TKIs May Be New Treatment Option for ALL Subtype

Veronica Hackethal, MD

September 11, 2014

Tyrosine kinase inhibitors (TKIs) are a possible new treatment option for a recently identified subtype of B cell acute lymphoblastic leukemia (ALL), called Philadelphia chromosome-like (Ph-like ALL), according to new research that highlights the genetic complexity of the disease.

Researchers found that more than 90% of patients with the subtype had kinase-activating gene changes.

Their study is published online September 10 in the New England Journal of Medicine.

"This study has defined the genetic basis of a recently described subtype of ALL called Ph-like ALL," commented senior author Charles Mullighan, MD, from the Department of Pathology at St. Jude Children's Research Hospital in Memphis, Tennessee. "We showed that the prevalence [of Ph-like ALL] increases with rising age. In both children and young adults the disease is driven by a diverse range of genetic changes that activate kinase signaling, which fuels the growth of leukemia cells."

ALL is a leading cause of cancer death in children, and older patients have worse outcomes, according to Dr. Mullighan.

The study results are from a large collaboration between childhood and adult cancer research groups: the St. Jude – Washington University Pediatric Cancer Genome Project and the National Cancer Institute TARGET initiative.

Strong Suggestion

In the study, researchers performed genomic profiling on 1725 children, adolescents, and young adults up to age 40 years with precursor B cell ALL, and found that 15% had Ph-like ALL. They also performed detailed genomic analysis in 154 patients with Ph-like ALL, and analyzed cell lines in mice and leukemia samples from patients.

Results suggested 2 key areas of clinical relevance: diagnosis and identification of the appropriate drug.

Ten percent of children with standard-risk ALL in this study had Ph-like ALL, and this percentage increased to 27% among young adults with ALL (P < .001). Across all age groups, patients with Ph-like ALL had worse survival rates than those with non–Ph-like ALL (P < .001).

The increase in Ph-like ALL with age, could "in part" explain the worse prognosis of older patients, Dr. Mullighan explained, highlighting the need to identify patients with Ph-like ALL who are at risk for worse outcomes.

"Accurate diagnosis of Ph-like ALL may be achieved by screening approaches followed by genetic testing, or ultimately, genome sequencing at diagnosis," Mullighan mentioned, "In the near future, we envisage that all patients will be tested for the presence of Ph-like ALL to enable the most appropriate treatment to be delivered."

Among patients with Ph-like ALL in this study, 91% had kinase-activating gene changes. In vitro analyses suggested that leukemia cells expressing ABL1, ABL2, CSF1R, and PDGFRB gene fusion were sensitive to the TKI dasatinib. Those expressing EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.

"We have shown efficacy of these inhibitors in cell lines and experimental models, and in a series of patients with refractory Ph-like ALL," Dr. Mullighan pointed out.

Though results "strongly" suggest that using TKIs will improve treatment for ALL, clinical trials are needed, and are being developed in children and adults, according to Dr. Mullighan.

"This is the largest and most comprehensive study so far of Ph-like ALL," commented Timothy Graubert, MD, director of hematopoietic malignancies at MGH Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston. Dr. Graubert is also the author of an accompanying editorial.

"It would not be considered standard of care to use [TKIs] today in this patient population," Dr. Graubert said. "But the authors of the study provided some very compelling data suggesting that some of the TKIs that are FDA [Food and Drug Administration] approved for other indications could potentially be repurposed for some of these patients."

"I would say that this study is not immediately practice-changing, but there is a high likelihood that it will change practice in the future," Dr. Graubert added. "Certainly it sets the stage for clinical trials that may ultimately change the way we treat these patients."

An important finding, Graubert pointed out, is that the Ph-like subtype of B cell ALL progressively increases with age, similar to the age-dependent increase for the Ph-positive subtype. Taken together, the Ph-like and the Ph-positive subtypes constitute almost half of B cell ALL cases in young adults up to age 40, Dr. Graubert explained. Although older adults were not the focus of the study, this result raises the question of whether these subtypes continue to increase in older adults.

"As I wrote in the editorial, this is a call to action for studies on the genetics of this disease in patients older than the ones studied here," Dr. Graubert emphasized.

To make progress, more reliable and cost-effective diagnostic methods will need to be developed — ones that can be used by a broad range of hospital laboratories to identify these subtypes in patients. Methods of identifying specific mutations that might predict the use of a drug will also be needed.

"All those pieces are going to need to come together to really move forward," Dr. Graubert concluded, "I'm optimistic that that will happen."

Multiple authors report patents pending related to high risk B cell ALL and report financial ties to industry.

N Engl J Med 2014;371:1005–1015, 1064-1066

Abstract Editorial


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