Clinical efficacy of ruxolitinib and chemotherapy in a child with Philadelphia chromosome-like acute lymphoblastic leukemia with GOLGA5-JAK2 fusion and induction failure

Abstract

Patients with Philadelphia chromosome-like B-cell lymphoblastic leukemia (Ph-like or BCR-ABL1-like B-ALL) experience high relapse rates and are difficult to cure with conventional chemotherapy. 1,2 The Ph-like ALL subtype comprises 15-25% of B-ALL in older children and adolescents/young adults (AYAs) and 20-40% of cases in older adults. 1,2 Ph-like ALL is driven by alterations in cytokine receptor signaling pathway genes that induce oncogenic kinase signaling, suggesting therapeutic potential for kinase inhibitors. 1 Approximately 50% of Ph-like ALL has rearrangements in CRLF2 (cytokine receptor-like factor 2), often with concomitant JAK2 or JAK1 point mutations, which leads to constitutive JAK/STAT signaling targetable by JAK inhibitors (JAKi) such as ruxolitinib. JAK2 and EPOR translocations comprise an additional 8-12% of Ph-like ALL in children/AYAs and adults.1-3 JAK2-or EPOR-rearranged ALLs are also characterized by hyperactive JAK/STAT signaling and are potentially very sensitive to JAK inhibition. 3,4 While JAKi addition to multi-agent chemotherapy is under current clinical investigation in children and adults with newlydiagnosed or relapsed CRLF2-R/JAK-mutant Ph-like ALL via early-phase trials (clinicaltrials.gov identifier 02723994, 03117751, 02420717), whether this therapeutic strategy haematologica 2018; 103:e427

Involvement of the central nervous system in acute lymphoblastic leukemia: opinions on molecular mechanisms and clinical implications based on recent data

“…In preclinical models, a further substance, the JAK inhibitor ruxolitinib was inferior in targeting BCP-ALL cells in the CNS compared to a monoclonal antibody against IL7R [36], but first case reports show that ruxolitinib can be clinically efficient in BCP-ALL. The combination of ruxolitinib with chemotherapy resulted in molecular remission in a high risk BCR-ABL-like refractory patient with macroscopic CSF involvement [90]. A further case report showed eradication of refractory ALL in the CNS [91].…”

Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia

“…Patient-derived xenograft (PDX) models were established in NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice via an Institutional Animal Use and Care Committee-approved protocol at the Children's Hospital of Philadelphia as described with serial transplantation of human ALL cells into secondary or tertiary recipients for experimental studies (36)(37)(38)(39). Additional established non-KMT2A-R ALL PDX models (primarily of the Philadelphia chromosome-like [Ph-like] subtype (15,(38)(39)(40); Supplemental Table 1) were used as negative controls.…”

New biological and genetic classification and therapeutically relevant categories in childhood B-cell precursor acute lymphoblastic leukemia

“…Sensitivity tests performed in vitro and in patient-derived xenografts provided a solid rationale for prospective clinical testing of TKIs in BCP-ALL with novel kinase-activating aberrations 17 , 53 . However, a relatively limited number of such children already treated by TKIs have been reported in the literature so far 10 , 14 , 65 – 73 . Although several case reports described good response to ABL class inhibitors in patients with ABL1 / ABL2 or PDGFRB gene-involving fusions 10 , 66 , 67 , 70 – 72 , 74 and overall results are generally encouraging, in some patients the TKI-involving treatment failed to induce long-term remission.…”