Residual Scope: A Phase 2 Study of the JAK1/JAK2 Inhibitor Ruxolitinib with Chemotherapy in Children with De Novo High-Risk CRLLF2-Rearranged and/or JAK Pathway-Mutant Acute Lymphoblastic Leukemia AALL1521

Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, potent, and selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% [IC50]=3.3 ± 1.2 nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity against TYK2 (tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. In particular, this pathway may be dysregulated in the majority of patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs, including myelofibrosis (MF) and polycythemia vera (PV)), suggesting that JAK inhibition may be efficacious in these diseases. Ruxolitinib is currently under development for the treatment of MF/PV/ essential thrombocytopenia (ET) and other hematologic malignan ies and has been granted Marketing Authorization Approval for the treatment of MF and PV.