Kinase-Activating Alterations Identified in Most Cases of  Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia May Be Targetable With Available Tyrosine Kinase Inhibitors


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Kathryn G. Roberts, PhD

[Philadelphia chromosome–like] ALL [is] characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors.

—Kathryn G. Roberts, PhD, and colleagues
[Philadelphia chromosome–like] ALL [is] characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors.

—Kathryn G. Roberts, PhD, and colleagues

In a study reported in The New England Journal of Medicine, Kathryn G. Roberts, PhD, of St. Jude Children’s Research Hospital, and colleagues performed detailed genomic analysis of patients with Philadelphia chromosome–like acute lymphoblastic leukemia (ALL) and identified kinase-activating alterations in the vast majority.1 These alterations affected a limited number of signaling pathways and may be targetable with existing tyrosine kinase inhibitors.

Study Details

The study involved genomic profiling of 1,725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Philadelphia chromosome–like ALL. Functional effects of fusion proteins and activity of tyrosine kinase inhibitors were assessed in mouse precursor B cells and Philadelphia chromosome–like ALL xenografts.

Overall, 264 (15.3%) of the 1,725 cases were identified as Philadelphia chromosome–like ALL. The prevalence of Philadelphia chromosome–like ALL increased significantly with age (P < .001), from 10% in children with standard-risk ALL and 13% in those with high-risk ALL to 21% in adolescents and 27% in young adults, and was more common in males. Among patients with Philadelphia chromosome–like ALL, median 5-year event-free survival was 58.2% for children with high-risk ALL, 41.0% for adolescents, and 24.1% for young adults, and 5-year overall survival was 72.8%, 65.8%, and 25.8% (significantly less, P < .001, vs patients with non–Philadelphia chromosome–like ALL for both comparisons).

Kinase-Activating Alterations

CRLF2 rearrangement was found in 47% of patients and concomitant JAK1 or JAK2 mutation was found in 55% of those with CRLF2 rearrangement. Genomic alterations that activate kinase signaling were identified in 91% of patients and were divided into distinct subgroups of kinase and cytokine receptor genes: ABL-class fusions (involving ABL1, ABL2, CSF1R, or PDGFRB; 12.6% of cases); EPOR (3.9%) or JAK2 (7.4%) rearrangements; CRLF2 rearrangements (49.7%); other JAK-STAT alterations, including alterations of IL7R, FLT3, SH2B3, JAK1, JAK3, TYK2, and IL2RB (12.6%); Ras pathway mutations (4.3%); and uncommon fusions (eg, involving NTRK3 or DGKH; 0.9%). No kinase-activating alteration was found in only 4.8% of patients. Another 3.9% did not have material suitable for analysis. The frequency of the subgroups varied by age, with, for example, ABL-class rearrangements being more common among children and JAK2 rearrangements being more common among young adults.

Effects of Kinase Fusions

Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions (all analyzed fusions = RCSD1–ABL1, RANBP2–ABL1, ZMIZ1–ABL1, RCSD1–ABL2, SSBP2–CSF1R, and PAX5–JAK2) resulted in cytokine-independent proliferation in mouse precursor B cells and activation of phosphorylated STAT5.

Tyrosine Kinase Inhibitor Activity

The ABL1, ABL2, and CSF1R fusions were sensitive to the ABL-class inhibitors imatinib (Gleevec) and dasatinib (Sprycel), whereas the PAX5–JAK2 fusion was not sensitive to either. Differences in signaling pathway activation were observed among the fusions. All fusions activated STAT5, which was inhibited by dasatinib in cells expressing ABL1, ABL2, CSF1R, or PDGFRB fusions; the JAK2 inhibitor ruxolitinib (Jakafi) attenuated phosphorylated STAT5 in cells expressing PAX5–JAK2. Phosphorylation of CRKL, a target of ABL1 and ABL2, was seen only in cells expressing the ABL1 and ABL2 fusions. Human leukemic cells expressing ATF7IP–JAK2 or IGH–EPOR fusions were sensitive to ruxolitinib but not imatinib. Cells expressing ETV6–NTRK3 were sensitive to the ALK inhibitor crizotinib (Xalkori). Dasatinib also exhibited antitumor efficacy in a xenograft model of ETV6–ABL1 ALL.

Targetable Fusions

As stated by the investigators, the high frequency of kinase-activating lesions in patients with Philadelphia chromosome–like ALL suggests that tyrosine kinase inhibitor therapy is likely to be effective in this setting, as it is in patients with BCR–ABL1-positive ALL. In a study in patients with precursor B-cell ALL who had high-risk clinical features, alterations on cytogenetic analysis suggestive of a tyrosine kinase gene rearrangement, or poor response to induction chemotherapy, 24 (86%) of 28 who underwent testing with a low-density gene-expression array were found to have Philadelphia chromosome–like ALL; 22 of these patients had a targetable kinase fusion involving ABL1 (10 patients), ABL2 (3 patients), CRLF2 (3 patients), JAK2 (3 patients), or PDGFRB (3 patients). In addition, four patients who failed induction therapy were found to have EBF1–PDGFRB fusion, which has been reported to exhibit good responses to tyrosine kinase inhibitor treatment.  Of the 12 of these patients who began tyrosine kinase inhibitor treatment, 11 with available data exhibited rapid and sustained responses.

Implications for Therapy

As reviewed by the investigators, the high frequency of CRLF2 rearrangement and concomitant JAK1 or JAK2 mutation in Philadelphia chromosome–like ALL and previous reports indicating activity of the JAK2 inhibitor ruxolitinib in models of ALL with CRLF2 rearrangement indicate the potential effectiveness of JAK inhibition in Philadelphia chromosome–like ALL. In Philadelphia chromosome–like ALL characterized by ABL-class fusions, the second major subgroup identified in the study, multiple ABL1 and PDGFRB fusions and new targets of rearrangement were found, including ABL2 and CSF1R, which were shown to respond to imatinib and dasatinib.

The investigators also observed that the high frequency of rearrangements activating JAK2, particularly in young adults, was a striking finding. The PAX5–JAK2 fusion activated JAK–STAT signaling and conferred cytokine-independent proliferation that was sensitive to ruxolitinib. Further, the study showed that insertion of EPOR into IGH or IGK enhancer loci is a recurring event in Philadelphia chromosome–like ALL. Leukemic cells with EPOR rearrangement also exhibit activation of JAK–STAT signaling and are sensitive to JAK inhibitors. “Thus,” stated the investigators, “JAK inhibition is a widely applicable treatment approach in [Philadelphia chromosome–like] ALL.”

The investigators concluded:

[Philadelphia chromosome–like] ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying [Philadelphia chromosome–like] ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia.

Dr. Roberts and Yongjin Li, PhD, of St. Jude Children’s Research Hospital, and James R. Downing, MD, of St. Jude Children’s Research Hospital and Children’s Oncology Group ­TARGET ALL project, National Institutes of Health, Stephen P. Hunger, MD, of Children’s Oncology Group TARGET ALL project, National Institutes of Health, Cheryl L. Willman, MD, of University of New Mexico Cancer Center and School of Medicine and Children’s Oncology Group ­TARGET ALL project, National Institutes of Health, Jinghui Zhang, PhD, of St. Jude Children’s Research Hospital and Children’s Oncology Group TARGET ALL project, National Institutes of Health, and Charles G. Mullighan, MD, of St. Jude Children’s Research Hospital and Children’s Oncology Group TARGET ALL project, National Institutes of Health, contributed equally to The New England Journal of Medicine article. ■

Disclosure: The study was funded by the American Lebanese Syrian Associated Charities, National Cancer Institute, Stand Up To Cancer, St. Baldrick’s Foundation, Leukemia and Lymphoma Society, Alex’s Lemonade Stand, and National Institute of General Medical Sciences. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Roberts KG, Li Y, Payne-Turner D, et al: Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371:1005-1015, 2014.

 


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