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Philadelphia Chromosome-Like ALL Linked to Poor Outcomes in Adults

NEW YORK (GenomeWeb) - The presence of expression signatures resembling those of the Philadelphia chromosome account for at least one-fifth of adult acute lymphoblastic leukemia cases, and tend to herald diminished survival times, according to a new study.

An international team led by researchers from St. Jude Children's Research Hospital tested samples from almost 800 adults with B-cell ALL, searching for expression signatures resembling those found in the presence of the Philadelphia chromosome, which includes a BLR-ABL1 fusion. The analysis, reported yesterday in the Journal of Clinical Oncology, revealed Philadelphia chromosome-like patterns in more than one-fifth of adult cases and nearly 28 percent of those diagnosed before the age of 40.

Individuals in the so-called Ph-like ALL group typically fared worse than their counterparts with other forms of ALL: the five-year event-free survival rate was more than 47 percent for adult in the non-Ph-like ALL group, but just shy of 21 percent in the Ph-like ALL group. Overall survival rates exceeded 52 percent in non-Ph-like cases, but did not reach 24 percent in the individuals with Ph-like ALL.

"The outcomes of this [Ph-like] group were as poor as, or worse than, other high-risk subtypes of leukemia," senior author Charles Mullighan, a pathology researcher and co-leader of the hematological malignancies program at St. Jude, told GenomeWeb.

The Philadelphia chromosome is a rearrangement marked by an abbreviated chromosome 22 and translocation that fuses the chromosome 22 gene BCR to the chromosome 9 tyrosine kinase enzyme-coding gene ABL. It has been detected in the majority of chronic myelogenous leukemia cases, where the constitutively active tyrosine kinase produced by the Philadelphia chromosome is often targeted with tyrosine kinase inhibitors such as imatinib (Novartis' Gleevec) or dasatinib (Bristol-Myers Squibb's Sprycel).

Studies going back to 2009 — including a Lancet Oncology paper by researchers in the Netherlands and a paper published in the New England Journal of Medicine by Mullighan and his collaborators from the Children's Oncology Group (COG) — suggest BCR-ABL1 rearrangements or BCL-ABL1-like alterations occur in a subset of childhood ALL cases.

Those findings have been expanded in subsequent studies on ALL in childhood and young adulthood, Mullighan explained, where Ph-like ALL tended to turn up in riskier cases diagnosed in somewhat older individuals. The prevalence of Ph-like ALL has not been explored in as much detail in adults, where there has been some debate over the prevalence of the high-risk form of disease.

"There weren't really comprehensive data in large numbers of patients looking right across the age spectrum. That was a major goal of this study, to rigorously look at not just the prevalence of Ph-like leukemia but also its genetic drivers," Mullighan said.

By analyzing diagnostic samples from more than 900 adults with B-cell ALL, the team identified 798 samples with enough quality genetic material for genetic analyses — samples from 344 individuals between the ages of 21 and 39, 304 cases involving 40 to 59 years old, and 150 individuals over 60.

Using Affymetrix arrays or low-density quantitative RT-PCR-based Taqman arrays from Thermo Fisher Scientific, the researchers searched the samples for expression patterns consistent with the BCR-ABL1 fusion or related alterations.

"Because there's such a range of different kinase-activating lesions, we identified and defined the subtype by that gene expression profile," Mullighan said, though he noted that the expression patterns associated with Ph-like cases are likely multi-factorial, reflecting "not just the kinase-activating lesion but other changes as well that influence it."

In general, the kinase-activating forms of Ph-like ALL described so far fall into several broad groups, he added. Some include CRLF2 rearrangements, often accompanied by other mutations, such as alterations affecting Janus kinase genes such as JAK1 or JAK2. Another set of Ph-like ALL cases can be traced to other JAK-STAT fusions or mutations activating the JAK-STAT signaling pathway. An ABL class of Ph-like ALLs is marked by fusions of tyrosine kinase genes susceptible to the same types of inhibitors used to treat ABL fusions.

Across the complete set of adult ALL cases, the team uncovered BCR-ABL1 fusions in more than 23 percent of individuals, including almost one-third of individuals in the oldest group. Meanwhile, the Ph-like ALL turned up in nearly 28 percent of cases affecting young adults, but was also detected in more than 20 percent of the 40 to 59 year olds and in almost one-quarter of cases involving individuals over 60. All told, some 88 percent of the Ph-like ALL individuals carried kinase-activating mutations and more than half had CRLF2 rearrangements.

As in past studies of ALL, older age at diagnosis did not bode well for survival. But Ph-like ALL was also associated with dips in progression-free survival and overall survival, particularly in the young adult group.

To take a closer look at the roots of the Ph-like ALL features, the team went on to do RNA sequencing with Illumina HiSeq 2500 or 4000 instruments on 86 individuals in the Ph-like ALL group — an analysis that helped in further teasing apart the types of rearrangements, fusions, and sequence mutations that can lead to Ph-like expression patterns.

From these and other analyses, the study's authors suggested that "identification of patients with Ph-like ALL should be incorporated into the design of future clinical trials."

For their part, the St. Jude researchers are gearing up to do a clinical trial on the effectiveness of targeted treatment for individuals with Ph-like ALL who are younger than 21, Mullighan said. That trial is expected to begin early next year. He noted that other groups, including COG, have related trials underway, following from work hinting at the effectiveness of tyrosine receptor kinase inhibitors in relapsed or treatment refractory Ph-like ALL cases.

"The challenge now is to address the responsiveness in a carefully designed prospective fashion," Mullighan said. "Particularly in childhood leukemia, we would not envisage these [tyrosine receptor kinase inhibitors] being used as single-agent therapy. We strongly feel that they need to be combined with a backbone of chemotherapy."

Following from their results so far, the St. Jude researchers are also doing studies focused on untangling the molecular alterations that drive leukemia development or mediate treatment response in engineered mouse models and patient-derived xenografts. Those models may offer a window into ALL vulnerabilities that might be targeted with other types of drugs, Mullighan noted.

He emphasized the importance of investigating strategies for using Ph-like ALL status to inform patient' diagnoses. "The big question that everyone is now grappling with is, 'How to implement this into frontline diagnostics,'" he said, noting that "the approaches are different depending on the center and its bandwidth and capability."

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