently identified alterations targeting 18 kinase or cytokine receptor genes. They then determined that these alterations contribute to the development of Philadelphia chromosome–like ALL and found that different FDA-approved tyrosine kinase inhibitors, including imatinib (Gleevec), dasatinib (Sprycel), ruxolitinib (Jakavi), and crizotinib (Xalkori), could potentially be used to treat this high-risk subtype. The study by Roberts et al was presented at the AACR conference Hematologic Malignancies: Translating Discoveries to Novel Therapies, held in Philadelphia on September 20 to 23.
Study Methodology and Findings
After performing genomic profiling of over 1,700 B-cell ALL cases and next-generation sequencing of over 150 Philadelphia chromosome–like ALL cases, researchers identified alterations targeting 18 kinase or cytokine receptor genes, including rearrangement, sequence mutation, and copy number alterations.
They then conducted laboratory experiments using normal mouse blood cells and found that introduction of genetic alterations to tyrosine kinases caused the development of Philadelphia chromosome–like ALL. In addition, the researchers found that the different types of kinase alterations triggered different cell signaling pathways.
Next, the researchers grew human Philadelphia chromosome–like ALL tumors in mice, treated them with dasatinib, and discovered that the tumors were reduced. As proof of principle, the STAT signaling pathway associated with the specific kinase alteration in the tumors was suppressed.
“These subtypes are very common,” said Kathryn G. Roberts, PhD, postdoctoral research associate in the Department of Pathology at St. Jude Children’s Research Hospital and principle investigator of the study, during a press briefing. “They account for 10% of childhood ALL, and up to over 25% in young adults with ALL and these patients all have a very poor outcome in all age ranges, so we need to identify better treatment for these patients to improve their survival.”
From Bench to Bedside
“This [study] is another example of the wonderful progress in science that is translating to patients,” said Kenneth C. Anderson, MD, Chair of the AACR conference, and Program Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer Institute in Boston, at a press briefing announcing the study results. “The ability to introduce the genetic abnormality into normal cells, create leukemia, test it in a mouse model, and then go forward with available kinase inhibitors and straight to personalized medicine.”
The study was funded by the ALSAC of St. Jude Children’s Research Hospital, the National Cancer Institute, Stand Up To Cancer, the St. Baldrick’s Foundation, the Leukemia and Lymphoma Society, and Alex’s Lemonade Stand Foundation.
Dr. Roberts reported no conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
