Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia

Abstract

BACKGROUND Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR–ABL1–positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults. METHODS We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL. RESULTS Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6–NTRK3 fusion was sensitive to crizotinib. CONCLUSIONS Ph-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 Ph-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. (Funded by the American Lebanese Syrian Associated Charities and others.)

Standards and Guidelines for the Interpretation and Reporting of Sequence Variants in Cancer

“…97 Clinical trials are being developed to test JAK inhibitor therapy in children with acute lymphoblastic leukemia and JAK2 mutations. 98 Another group of variants of level C evidence are variants that qualify patients for clinical trials for investigative targeted therapies. For instance, patients with FLT3 ITD mutated acute myeloid leukemia may be included in phase 2/3 studies for FLT3 inhibitors (ClinicalTrials.gov, https://clinicaltrials.gov/ct2/results?term=flt3þINHIBITOR& SearchZSearch, last accessed May 16, 2016).…”

Allogeneic transplantation is not superior to chemotherapy in most patients over 40 years of age with Philadelphia‐negative acute lymphoblastic leukemia in first remission

“…Based on the results of this study and others, we propose that older patients with ALL be prospectively allocated to postremission therapy based on specific risk factors, such as MRD postinduction, WBC count at diagnosis and genetic alterations. The incorporation of novel immunologic interventions in the upfront setting for older patients with ALL such as monoclonal antibodies as well as targeted interventions in patients with Ph-like genetic alterations may further change the landscape of ALL therapy and refine the indications for HSCT in adults with ALL in first remission [35,36]. Likewise, with the increasing use of "reduced toxicity" myeloablative and reduced intensity conditioning regimens for HSCT in the modern era, NRM after HSCT has declined significantly, and this should also have a positive impact on long-term survival of patients transplanted for ALL.…”

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

“…All of the latter pathways are activated by the Kit D814V mutation [52] and contributed in Kit D814V pro-B cell lines to growth factor independent proliferation as demonstrated by treatment with PKC412 and Dasatinib. Moreover, Philadelphia chromosome-like (Ph-like) ALL, a subtype with unfavorable prognosis exhibits defined genomic alterations, which in most cases lead to deregulated kinase activity [53]. Therefore, deregulated tyrosine kinase activity in Kit D814V+ B-ALL may model an important aspect of human Ph-like ALL with activation of similar downstream pathways.…”