Acute lymphoblastic leukemia (ALL) is less common in adults than in children, but adults are far
less likely to survive. Adults make up about 40% of the estimated
6,590 new cases of ALL identified annually in the United States.
A high-risk subtype of acute lymphoblastic leukemia first
identified in children is highly prevalent in adults with ALL and is
associated with a poor outcome, revealed an international
collaboration led by St. Jude Children's Research Hospital. The
findings, published today in the Journal of Clinical Oncology
, suggest that affected patients may benefit from treatment with available medications.
‘A high-risk subtype of acute lymphoblastic leukemia (ALL) first identified in children is highly prevalent in adults with ALL and is associated with a poor outcome.’
The study of 798 adults, who were between the ages of 21 and 86
years old when their cancer was diagnosed, showed that 194 patients,
almost 25%, had the high-risk subtype Philadelphia
chromosome-like ALL (Ph-like ALL). Many patients had genetic changes
that suggest they may be treatable with targeted agents known as
tyrosine kinase inhibitors, including dasatinib, imatinib and
ruxolitinib. The drugs are already widely used to treat other types of
leukemia that are common in adults.
"This study establishes that a large percentage of adults with ALL
have this high-risk subtype," said corresponding author Charles
Mullighan, a member of the St. Jude Department of Pathology.
"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."
At St. Jude,
about 94% of pediatric ALL patients are alive five years after
diagnosis. In this study, adults with Ph-like ALL had a five-year
survival rate of 23.8% compared to 52.4% for adults with
other ALL subtypes.
The study builds on previous research from St. Jude, the federally
funded Children's Oncology Group and other adult cooperative groups that
identified Ph-like ALL as a distinct subtype of ALL first in children
and then in young adults. "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," Mullighan said. "In this study we determined that the prevalence
remains high across the age spectrum of adults with ALL."
Researchers used gene expression profiling to identify cases of
Ph-like ALL. The incidence among adults with ALL peaked at 27.9%
in young adults between the ages of 21 and 39 years old. It remained 20% or more in patients between 40 and 86 years old.
Detailed genomic analysis of 180 of the Ph-like ALL cases showed
that 88 percent of patients had genetic alterations fueling the cell
proliferation that is a hallmark of cancer. The alterations result in
abnormal activation of cell surface proteins called cytokine receptors
or enzymes called kinases that cytokine receptors regulate. Tyrosine
kinase inhibitors are designed to block different cytokine receptor
signaling pathways. For example, dasatinib works by inhibiting ABL1
proteins while ruxolitinib targets the JAK2 protein.
"Our comprehensive sequencing showed that Ph-like ALL in adults is
the most genetically diverse subtype of leukemia that has been
described," said first author Kathryn Roberts, a St. Jude staff
scientist. "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."
The diversity of kinase-activating alterations in Ph-like ALL has
important clinical implications, said co-author Hagop Kantarjian,
of the University of Texas MD Anderson Cancer Center, 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 co-author Elisabeth
Paietta, of the Montefiore Health System and Albert Einstein
College of Medicine. "Lymphoblasts from almost half of the patients with
Ph-like ALL harbor a genomic rearrangement of CRLF2 (cytokine
receptor-like factor 2), which can be detected by flow cytometry using
an antibody to CRLF2. This is very important as it allows a quick
characterization of this Ph-like ALL subtype, prior to any detailed
sequencing," she said.
The study reflects a growing effort to understand cancer genetics
across the age spectrum. "We have recognized for many years that
childhood ALL does not exist in isolation, but is a subset of a disease
that affects people of varying ages," Mullighan said.