Ph-like acute lymphoblastic leukemia

Abstract

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute-defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.

Figure 1.

Outcomes of children, adolescents, and young adults with Ph-like ALL. (A) Patients with Ph-like ALL have an inferior outcome compared with patients with non–Ph-like patients treated on AALL0232. (B) Among patients with Ph-like ALL, young adults have the worst prognosis compared with children and adolescents. Adapted from Roberts et al and Loh et al, with permission.

Figure 2.

Distribution of Ph-like ALL subgroups among children, adolescents, and young adults. CRLF2 rearrangements are the most prevalent genetic alteration across all age groups. ABL-class gene rearrangements are more frequent in childhood, whereas there is a striking increase in the frequency of JAK2 rearrangements among young adults with Ph-like ALL. HR, high-risk. Adapted from Roberts et al, with permission.

Figure 3.

Testing algorithm for Ph-like ALL in COG trials. COG, Children’s Oncology Group; LDA, low-density array; mPCR, multiplex polymerase chain reaction; sPCR, singleplex polymerase chain reaction. Courtesy of Shalini Reshmi, Cytogenetics/Molecular Genetics Laboratory, National Children’s Hospital, Columbus, OH.