Prognostic Impact of Chromosomal Abnormalities and Copy Number Alterations Among Adults with B-Cell Precursor Acute Lymphoblastic Leukaemia Treated on UKALL14

Chromosomal abnormalities are established prognostic markers in adult ALL. Analysis of the UKALLXII/ECOG2993 trial (Blood, 2007;109:3189) revealed that patients (15-65 years) with BCR-ABL1, KMT2A-AFF1, low hypodiploidy (HoL) or a complex karyotype (CK) had a significantly inferior outcome in multivariable analysis. In UKALL14 (ISRCTN 66541317), all patients (25-65 years) with these genetic abnormalities were stratified to the high-risk arm to receive allogeneic stem cell transplant (alloSCT), where possible, or an unrelated transplant. Patients with BCR-ABL1 received imatinib. The objectives of this study were to determine the frequency and outcome of patients with high-risk chromosomal abnormalities and identify new high-risk genetic abnormalities by screening for novel gene rearrangements and copy number alterations. All genetic screening was performed using diagnostic marrow samples and by cytogenetics, FISH and MLPA. Survival endpoints were defined according to the trial protocol and analysed using standard statistical methods. After a median follow-up time of 3.4 years the 3 year survival rates for the whole B-cell precursor ALL cohort were: overall survival (OS) 52% (95% 48-56), event-free survival (EFS), 45% (41-49), relapse rate (RR) 34% (30-39). Among 653 patients, 319 (49%) harboured high-risk primary chromosomal abnormalities: BCR-ABL1 (197/635, 31%), KMT2A-AFF1 (49/616, 8%), HoL (49/525, 9%), and CK (21/512, 5%). The OS of patients with CK and HoL was 24% (95% CI 9-43) & 19% (9-33) which was driven by high RR: 60% (36-85) & 56% (39-75), respectively, despite alloSCT in first remission. This outcome was not obviously improved compared to UKALLXII (28% and 22%); however, the patient population was older. Patients with KMT2A-AFF1 fusion had OS and RR similar to the small number of patients (n=9) with other KMT2A fusions: 44% (29-58) & 49% (34-65) v 42% (11-71) & 56% (22-93). The outcome of BCR-ABL1 positive patients was not different from the remaining BCP-ALL patients (hazard ratios 0.92 (0.72-1.18), p=0.5 & 0.93 (0.67-1.29), p=0.7). Additional primary chromosomal abnormalities were detected as follows: ABL-class fusions (ABL1, ABL2, PDGFRB, CSF1R) (n=6, 1.3%), JAK-STAT abnormalities (P2RY8-CRLF2, IGH-CRLF2, JAK2 fusions) (n=34, 1.3%) and ZNF384 fusions (n=12, 3%). Patients with JAK-STAT abnormalities had high rates of MRD positivity post phase 2 induction (76%), high RR (62% (42-82)) and lower OS (35% (18-52)) despite 82% being stratified as hig