Abstract
Chromosomal abnormalities are established prognostic markers in adult ALL. We assessed the prognostic impact of established chromosomal abnormalities and key copy number alterations (CNA) among 652 patients with B-cell precursor ALL treated on a modern MRD driven protocol. Patients with KMT2A-AFF1, complex karyotype (CK) and low hypodiploidy/near-triploidy (HoTr) had high relapse rates 50%, 60% & 53% and correspondingly poor survival. Patients with BCR-ABL1 had an outcome similar to other patients. JAK-STAT abnormalities (CRLF2, JAK2) occurred in 6% patients and were associated with a high relapse rate (56%). Patients with ABL-class fusions were rare (1%). A small group of patients with ZNF384 fusions (n = 12) had very good survival. CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and PAR1 were assessed in 436 patients. None of the individual deletions or profiles were associated with survival, either in the cohort overall or within key subgroups. Collectively these data indicate that primary genetic abnormalities are stronger prognostic markers than secondary deletions. We propose a revised UKALL genetic risk classification based on key established chromosomal abnormalities: (1) very high risk: CK, HoTr or JAK-STAT abnormalities; (2) high risk: KMT2A fusions; (3) Tyrosine kinase activating: BCR-ABL1 and ABL-class fusions; (4) standard risk: all other patients.
Highlights
The outcome for adults with acute lymphoblastic leukaemia (ALL) treated with multi-agent chemotherapy remains unsatisfactory
SNP array analysis of these 14 patient specimens plus an additional 9 t(1;19) cases from UKALLXII [2] showed that all patients with der(19)t(1;19) harboured heterodisomy of chromosome 1 rather than uniparental disomy of chromosome 1 (Fig. S2a, b); suggesting the translocation arose during the G2 phase of the cell cycle rather following after duplication of a normal copy of chromosome 1 [33]
minimal residual disease (MRD) was not performed on all cases at either time-point; (3) allo-SCT, allogeneic stem cell transplant; “other” includes patients who died before post-induction could be delivered or who received off-trial therapy; (4) Hazard ratio representing the risk of an event for patients in the high, very high, or tyrosine kinase activating group compared with those patients in the standard risk group; (5) hazard ratio reduces and is no longer significant (1.32 (0.99–1.75), p = 0.06) if analysis is restricted to cases recruited after the April 2012 amendment which removed induction asparaginase and halved induction dose of daunorubicin for BCR-ABL1 positive cases; (6) Hazard ratio adjusted for sex, age and white cell count
Summary
Full details of patients and methods are provided in the supplementary methods section. Patients were assigned to high-risk treatment if they had any of the following features: BCR-ABL1, KMT2A-AFF1, HoTr, CK, WCC > 30 × 109/l, MRD post phase 2 induction and ≥41 years. SNP array analysis of these 14 patient specimens plus an additional 9 t(1;19) cases from UKALLXII [2] showed that all patients with der(19)t(1;19) harboured heterodisomy of chromosome 1 rather than uniparental disomy of chromosome 1 (Fig. S2a, b); suggesting the translocation arose during the G2 phase of the cell cycle rather following after duplication of a normal copy of chromosome 1 [33]. Frequency of copy number alterations and correlation with primary chromosomal abnormalities CNA affecting IKZF1, CDKN2A/B, PAX5, BTG1, ETV6, EBF1, RB1 and the PAR1 region were determined by MLPA in a representative cohort of 437 patients (Table S2). Ninety-three patients (57% of those with an IKZF1 deletion)
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