High Frequency and Poor Outcome of Philadelphia Chromosome-Like Acute Lymphoblastic Leukemia in Adults

Abstract

Purpose Philadelphia chromosome (Ph) -like acute lymphoblastic leukemia (ALL) is a high-risk subtype of childhood ALL characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. We sought to define the prevalence and genomic landscape of Ph-like ALL in adults and assess response to conventional chemotherapy. Patients and Methods The frequency of Ph-like ALL was assessed by gene expression profiling of 798 patients with B-cell ALL age 21 to 86 years. Event-free survival and overall survival were determined for Ph-like ALL versus non-Ph-like ALL patients. Detailed genomic analysis was performed on 180 of 194 patients with Ph-like ALL. Results Patients with Ph-like ALL accounted for more than 20% of adults with ALL, including 27.9% of young adults (age 21 to 39 years), 20.4% of adults (age 40 to 59 years), and 24.0% of older adults (age 60 to 86 years). Overall, patients with Ph-like ALL had an inferior 5-year event-free survival compared with patients with non-Ph-like ALL (22.5% [95% CI, 14.9% to 29.3%; n = 155] v 49.3% [95% CI, 42.8% to 56.2%; n = 247], respectively; P < .001). We identified kinase-activating alterations in 88% of patients with Ph-like ALL, including CRLF2 rearrangements (51%), ABL class fusions (9.8%), JAK2 or EPOR rearrangements (12.4%), other JAK-STAT sequence mutations (7.2%), other kinase alterations (4.1%), and Ras pathway mutations (3.6%). Eleven new kinase rearrangements were identified, including four involving new kinase or cytokine receptor genes and seven involving new partners for previously identified genes. Conclusion Ph-like ALL is a highly prevalent subtype of ALL in adults and is associated with poor outcome. The diverse range of kinase-activating alterations in Ph-like ALL has important therapeutic implications. Trials comparing the addition of tyrosine kinase inhibitors to conventional therapy are required to evaluate the clinical utility of these agents in the treatment of Ph-like ALL.

Fig 1.

Overall outcome of adult acute lymphoblastic leukemia. Kaplan-Meier estimates of (A) event-free survival and (B) overall survival of young adults, adults, and older adults combined. Outcome data were available for 582 of 798 patients studied.

Fig 2.

Outcome of adults with Philadelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL). Kaplan-Meier estimates of (A) event-free survival and (B) overall survival of all patients with Ph-like ALL compared with patients with non–Ph-like ALL (including ETV6-RUNX1, TCF3-PBX1, DUX4/ERG, and all other ALLs). Outcome data were available for 340 of 490 patients with Ph-like and non–Ph-like ALL.

Fig 3.

Kinase alterations identified in patients with Philadelphia chromosome (Ph) –like acute lymphoblastic leukemia (ALL). Data are shown for 86 patients with Ph-like ALL who underwent transcriptome sequencing. The cohort is divided into patients with ABL class fusions (ABL1, ABL2, CSF1R, PDGFRA, and PDGFRB); EPOR or JAK2 rearrangements; other JAK-STAT sequence mutations (IL7R, SH2B3, JAK1, JAK3, and TYK2); other kinase alterations (FLT3, NTRK3, PTK2B, and BLNK); RAS pathway alterations (KRAS, PTPN11, NF1, NRAS, and CBL); or no kinase identified. The Ph-like coefficient was obtained from the low-density array card using an algorithm including 15 genes highly expressed in patients with Ph-like ALL.

Fig A1.

CONSORT diagram. Among the 909 eligible patients with B-cell acute lymphoblastic leukemia (B-ALL), 798 had adequate samples to screen for the Philadelphia chromosome (Ph) –like ALL signature.