Genetic Characteristics and Long-Term Outcomes of Korean Adult Patients with Ph-like Acute Lymphoblastic Leukemia Versus Non-Ph-like Acute Lymphoblastic Leukemia
Authors: Yoon Jae-Ho , Cho Hanwool , Yoon Seug Yun , Min Gi June , Park Sung-Soo , Park Silvia , Jeon Young-Woo , Lee Sung-Eun , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Kim Hee-Je , Min Chang-Ki , Cho Seok-Goo , Kim Dong-Wook , Lee Jong-Wook , Kim Myungshin , Kim Yonggoo , Lee Seok 
Published: October 2019

Abstract
Background: Recently, a high-risk subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) called Philadelphia chromosome (Ph)-like ALL was identified in adolescents and young adults. However, there are conflicting data regarding the incidence and prognosis of Ph-like ALL in adult patients, and no data have yet been introduced in Asian countries.
Aim: We tried to identify the prevalence and genetic characteristics of Ph-like ALL in adult patients with newly diagnosed BCP-ALL. Furthermore, we analyzed the clinical characteristics, long-term outcomes, and prognostic impact of Ph-like ALL compared with non-Ph-like ALL (Ph-positive ALL or BCP-other ALL).
Methods: Between December 2008 and March 2016, 334 adult patients with newly diagnosed BCP-ALL who received modified hyper-CVAD chemotherapy and had suitable material for genomic analysis were included in this analysis (median age, 43 years [range, 16-65 years]). Our post-remission therapy was based on allogeneic hematopoietic cell transplantation (HCT) if a donor is available. Ph-like ALL was determined by next generation sequencing using the Archer® FusionPlex® ALL Kit (ArcherDX Inc., CO) which can detect fusions, point mutations, and expression levels in 81 genes associated with ALL and additional FISH analysis was done.
Results: Overall, 48 (14.4%) of the 334 patients were Ph-like ALL, and the cohort was divided into patients with ABL1-class rearrangements (n=4), CRLF2 rearrangements (n=11), JAK2 rearrangements (n=4), other JAK-STAT sequence mutations (n=12), and RAS mutations (n=17). The remaining 286 patients had Ph-positive ALL (n=197) and BCP-other ALL (n=89; including 19 patients with KMT2A [MLL] rearrangements). No significant differences in baseline characteristics were observed between the Ph-like ALL and BCP-other ALL subgroups, whereas patients with Ph-positive ALL were older (median age, 47 vs 37 years; p=0.003) and had higher presenting leukocyte counts (median, 33.1 vs 11.4´109/L; p=0.001) compared with Ph-like ALL. The complete remission rate was somewhat different between the 3 disease subgroups (Ph-like ALL, 97.9%; Ph-positive ALL, 95.9%; BCP-other ALL, 88.8%; p=0.027). A higher proportion of patients with Ph-like ALL actually received allogeneic HCT in CR1 than patients with non-Ph-like ALL (Ph-like ALL, 91.6%; Ph-positive ALL, 84.2%; BCP-other ALL, 71.9%; p=0.007). With a median follow-up of 58.1 months (range; 6.0-121.0), outcomes of patients with Ph-like ALL were not inferior compared with outcomes of patients with non-Ph-like ALL. Disease-free survival rates at 5 years were 56.0% for Ph-like ALL, 42.6% for Ph-positive ALL, and 40.6% for BCP-other ALL (p=0.138). The 5-year cumulative incidence of relapse were 19.2% for Ph-like ALL, 35.3% for Ph-positive ALL, and 33.5% for BCP-other ALL (p=0.076). These findings were maintained when only patients receiving HCT were considered. Within the Ph-like ALL subgroup, patients with ABL1-class and CRLF2-rearrangements had worse outcomes than patients with other JAK-STAT sequence and RAS mutations. Also, patients with higher CRLF2 expression had inferior outcomes.
Conclusion: Within the limitation of sample size, our data showed a different frequency of subtypes (e.g., lower incidence of CRLF2 rearrangements, higher RAS mutations) and treatment outcomes of adult patients with Ph-like ALL compared with other Western reports. Racial and ethnic differences in the patient population studied may have contributed to these differences. We also suggest that HCT-based post-remission therapy may overcome the poor prognosis of Ph-like ALL.

Disclosures
Kim: BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.