Philadelphia chromosome–like acute lymphoblastic leukemia

Abstract

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as --like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph) ALL and is suggestive of activated kinase signaling. Although Ph ALL is defined by - fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.

Toward the potential cure of leukemias in the next decade

“…In adult ALL, the pediatric regimens were modified over time to resemble more the adult AML treatments, with a shorter duration of maintenance chemotherapy (long maintenance likely is responsible for an increased cure rate of 10%-15%) and truncated classical postinduction consolidation in favor of early autologous and allogeneic SCT. [92][93][94][95] Sixty percent of patients with Ph-like ALL have CRLF2 (cytokine receptor-like factor 2) overexpression with or without Janus kinase 2 (JAK2) mutations (in approximately one-half). 88 However, using regimens that keep the backbone of pediatric regimens with intensive induction-consolidation-intensification-maintenance, together with intrathecal chemotherapy prophylaxis, has resulted in CR rates of 90%, but cure rates have plateaued at 50% to 60%.…”

Clinical and pathologic features of Philadelphia chromosome-like acute lymphoblastic leukemia in a pediatric patient

“…The frequency of certain genomic alteration varies with certain genetic and ethnic backgrounds. For example, individuals with Native American genetic ancestry and Hispanics have a higher frequency of IGH/CRLF2 translocations, while CRLF2 translocations are very common in children with Down syndrome [2,4].…”

“…While some of these translocations may be detected by standard cytogenetic analysis (karyotype), CRLF2 interstitial deletions are often cryptic and require other diagnostic methodologies. Of note, about half of the cases of Ph-like ALL with CRLF2 rearrangements have also mutations of JAK2 or JAK1 [2,4].…”

Successful Use of Nilotinib in the Therapy of a Patient with a Chemoresistant Relapse of <b><i>BCR-ABL1</i></b>-Like Phenotype Acute Lymphoblastic Leukemia

“…Certain pathways can be inhibited by molecular targeted agents such as TKIs (imatinib, dasatinib, nilotinib), a JAK1/2 inhibitor (ruxolitinib) or m-TOR inhibitors (e.g. sirolimus) [7,9]. In the case of our patient, the phenotype was diagnosed on the basis of gene overexpression.…”