Genomic Analysis Reveals Targetable Kinase-Activating Alterations in Ph-like Acute Lymphoblastic Leukaemia

Stage set to determine if tyrosine kinase inhibitors will extend the lives of patients with high-risk acute ALL

More than one-quarter of young adults with the most common form of acute lymphoblastic leukaemia (ALL) have a high-risk subtype with a poor prognosis. Philadelphia chromosome-like ALL (Ph-like ALL) was found to be characterised by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors, according to multi-institutional research led by St. Jude Children's Research Hospital investigators. The study appears in the 11th September 2014 issue of The New England Journal of Medicine.

Ph-like ALL is characterised by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults, the authors explained in study background.

Next-generation sequencing study

ALL is the most common childhood cancer. In 2009, St. Jude scientists, working with the Children's Oncology Group (COG), were among the first to describe the Ph-like ALL subtype in children.

The present study found the prevalence of Ph-like ALL increases with age and that the subtype is associated with poor survival. The discovery followed a detailed genomic analysis of 1,725 patients ages 1 to 39 with the most common form of ALL, B-ALL.

Researchers also used next-generation sequencing to identify the genetic alterations that give rise to Ph-like ALL, including some involving genes not previously linked to cancer. The results highlight the genetic diversity of Ph-like ALL, but also demonstrate that alterations affect a limited number of biological signaling pathways. Those pathways regulate genes controlling cell growth and proliferation, which are disrupted in cancer.

The findings, combined with earlier work from St. Jude and other institutions, laid the foundation for clinical trials to determine whether tyrosine kinase inhibitors could help improve patient outcomes. A study in USA meant to answer that question in children is scheduled to begin later this year or early in 2015.

"We showed that Ph-like ALL is a common disease that spans the age spectrum, and we identified new genomic alterations that converge on a handful of signaling pathways that are vulnerable to treatment with tyrosine kinase inhibitors," said corresponding author Dr Charles Mullighan, a member of the St. Jude Department of Pathology. "The findings lead the way for clinical trials that could help to transform the outlook for patients regardless of age."

Trials are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival

Tyrosine kinase inhibitors, including drugs like dasatnib and imatinib, are widely used to treat other types of leukaemia that are more common in adults. The drugs have also been used in a small number of patients with Ph-like ALL. This study reports the experiences of eight such patients, including seven children who were treated at different medical centers. All had leukaemia that persisted despite chemotherapy. Each patient experienced a dramatic, immediate benefit when a tyrosine kinase inhibitor was added to the treatment regimen. Five patients remain in remission with no detectable cancer, one for more than a year.

"The findings are tremendously exciting and pave the way for clinical trials testing TKIs plus chemotherapy in subsets of children and adolescents with ALL," said corresponding author Prof. Stephen Hunger, professor at the University of Colorado School of Medicine and the chair of the COG ALL Committee.

Investigators from the COG have developed plans to test more than 800 children annually enrolled in COG ALL clinical trials to identify those who might benefit from this treatment approach. That is the clinical trial expected to open this year or early in 2015.

Ph-like ALL

Ph-like ALL is named for a chromosomal rearrangement known as the Philadelphia (Ph) chromosome, which is associated with a different subtype of ALL. Both Ph-positive and Ph-like subtypes of ALL share similar patterns of gene expression, but patients with Ph-like ALL lack the fusion of the BCR and ABL1 genes that is a feature of Ph-positive ALL.

In this study, Ph-like ALL comprised 10% of children 1 to 9 years old with standard-risk B-ALL. The percentage rose with age and accounted for 27% of B-ALL cases among those ages 21 to 39. Work is underway to establish the incidence in older adults.

Regardless of their age, patients with Ph-like ALL were less likely than other B-ALL patients to be alive and cancer free five years after their disease was discovered. Overall survival for children, adolescents and young adults with Ph-like ALL was 62% compared to 91% for other B-ALL patients of the same age. Leukaemia-free survival was about 47% for patients with Ph-like ALL and about 83% for other patients.

The search for the genetic changes that give rise to Ph-like ALL included whole genome sequencing of 42 patients plus additional sequencing, including of RNA from the leukaemic cells of 136 patients.

Researchers found that 91% of patients with Ph-like ALL had chromosomal rearrangements or other genetic alterations that activate cytokine receptor or kinase signaling. An analytic tool CICERO, which was developed by St. Jude researchers, played a key role in identifying the changes.

"We identified several new subgroups of Ph-like ALL that were distinguished by the type of cytokine receptor or kinase gene alteration," said Dr Kathryn Roberts, a St. Jude postdoctoral fellow. She and Dr Yongjin Li, a St. Jude Department of Computational Biology research scientist, are the paper's co-first authors.

Evidence suggests that several of the newly identified Ph-like ALL subtypes are vulnerable to tyrosine kinase inhibitors and other targeted therapies. For example, about 12% of patients had rearrangements involving the genes ABL1, ABL2, CSF1R and PDGFRB, which are known to respond to dasatnib and related tyrosine kinase inhibitors.

Numerous other Ph-like ALL patients had gene rearrangements involving JAK2, EPOR and other genes that can be targeted by ruxolitinib.

The research was part of the Pediatric Cancer Genome Project, a collaboration of St. Jude and Washington University School of Medicine in St. Louis that uses next-generation genome sequencing technology to improve understanding and treatment of some of the most aggressive and least understood childhood cancers. The complete normal and tumour genomes of 700 young cancer patients have been sequenced as a result of the project, which began in 2010.

The study was also part of the USA National Cancer Institute's (NCI) Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative. That effort uses genomics to identify therapeutic targets and spur development of more effective treatment for childhood cancer. Study collaborators include St. Jude, COG, the Eastern Cooperative Oncology Group, the Alliance – Cancer and Leukemia Group B and MD Anderson Cancer Center.

The research was supported in part by funding from the American Lebanese Syrian Associated Charities, grants from the National Cancer Institute (CA 21765, U01 CA157937-01, F32 CA141762, R37 CA36401, U24-CA114737, U10 CA21115, CA14958, U10 CA101140, CA145707, U10 CA98543, U10 CA98413, U24 CA114766), a Stand Up to Cancer Innovative Research Grant and a St. Baldrick’s Foundation Scholar Award, a St. Baldrick’s Consortium Award, a grant from the Leukemia and Lymphoma Society Specialized Center of Research, a Leukemia and Lymphoma Society Special Fellow Award, Alex’s Lemonade Stand Foundation Young Investigator Awards, an Alex’s Lemonade Stand Foundation Scholar in Developmental Therapeutics Award, and a grant from the USA National Institute of General Medical Sciences (92666).

Reference

Roberts KG, Li Y, Payne-Turner D, et al. Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia. N Engl J Med 2014; 371:1005-1015.