Severe subtype of acute lymphoblastic leukemia susceptible to FDA-approved kinase inhibitors
1. The prevalence of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) increased with age and was associated with worse overall survival compared to non-Ph-like ALL.
2. Ph-like ALL cell lines had a high prevalence of genomic alterations affecting kinase signaling pathways which proved susceptible to targeted kinase inhibitor therapies in vitro and in mouse models.
Evidence Rating Level: 2 (Good)Â
Study Rundown: Generally, ALL is the most common childhood cancer as well as a major cause of death and illness in adults. Ph-like ALL is a subtype of ALL in which patients have a gene-expression profile similar to that of patients with the BCR-ABL1 fusion protein. However, little is known about the spectrum of genetic alterations in patients with Ph-like ALL and how these may be used as potential drug targets.
This study is an exploratory genomic analysis of a cohort of 1725 patients with ALL, including children and young adults. In this study, patients underwent detailed genomic analysis including further sequencing in a subset of 154 patients. There was a significant association between increasing age and increasing prevalence of Ph-like ALL across children, adolescents, and young adults. Furthermore, the authors found that across all age groups, the 5-year event-free survival rates and 5-year overall survival rates were lower in patients with Ph-like ALL compared to patients without Ph-like ALL, suggesting that this subtype is a severe form of disease. There was a high number of genomic alterations involving kinase signaling. Finally, there was reduced cancer cell growth in cell lines and in mouse models treated with specifically targeted kinase inhibitors such as dasatinib, ruxolitinib, and o.
The strength of this study is the genomic characterization of Ph-like ALL in a large cohort of both children and young adults. These data will prove invaluable for the research community as this disease continues to be defined and specifically targeted by kinase inhibitors. However, the research remains at an early stage, with the kinase inhibitor therapies being used in vitro and in mouse models. This will set the stage for potential larger randomized trial designs involving human subjects.
Click to read the study, published today in NEJM
Click to read an accompanying editorial in NEJM
Relevant Reading: Acute lymphoblastic leukemia
Study Author, Dr. Charles Mullighan, MD, MBBS, MSc, talks to 2 Minute Medicine: St. Jude Department of Pathology.Â
“Acute lymphoblastic leukemia (ALL) remains a leading cause of cancer death in children, and the prognosis worsens with increasing age. Current therapies are inadequate for many patients. This study has defined the genetic basis of a recently described subtype of ALL called Ph-like ALL. We show that the prevalence increases with rising age, and that in both children and young adults the disease is driven by a diverse range of genetic changes that activate kinase signaling, which fuels the growth of leukemia cells. Ph-like ALL currently has a poor outcome. The activated kinases may be inhibited by currently approved tyrosine kinase inhibitors (TKIs). We have shown efficacy of these inhibitors in cell lines and experimental models, and in a series of patients with Ph-like ALL treated with TKIs.
The study is clinically significant as Ph-like ALL currently has a poor outcome and new treatments are needed, and we have shown efficacy of TKIs in cases of refractory Ph-like ALL. In the near future, we envisage that all patients will be tested for the presence of Ph-like ALL to enable the most appropriate treatment to be delivered.”
In-Depth [genetic cohort study]: This genetic cohort study aimed to define the frequency and genomic landscape of Ph-like ALL in a cohort of 1725 children and young adults with precursor B-cell ALL. It also involved detailed genomic analysis (including transcriptome sequencing, whole-genome sequencing, and whole-exome sequencing) of 154 of these patients. The authors report that the prevalence of Ph-like ALL significantly increased with age: 10% in children with standard-risk ALL, 13% in children with high-risk ALL, 21% in adolescents with ALL, and 27% in young adults with ALL (P<0.001 for comparing children to adolescents and children to young adults). Using the Kaplan-Meier estimator, with an event signifying failure to achieve remission, relapse after remission, or development of a second malignant neoplasm, it was found that across all age groups, the 5-year event-free survival rates and 5-year overall survival rates were inferior in patients with Ph-like ALL compared to those without Ph-like ALL (P<0.001 for both comparisons).
In the next-generation sequencing analyses, 91% of patients with Ph-like ALL had genomic alterations activating kinase signaling including fusions predicted to respond to ABL1 inhibitors, rearrangements of EPOR or JAK2, and rearrangements of CRLF2. To determine the transforming properties of kinase fusions, the mutated cell lines were assessed for their ability to induce cytokine-independent proliferation in mouse models. This cytokine-independent proliferation was found in all fusions that were tested. The growth of primary human leukemia cells was inhibited in vitro and in mouse models when cells were exposed to specifically targeted kinase inhibitors.
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