Prognostic impact of chromosomal abnormalities and copy number alterations in adult B-cell precursor acute lymphoblastic leukaemia: a UKALL14 study

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.

Fig. 1. Frequency of primary chromosome abnormalities (A) and secondary copy numbers alterations (B) in adults with B-cell precursor ALL enroled to UKALL14.

A Pie chart showing the frequency of chromosomal abnormalities. Most KMT2A rearranged cases had KMT2A-AFF1 (i.e., t(4;11), 49/58, 84%) but other partner genes were observed: MLLT1 (n = 6) and MLLT4, EPS15, LASP1, unknown (one each). The low hypodiploidy (30–39 chromosomes) group included two cases of near-haploidy (26–28 chromosomes). The JAK-STAT group comprised IGH-CRLF2 (n = 23), P2RY8-CRLF2 (n = 9) and JAK2 fusions (n = 2, PAX5-JAK2 & BCR-JAK2). P2RY8-CRLF2 fusions were identified by MLPA (n = 4), FISH (n = 3) or both techniques (n = 2). We were able to identify the partner gene in 3/6 cases: EBF1-PDGFRB (n = 2), FOXP1-ABL1 (n = 1). The remaining three cases had a PDGFRB/CSF1R (n = 2) or ABL1 (n = 1) rearrangement. Twelve patients had a ZNF384 rearrangement with EP300 (n = 5) and TCF3 (n = 4) being the most prevalent partners along with single cases of AKAP8-ZNF384 and EWSR1-ZNF384 and one where the partner gene is unknown. B Bar chart and table showing the frequency and co-occurrence of copy number alterations.

Fig. 2. Relationship between selected copy number alterations and genetic subtype in adults with B-cell precursor ALL enroled to UKALL14.

Oncoplot showing the pattern of individual copy number alterations, IKZF1plus profile and the UKALL-CNA profile per case according genetic subtype. Purple cells indicate the presence of a deletion affecting that gene. Notes: (1) Patients with low hypodiploidy were under-represented in the tested cohort due to a high failure rate. Calling copy number alterations by MLPA on a backdrop of large-scale chromosomal loss and ploidy doubling is a recognised limitation of the assay (Genes, Chromosomes & Cancer 2010, 49:1104); (2) PAX5 alterations included a single case with an intragenic PAX5 amplification (Blood Advances 2017, 1:1473); (3) Among 170 cases with an IKZF1 deletion, 93 were classified as fulfilling the definition of IKZF1plus (IKZF1 deletion with concomitant CDKN2A/B, PAX5 or PAR1 deletion in the absence of an ERG deletion). All 93 cases had IKZF1 deletion with concomitant CDKN2A/B, PAX5 or PAR1 deletion. Among these cases, 68 cases with an established primary genetic abnormality were assumed to lack an ERG deletion as they are extremely rare in the absence of IGH-DUX4. A further 18 cases tested negative for an ERG deletion by MLPA. The remaining 7 cases, who were not tested due to lack of material, were included on the basis that ERGdeletions are rare in B-other (4/150, <3%) and hence <1 case is likely be incorrectly classified.

Fig. 3. Box plot showing the frequency of copy number alterations and the IKZF1plus profile in selected genetic subtypes.

The size and colour of each box represents the proportion of cases in each genetic subtype that have the copy number alteration in question (see legend). The red asterisks marks the significant associations (p < 0.05). PAR1 = PAR1 deletions aka P2RY8-CRLF2.

Fig. 4. A revised genetic risk classification system for adult ALL.

A Definition and frequency of the five genetic risk groups; (B–D) Kaplan–Meier survival curves showing the risk of relapse, event-free survival and overall survival of patients treated in UKALL14 according to this revised genetic classification.