Charles Mullighan, MD, MBBS

Photo courtesy of St. Jude

Children’s Research Hospital

Researchers have found evidence to suggest that a high-risk subtype of acute lymphoblastic leukemia (ALL) is “highly prevalent” in adults with ALL.

In a study of nearly 800 adults with ALL, roughly a quarter of the patients had Philadelphia chromosome-like (Ph-like) ALL.

Patients with Ph-like ALL had inferior overall survival (OS) and event-free survival (EFS), but most of them also had kinase-activating alterations that suggest they might respond well to tyrosine kinase inhibitors.

The researchers reported these findings in the Journal of Clinical Oncology.

“This study establishes that a large percentage of adults with ALL have this high-risk subtype,” said study author Charles Mullighan, MD, MBBS, of St. Jude Children’s Research Hospital in Memphis, Tennessee.

“The finding provides a compelling reason to identify those with Ph-like ALL and move forward with clinical trials of these targeted therapies in combination with current chemotherapeutic regimens.”

This study builds on previous research, which suggested that Ph-like ALL becomes more common with age, is associated with poor prognosis, and is characterized by genomic alterations that appear to make patients responsive to treatment with tyrosine kinase inhibitors.

“Our 2014 findings that the prevalence of Ph-like ALL increased with age and was particularly common in young adults generated tremendous interest because adult ALL is difficult to treat,” Dr Mullighan said. “In this study, we determined that the prevalence remains high across the age spectrum of adults with ALL.”

Prevalence and outcomes

The study included 798 adults who were between the ages of 21 and 86 when diagnosed with ALL. A total of 194 patients (24%) had Ph-like ALL.

The incidence of Ph-like ALL was 27.9% among young adults (ages 21 to 39), 20.4% in adults (ages 40 to 59), and 24.0% in older adults (ages 60 to 86).

Patients with Ph-like ALL had significantly inferior 5-year OS compared to patients with non-Ph-like ALL—23.8% and 52.4%, respectively (P<0.001). The same was true for 5-year EFS—22.5% and 49.3%, respectively (P<0.001).

Among Ph-like ALL patients, the 5-year EFS rates were 40.4% for young adults, 29.8% for adults, and 18.9% for older adults. The 5-year OS rates were 45.2%, 35.1%, and 16.2%, respectively.

Genomic analysis

The researchers performed genomic analysis of 180 of the Ph-like ALL cases and found that 88% had kinase-activating alterations.

This included CRLF2 rearrangements in 51% of cases, JAK2 or EPOR rearrangements in 12.4%, ABL class fusions in 9.8%, other JAK-STAT sequence mutations in 7.2%, other kinase alterations in 4.1%, and Ras pathway mutations in 3.6%.

“Our comprehensive sequencing showed that Ph-like ALL in adults is the most genetically diverse subtype of leukemia that has been described,” said study author Kathryn Roberts, PhD, of St. Jude.

“Cumulatively, more than 50 different chromosomal rearrangements involving 15 different kinases and cytokine receptors have been identified. In this study, we identified 11 chromosomal rearrangements that are new to Ph-like ALL.”

These 11 rearrangements are FIP1L1-PDGFRA, SNX29-PDGFRB, SMU1-JAK2, ZNF340-JAK2, THADA-EPOR, SMARCA4-TYK2, ZNF340-TYK2, ZYMM2-FLT3, DNTT-BLNK, TMEM2-PTK2B, and KANK1-CBL1.

The diversity of kinase-activating alterations in Ph-like ALL has important clinical implications, said study author Hagop Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston.

“It is important that we now identify patients with Ph-like ALL at diagnosis to provide optimal treatment with targeted agents,” he said.

The findings also highlight the importance of centralized comprehensive genomic sequencing for patients, said study author Elisabeth Paietta, PhD, of the Montefiore Health System and Albert Einstein College of Medicine in Bronx, New York.

“Lymphoblasts from almost half of the patients with Ph-like ALL harbor a genomic rearrangement of CRLF2, which can be detected by flow cytometry using an antibody to CRLF2,” Dr Paietta said. “This is very important as it allows a quick characterization of this Ph-like ALL subtype prior to any detailed sequencing.”

ALL subtype ‘highly prevalent’ in adults