IGH@ translocations, CRLF2 deregulation, and microdeletions in adolescents and adults with acute lymphoblastic leukemia.

PURPOSE: To determine the prevalence and prognostic impact of significant acute lymphoblastic leukemia (ALL) -related genes: CRLF2 deregulation (CRLF2-d), IGH@ translocations (IGH@-t), and deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, and EBF1 in adolescents and adults. PATIENTS AND METHODS: The cohort comprised 454 patients (age 15 to 60 years old) treated on the multicenter United Kingdom Acute Lymphoblastic Leukaemia Trial XII/Eastern Cooperative Oncology Group 2993 trial (UKALLXII/ECOG2993) with Philadelphia-negative B-cell precursor ALL. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used to detect these genetic alterations. RESULTS: Twenty patients (5%) had CRLF2-d (P2RY8-CRLF2, n = 7; IGH@-CRLF2, n = 13), and 36 patients (8%) harbored an IGH@-t with a different partner gene. There was little overlap between IGH@-t, CRLF2-d, and established chromosomal abnormalities. Deletions of CDKN2A/B, IKZF1, PAX5, ETV6, RB1, BTG1, or EBF1 were prevalent with 101 (33%) of 304 patients harboring one and 102 (33%) harboring two or more alterations, occurring with varying frequency in all cytogenetic subgroups. The 5-year event-free survival, relapse-free survival (RFS), and overall survival (OS) rates for the whole cohort were 40%, 55%, and 43%, respectively. Patients with CRLF2-d, IGH@-t, and IKZF1 deletions were associated with an inferior outcome in univariate but not multivariate analysis. In particular, CRLF2-d patients had a lower RFS compared with other patients (30%), whereas those with IGH@-t or IKZF1 deletions had a lower OS (27% and 35%, respectively). CONCLUSION: CRLF2-d and IGH@-t represent distinct subtypes of adolescent and adult ALL. Deletions of key B-cell differentiation and cell cycle control genes are highly prevalent but vary in frequency by cytogenetic subgroup. CRLF2-d, IGH@-t, and IKZF1 deletions are associated with poor outcome in adolescent and adult ALL.

Treatment outcome of CRLF2-rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups.

The prognostic relevance of CRLF2 -rearrangements in childhood acute B-cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non-Down-syndrome patients (99 P2RY8-CRLF2+ , 15 IGH@-CRLF2+ ), 76 from the AIEOP-BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6-year cumulative relapse incidence of P2RY8-CRLF2+ patients treated on the two trials was not statistically different: 0·37 ± 0·06 vs. 0·25 ± 0·08 (P = 0·194). In contrast, 0/9 IGH@-CRLF2+ AIEOP-BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8-CRLF2+ patients had an intermediate protocol-independent outcome while the different prognosis of IGH@-CRLF2+ patients could be related to the different structures of the applied treatment protocols.

Demographic, clinical, and outcome features of children with acute lymphoblastic leukemia and CRLF2 deregulation: results from the MRC ALL97 clinical trial.

Deregulated expression of CRLF2 (CRLF2-d) arises via its juxtaposition to the IGH@ enhancer or P2RY8 promoter. Among 865 BCP-ALL children treated on MRC ALL97, 52 (6%) had CRLF2-d, but it was more prevalent among Down syndrome patients (54%). P2RY8-CRLF2 (n = 43) was more frequent than IGH@-CRLF2 (n = 9). CRLF2-d was not associated with age, sex, or white cell count, but IGH@-CRLF2 patients were older than P2RY8-CRLF2 patients (median 8 vs 4 years, P = .0017). Patients with CRLF2-d were more likely to present with enlarged livers and spleens (38% vs 18%, P < .001). CRLF2-d was not seen in conjunction with established chromosomal translocations but 6 (12%) cases had high hyperdiploidy, and 5 (10%) had iAMP21. Univariate analysis suggested that CRLF2-d was associated with an inferior outcome: (event-free survival [EFS] hazard ratio 2.27 [95% confidence interval 1.48-3.47], P < .001; OS 3.69 [2.34-5.84], P < .001). However, multivariate analysis indicated that its effect was mediated by other risk factors such as cytogenetics and DS status (EFS 1.45 [0.88-2.39], P = .140; OS 1.90 [1.08-3.36], P = .027). Although the outcome of IGH@-CRLF2 patients appeared inferior compared with P2RY8-CRLF2 patients, the result was not significant (EFS 2.69 [1.15-6.31], P = .023; OS 2.86 [1.15-6.79], P = .021). Therefore, we concluded that patients with CRLF2-d should be classified into the intermediate cytogenetic risk group.

Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial.

BACKGROUND: Chromosomal abnormalities in childhood acute lymphoblastic leukaemia are well established disease markers and indicators of outcomes. However, the long-term prognosis and independent prognostic effect of some abnormalities has been questioned. Also, little is known about the association between cytogenetics and the characteristics of relapse (eg, time and site of relapse) that are known to predict outcome after relapse. METHODS: We analysed cytogenetic data from 1725 children with B-cell precursor acute lymphoblastic leukaemia who were included in the UK Medical Research Council ALL97/99 study and followed up for a median time of 8.2 years. Univariate and multivariate analysis were done to examine risk of relapse, event-free survival, and overall survival associated with 21 chromosomal abnormalities and three cytogenetic risk groups constructed from these data. FINDINGS: Two chromosomal abnormalities were associated with a significantly better outcome (ETV6-RUNX1, hazard ratio [HR] 0.51, 95% CI 0.38-0.70 and high hyperdiploidy, 0.60, 0.47-0.78), whereas five abnormalities were associated with an increased risk of relapse (intrachromosomal amplification of chromosome 21 [iAMP21], 6.04, 3.90-9.35; t(9;22), 3.55, 2.21-5.72; MLL translocations, 2.98, 1.71-5.20; abnormal 17p, 2.09, 1.30-3.37; and loss of 13q, 1.87, 1.09-3.20). Multivariate analysis incorporating age, white-cell count, and treatment parameters showed that six cytogenetic abnormalities (ETV6-RUNX1, high hyperdiploidy, iAMP21, t(9;22), loss of 13q, and abnormal 17p) retained their significance for effect on relapse risk. Based on these data, patients were classified into good, intermediate, and poor cytogenetic risk groups. Slow early treatment response correlated with cytogenetic risk group: 34 of 460 (7%) in the good-risk group, 22 of 211 (10%) in the intermediate-risk group, and 27 of 95 (28%) in the poor-risk group had a slow response (p<0.0001). Additionally, the proportion of patients with a very early (<18 months) relapse varied by cytogenetic risk group: eight of 129 (6%) patients in the good-risk group had a very early relapse, compared with 24 of 98 (24%) in the intermediate-risk group, and 37 of 82 (45%) in the poor-risk group (p<0.0001). However, there was no difference in the site of relapse by cytogenetic risk group. INTERPRETATION: Individual chromosomal abnormalities are strong independent indicators of outcome, especially risk of relapse. Diagnostic cytogenetics identifies patients with a higher rate of relapse and those who are likely to have a high-risk relapse. FUNDING: Leukaemia and Lymphoma Research (LLR).

A population-based cytogenetic study of adults with acute lymphoblastic leukemia.

Chromosomal abnormalities are increasingly used to risk stratify adults with acute lymphoblastic leukemia. Published data describing the age-specific incidence of chromosomal abnormalities and their prognostic relevance are largely derived from clinical trials. Trials frequently have age restrictions and low recruitment rates. Thus we investigated these factors in a population-based cohort of 349 patients diagnosed during the course of 19 years in the northern part of England. The incidence of most chromosomal abnormalities varied significantly with age. The incidence of t(9;22)(q34;q11) increased in each successive decade, up to 24% among 40- to 49-year-old subjects. Thereafter the incidence reached a plateau. t(4;11)(q21;q23) and t(1;19)(q23;p13) were a rare occurrence among patients older than 60 years of age. In contrast, the frequency of t(8;14)(q24;q32) and t(14;18)(q32;q21) increased with age. High hyperdiploidy occurred in 13% of patients younger than 20 years of age but in only 5% of older patients. The incidence of low hypodiploidy/near-triploidy and complex karyotype increased with age from 4% (15-29 years) to 16% (>or= 60 years). Overall survival varied significantly by age and cytogenetics. Older patients and those with t(9;22), t(4;11), low hypodiploidy/near-triploidy, or complex karyotype had a significantly inferior outcome. These population-based results demonstrate the cytogenetic heterogeneity of adult acute lymphoblastic leukemia. These data will inform the delivery of routine clinical services and the design of new age-focused clinical trials.