Aneuploidy in children with relapsed B‐cell precursor acute lymphoblastic leukaemia: clinical importance of detecting a hypodiploid origin of relapse

Abstract

Summary Aneuploidy is common in paediatric B‐cell precursor acute lymphoblastic leukaemia (ALL). Specific subgroups, such as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) and hypodiploidy (<45 chromosomes), predict outcome of patients after primary treatment. Whether aneuploidy has a prognostic value for relapsed disease is yet to be determined. Using DNA index and centromere screening by multiplex ligation‐dependent probe amplification, we investigated aneuploidy in 413 children treated for first relapse of B‐cell precursor ALL according to the ALL‐REZ BFM 2002 protocol. Ten‐year event‐free survival of patients with high hyperdiploid relapses approached 70%, whereas it was only 40% in low hyperdiploid relapses. Three patients with apparent hyperdiploid relapse had TP53 mutations. In these cases, array‐based allelotyping revealed a hypodiploid origin with absence of the hypodiploid founder clone (masked hypodiploidy). Collectively, patients with evident or masked hypodiploid relapses showed an extremely low event‐free survival rate of 9%. Importantly, the current relapse risk stratification did not identify cases with masked hypodiploidy as high‐risk patients, due to their favourable clinical presentation. In multivariate analysis, hypodiploidy proved to be an independent prognostic factor. This finding supports stratification of relapses with hypodiploid origin into high‐risk arms in future trials or allocation of patients to alternative treatment approaches.

Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics

“…[19][20][21] Other genetic alterations associated with poor outcome in newly diagnosed or relapsed ALL, such as IKZF1 + , 22 KRAS mutations, 14,21 or IKZF1 or PAX5 deletions, 18 are either rare in our comparably favorable-risk cohort and thus they are of little prognostic relevance or were not associated with prognosis in our cohort. The only exception here is the presence of hypodiploidy, 13 which mainly overlaps with the occurrence of TP53 mutations or deletions in our cohort. A more comprehensive genetic characterization using genome-wide technologies, such as RNA sequencing, epigenetic approaches, and high-density single nucleotide polymorphism arrays in large collaborative studies for children with ALL relapses may identify new genetic and epigenetic characteristics predicting response to induction or associated with survival.…”

“…TP53 deletions were detected by using the SALSA MLPA P056 probe mix and were confirmed by FISH. Mutations in key TP53, KRAS, NRAS, and FLT3 exons were identified by Sanger sequencing [13][14][15].…”

MLPA and DNA index improve the molecular diagnosis of childhood B-cell acute lymphoblastic leukemia

“…Masked hypodiploidy can be difficult to diagnose. Another study used a similar MLPA approach to identify the aneuploidy status of relapsed B-cell ALL 12 . Three patients with high hyperdiploidy had the highest number of chromosomal gains (median 11).…”

Aneuploidy in childhood B cell acute lymphoblastic leukaemia – also a relevant prognostic factor in relapsed disease?

“…For this reason, it might be appropriate to define MRD as ‘measurable disease’. In this issue, Groeneveld‐Krentz et al (in press) address the role of aneuploidy, a common genetic alteration, in relapsed B cell ALL. Aneuploidy, defined as high hyperdiploidy (>50 chromosomes or DNA Index ≥1·16) or as hypodiploidy (<45 chromosomes) is an important prognostic factor after primary treatment.…”

“…Whether aneuploidy has a prognostic value for relapsed B cell ALL has not been clear. Groeneveld‐Krentz et al (in press) assessed aneuploidy in 413 children treated for first relapse of B‐cell ALL by application of the DNA Index and centromere screening by multiplex ligation‐dependent probe amplification. The 10‐year EFS of patients with high hyperdiploid relapses reached 70%, and was 40% in low hyperdiploid relapses.…”