New Hope in High-Risk Leukemia Subtype

Philadelphia chromosome-like acute lymphocytic leukemia (Ph-like ALL) is a precursor of B-cell ALL. Unfortunately, pediatric patients with Ph-like ALL face worse outcomes. Adding tyrosine kinase inhibitors (TKIs) to the treatment protocol, however, may turn things around for them, according to new research.

In a genomic profiling analysis, Kathryn Roberts, PhD, from St. Jude Children’s Research Hospital in in Memphis, Tennessee, identified genetic alternations in Ph-like ALL that may be “amenable” to inhibition with TKIs, such as dasatinib and imatininb.

Their findings, published in the New England Journal of Medicine, lay the groundwork for clinical trials to assess whether adding TKIs to current Ph-like ALL therapy improves survival odds for these patients, explained co-author Charles Mullighan, MD. 

“Our study has shown that the prevalence of Ph-like ALL increases with age, and it is associated with poor outcome,” Dr. Mullighan told ASH Clinical News. “We defined the genetic basis of Ph-like ALL and identified a range of genetic changes activating kinase signaling pathways.” The majority of these pathways, he noted, are targetable with approved TKIs.

In the current study, Roberts et al. identified 264 cases of Ph-like ALL among more than 1,000 cases of standard or high-risk precursor B-cell ALL. A total of 154 patients (age range, 1 to 39 years) with Ph-like ALL underwent next-generation genome sequencing. The investigators also looked at the associations between Ph-like ALL status, event-free survival, and overall survival.

In their analysis, kinase-activating alterations were pinpointed in 91percent of Ph-like ALL patients, with rearrangements involving 11 genes, including CRLF2 and JAK2. They also noted sequence mutations involving FLT3, IL7R, and SH2B3.

Across the whole cohort, the authors identified rearrangements activating kinase signaling in 96 of 154 patients (62%). All kinase fusions retained an intact TKI. Dr. Mullighan said many of the underlying genetic changes in these patients can be identified with standard assays, such as PCR and FISH.

“We have developed simple screening tests for Ph-like ALL that are being implemented in clinical trials, and several centers, including St. Jude, will use genome sequencing at diagnosis to detect Ph-like ALL and the underlying genetic alterations.” In other findings, Ph-like ALL was more common among males than females. Also, prevalence of Ph-like ALL significantly increased with age: 10 percent and 21 percent of children and adolescents, respectively, with standard-risk ALL; 13 percent and 27 percent among children and adolescents with high-risk ALL.

Among high-risk Ph-like ALL patients, the median five-year event-free survival was reached in:

  • 58.2 percent of children
  • 41 percent of adolescents
  • 24.1 percent of young adults

Rates of five-year overall survival ranged from a high of nearly 73 percent for children to almost 26 percent for young adults. Finally, using a mouse model, Dr. Roberts and colleagues noted that ABL1, ABL2, and CSF1R fusions were sensitive to imatinib and dasatinib – two ABL-class inhibitors. They also found that there was a high frequency of rearrangements activating JAK2 in young adult patients, making ruxolitinib a potential treatment option in these patients.

Among a dozen patients in the cohort who received TKI therapy, all but one showed “rapid and sustained responses” to treatment, the authors stated. “Cases of refractory Ph-like ALL showed a dramatic response to TKI therapy,” Dr. Mullighan added, “providing the justification and rationale for prospective trials of TKI therapy in Ph-like ALL.”

In terms of future research, Dr. Mullighan said that the Children’s Oncology Group will commence a national trial in 2015 to screen for Ph-like ALL, with an eye toward identifying the underlying genetic alterations. The trial also will incorporate ABL-class inhibitors into treatment in patients with targetable alterations. St. Jude will perform genome sequencing of all patients at diagnosis and TKI therapy will be incorporated in the next front-line study of ALL. The trial, called Total XVII, will open in 2015, he said.


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.

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