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Philadelphia chromosome–like subtype accounts for more than 20% of adult ALL cases
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Philadelphia chromosome–like acute lymphoblastic leukemia appears to be a highly prevalent ALL subtype and is associated with inferior 5-year EFS, according to a study published in Journal of Clinical Oncology.
“We had previously reported that the frequency of Philadelphia chromosome (Ph)–like ALL increases from 15% in children to 25% in young adults up to the age of 39 years; however, the frequency of this subtype in patients older than 40 years of age was unknown,” Kathryn Roberts, PhD, staff scientist and ASH Scholar in the department of pathology at St. Jude Children’s Research Hospital, told HemOnc Today. “In this study, we show the prevalence of Ph–like ALL remains above 20% in patients up to the age of 86 years. Furthermore, Ph–like ALL adult patients harbor a similar spectrum of tyrosine kinase– and cytokine receptor–activating alterations as those identified in children. We also show that the EFS and OS outcomes of adult patients with Ph–like ALL is inferior to patients who do not have Ph–like ALL.”
Ph–like ALL is a high-risk subtype of ALL characterized by rearrangements, sequence mutations and copy number alterations involving kinase or cytokine receptor genes. Despite improvements in the outcome for children with ALL, the prognosis of adults with ALL is poor, with 5-year survival rates of 40% overall and approximately 7% for patients who experience a relapse. Compared with children, adults with ALL have an increased frequency of high-risk genetic alterations and complex karyotypes.
Roberts and colleagues profiled 798 patients with B-cell ALL aged 21 to 86 years. Researchers compared EFS and OS for patients with Ph–like ALL vs. non-Ph–like ALL.
Patients with Ph–like ALL accounted for 27.9% of adults aged 21 to 39 years, 20.4% of adults aged 40 to 59 years, and 24% of adults aged 60 to 86 years.
Overall, rate of 5-year EFS was 22.5% (95% CI, 14.9-29.3) among patients with Ph–like ALL compared with 49.3% (95% CI, 42.8-56.2) among patients with non-Ph–like ALL (P < .001).
A significantly smaller proportion of patients with Ph–like ALL also achieved 5-year OS (23.8%; 95% CI, 16.0-32.4 vs. 52.4%; 95% CI, 45.4-59.9; P < .001).
Researchers conducted detailed genomic analyses in 180 of 194 patients with Ph–like ALL.
Researchers identified kinase-activating alterations in 88% of patients with Ph–like ALL, which included CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK–STAT sequence mutations (7.2%), other kinase alterations (4.1%) and Ras pathway mutations (3.6%). They identified 11 new kinase rearrangements, four of which involved new kinase or cytokine receptor genes and seven that involved new partners for previously identified genes.
“These findings can be applied to clinical practice through the development and implementation of diagnostic assays that identify patients with Ph–like ALL,” Roberts said. “This is possible since our study defined the genetic landscape of alterations in these patients. This knowledge has the potential to identify Ph–like ALL patients at diagnosis and direct them to targeted therapy, such as tyrosine kinase inhibitors, which are specific for the underlying genetic lesion present in each patient. The addition of these agents to chemotherapeutic regimens has the potential to improve the outcome for these high-risk patients who currently have a dismal prognosis.”
Patients with Ph–like and non-Ph–like ALL are treated the same at diagnosis, Roberts said.
“This is one of the first studies to define the prevalence and importance of Ph-like ALL in adults, so we anticipate the adult cooperative groups will start to develop clinical trials that assess the efficacy of TKIs in adults with Ph-like ALL,” she added. “This study illustrates the importance and clinical utility of performing unbiased genomic profiling using next-generation sequencing techniques, such as whole-transcriptome sequencing to identify all genetic alterations in patients with acute leukemia. Although these platforms are not currently available in every clinical lab, they will play an integral component of diagnostic tests in the near future as we make the transition to next-generation sequencing-based assays.” – by Chuck Gormley
For more information:
Kathryn G. Roberts, PhD, can be reached at kathryn.roberts@stjude.org.
Disclosure: Roberts reports a pending patent application related to gene-expression signatures for detection of underlying Ph–like events and therapeutic targeting in leukemia. Please see the study for a full list of other researchers’ relevant financial disclosures.
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