SAN DIEGO – Novel genetic alterations have been identified in a new subtype of high-risk B-cell acute lymphoblastic leukemia that could be effectively targeted with existing therapies.
The subtype, termed Ph-like ALL, was first identified by the Children’s Oncology Group in 2009 (N. Engl. J. Med. 2009;360:470-80), and accounts for up to 15% of pediatric acute lymphoblastic leukemia (ALL) cases.
"Until this study, the genetic basis of Ph-like ALL was unknown," said Kathryn G. Roberts, Ph.D., lead author of the cooperative research study.
Ph-like ALL is associated with alteration of lymphoid transcription factors, most commonly IKZF1, and has a gene expression profile similar to that of Philadelphia chromosome–positive (Ph+) ALL. Ph+ ALL accounts for just 5% of pediatric ALL cases, but because it is driven by the oncogenic tyrosine kinase, BCR-ABL1, it can be effectively treated with available tyrosine kinase inhibitors such as imatinib (Gleevec).
Ph-like ALL, however, is BCR-ABL negative, so patients with this poor-outcome subtype are currently treated with conventional chemotherapy. Higher doses and intensified regimens are limited by toxicity.
Screening ALL patients at the time of diagnosis could identify those with Ph-like ALL, and determine who may benefit from more-aggressive treatment with targeted therapies, said Dr. Roberts, a postdoctoral pathology fellow at St. Jude Children’s Research Hospital in Memphis, Tenn.
In an effort to better understand the genetic basis of Ph-like ALL, the investigators used next-generation genome sequencing and other techniques to analyze the transcriptome or RNA sequence of 12 patients with Ph-like ALL. Strikingly, 11 of the 12 cases harbored alterations disrupting kinase and cytokine receptor signaling, which provides a treatable target with current drugs, she said. The alterations included novel rearrangements, structural variations, and sequence mutations.
Specifically, the spectrum of alterations included NUP214-ABL1 or RANBP2-ABL1 rearrangements, immunoglobulin heavy chain rearrangements involving the cytokine receptor genes CRLF2 and EPOR, and in-frame fusions of EBF1-PDGFRB (platelet-derived growth factor receptor beta), BCR-JAK2 or STRN3-JAK2. In addition, activating mutations within IL7R, and loss of function SH2B3 deletions were also identified.
Importantly, laboratory studies showed that patient samples harboring the ABL1 rearrangement were sensitive to the tyrosine kinase inhibitors imatinib, dasatinib (Sprycel), and XL228, whereas the JAK2-rearranged samples were sensitive to the JAK2 inhibitors XL019 and ruxolitinib (Jakafi), which was recently approved for the treatment of myelofibrosis. Furthermore, mouse cells harboring the EBF1-PDGFRB fusion responded to imatinib, dasatinib, and dovitinib, a specific PDGFRB/FGFR (fibroblast growth factor receptor) inhibitor, Dr. Roberts reported.
The group also screened 231 additional high-risk ALL patients (aged 1 year 2 months to 17 years 6 months) and found that the genetic alterations were present in 40 cases (17%), suggesting that these genetic lesions are "hallmarks of this subtype of ALL," she said.
Dr. Martin Tallman, chief of the leukemia service at Memorial Sloan-Kettering Cancer Center in New York, told reporters at a press briefing that the study could potentially change the standard of care, and "provides further evidence that we’re able to target specific leukemias with specific, directed therapy rather than continuing to give relatively indiscriminate chemotherapy."
The diversity of lesions in Ph-like ALL suggests that screening methods to identify patients at diagnosis may be more attractive than transcriptome sequencing, Dr. Roberts noted. Phosphoflow cytometric signaling analysis can be used to detect activation of pathways common to the novel genetic lesions and to identify patients who will most likely respond to targeted therapy. Gene expression profiling is also being investigated as a complimentary approach to identify Ph-like ALL patients.
Kathryn G. Roberts
St. Jude is currently not screening its ALL patients for Ph-like ALL, but the researchers hope to be able to start treating children who have ALL based on their genetic alterations in the next 12 months, she said in an interview.
The researchers are also currently establishing Ph-like ALL animal models and plan to broaden the scope of their testing to include young adolescents and adults. The current study earned the outstanding abstract achievement award for a postdoctoral fellow at the meeting.
Dr. Roberts reported no conflicts of interest. A coauthor, Dr. Steve Hunger, reported that his children own stock in Bristol-Myers Squibb and that he is a member of an entity’s board of directors or advisory committee.