High Frequency and Poor Outcome of Ph-like Acute Lymphoblastic Leukemia in Adults

Abstract

▪Introduction: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype characterized by kinase-activating alterations that are amenable to treatment with tyrosine kinase inhibitors. The prevalence of Ph-like ALL increases with age and accounts for over 25% of patients with B-progenitor ALL between the ages of 21-39 years. However, the frequency, outcome and genetic basis of Ph-like ALL in adults over the age of 39 is unknown. The goals of this study were to define the prevalence of Ph-like ALL across the adult age spectrum, assess response to conventional chemotherapy, and define the genetic landscape of Ph-like ALL in adults.Methods: We studied 692 adults with B-ALL obtained from multiple groups including the Alliance (Cancer and Leukemia Group B), ECOG-ACRIN, MD Anderson Cancer Center, Northern Italy Leukemia Group, Princess Margaret Cancer Centre, SWOG and UK NCRI. The cohort was divided into three age groups: 21-39 years (median age 28±6 years, n=333), 40-59 years (median age 47±6 years, n=246) and 60-79 years (median age 67±7 years, n=101). RNA samples were screened using a Taqman low density array (LDA) card that identifies patients with the Ph-like ALL gene signature, in addition to BCR-ABL1, ETV6-RUNX1, TCF3-PBX1, MLL-rearranged and ERG altered ALL. Cytogenetic data was also available for the majority of cases. High expression of CRLF2 was determined by the LDA card, and CRLF2 rearrangement (IGH-CRLF2 or P2RY8-CFRLF2) was confirmed using fluorescence in situ hybridization. Total stranded transcriptome sequencing (RNA-seq) using the Illumina platform was performed on 99 cases and sequencing data was analyzed using FusionCatcher and CICERO.Results: The overall prevalence of ETV6-RUNX1, TCF3-PBX1 and ERG ALL in adults was low (1.3%, 3.6% and 3.1%, respectively), whilst the prevalence of patients with BCR-ABL1, Ph-like and MLL-rearranged ALL was 20%, 24% and 14%, respectively. Ph-like ALL comprised 26% of patients between 21-39 years of age and 20% of patients aged 40-79. Patients with BCR-ABL1 and Ph-like ALL presented with higher white blood counts at diagnosis compared to non Ph-like ALL patients (57.7 and 65.0 vs 28.5 x 109/L). Patients with Ph-like ALL were also more likely to be male compared to patients with BCR-ABL1 and non Ph-like ALL, with 66% vs 50% and 50%, respectively(p<0.0001; Fisher's exact test). The outcome of patients with Ph-like ALL was markedly inferior to other ALL subtypes (excluding patients with BCR-ABL1 and MLL rearrangement), with 5-year event free survival rates of 23.2±5.4 vs 51.2±4.7 (p<0.0001) and overall survival rates of 26.5±5.5 vs 56.3±4.6 (p<0.0001).We then characterized the kinase-activating alterations in adult Ph-like ALL. Similar to previous reports, 99 of 186 (53%) of patients with Ph-like ALL had high expression of CRLF2. Of 75 cases tested, 56 harbored IGH-CRLF2 and 19 P2RY8-CRLF2. Of the 87 Ph-like ALL patients with low CRLF2 expression, we identified rearrangements involving tyrosine kinase or cytokine receptor genes in 45 patients: ABL1 (n=5 patients), ABL2 (n=7), CSF1R (n=1), EPOR (n=8), JAK2 (n=18), PDGFRA (n=1), PDGFRB (n=2), PTK2B (n=1) and TYK2 (n=2). Nine of these 45 fusions have not previously been identified in Ph-like ALL including MEF2D-CSF1R, HMBOX1-JAK2, SMU1-JAK2, SNX29-JAK2 (n=2 patients), ZNF340-JAK2, FIP1L1-PDGFRA, TMEM2-PTK2B and ZNF340-TYK2. Exome sequencing is being performed on cases that do not harbor a kinase fusion by RNA-seq analysis.Conclusion: Ph-like ALL is common across the age spectrum of adult ALL, comprising over 20% of patients from ages 21-79 years, with a notably high prevalence of fusions involving JAK2. These findings warrant the development of clinical trials that assess the efficacy of tyrosine kinase inhibitors to improve the treatment outcome, similar to those that are being established for pediatric ALL. DisclosuresFielding:Amgen: Consultancy, Honoraria. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Mullighan:Amgen: Honoraria; Incyte: Consultancy.