MOLECULAR CLASSIFICATION OF LEUKEMIAS

Rather than being a uniform disease, acute myeloid leukemia (AML) consists of at least 11 subgroups, 3 of which were previously unknown, suggest US data, while a European study has identified 2 novel subtypes of acute lymphoblastic leukemia (ALL).

The AML findings come from a study of more than 1500 patients that was published online June 8 in the New England Journal of Medicine. Lead author, Elli Papaemmanuil, PhD, from the Memorial Sloan Kettering Cancer Center, New York, New York, and colleagues from the Wellcome Trust Sanger Institute, London, United Kingdom, were able to categorize patients with AML into 11 subgroups. Three of these subgroups were identified for the first time and together accounted for more than 25% of patients.

The findings have "important biological and clinical implications," say experts in an accompanying editorial. Aaron D. Viny, MD, and Ross L. Levine, MD, from the Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, write: "These data, which are greatly empowered by the large patient cohort in this study, provide critical insights into AML pathogenesis and prognosis that were not seen in studies of smaller cohorts."

The editorialists note that studies such as these help improve not only risk stratification but also the "development of precision-medicine strategies that use genomic data to improve our ability to match individual patients with the best therapy for their disease."

They conclude: "The clonal phylogeny of AML is not random but follows distinct roads characterized by unique initiating and transforming events — and that has made all the difference."

The ALL finding was published online June 6 in Nature Communications. Lead author, Thoas Fioretos, MD, PhD, professor of clinical genetics at Lund University, Sweden, and colleagues isolated two novel subtypes of B-cell precursor ALL that are based on two sets of genetic alterations.

"[T]his study provides a detailed view of the fusion gene landscape in paediatric BCP ALL, identifying several new gene fusions as well as distinct subgroups of BCP ALL," the researchers comment.

"Apart from increasing our understanding of the pathogenesis of paediatric BCP ALL, this may help improve risk stratification and eventually increase the therapeutic options for this most common form of childhood malignancy," they add.

Details of AML Findings 

For the AML study, Dr Papaemmanuil and colleagues enrolled 1540 patients in three prospective multicenter clinical trials conducted by the German–Austrian AML Study Group.

The patients had been treated with idarubicin, cytarabine, and etoposide, with or without all-trans retinoic acid, and were followed up for a median of 5.9 years. The team performed genetic profiling, comprising cytogenetic analyses and sequencing, for 111 genes to identify "driver mutations" associated with AML.

The researchers identified 5234 driver mutations across 76 genes or genomic regions, with 86% of patients found to have at least 2 driver mutations. Combining these findings with clinical data, the team used patterns of co-mutation to specify 11 different AML subgroups, each with its own diagnostic features and clinical outcomes. 

In addition to the previously identified AML subgroups, the team isolated 3 heterogeneous genomic categories, as follows:

• The first, found in 18% of patients, was AML with mutations in genes for chromatin, RNA-splicing regulator, or both.
• The second consisted of AML with mutations in TP53, chromosomal aneuploidies, or both and was seen in 13% of patients.
• The third subgroup, which combined AML with IDH2^R172mutations, accounted for 1% of patients.

The team found that 80% of the patients were "unambiguously classified' in a single subgroup, while 4% met the criteria for 2 or more categories, typically the TP53–aneuploidy and chromatin–spliceosome groups. A further 11% of patients were unclassified.

Patients in the TP53–aneuploidy subgroup had poor outcomes, as did those in the chromatin–spliceosome group. While the latter, under current guidelines, would be identified as at intermediate risk, these patients were older and had lower white cell and blast counts, higher relapse rates, and a poor long-term clinical outlook compared with other groups.

Analysis revealed that overall survival was related to the number of driver mutations, with 11% of the explained variation in survival attributable to gene–gene interactions. "This suggests that the clinical effect of some driver mutations is modified by the wider genomic context in which they occur," the team writes.

Details of ALL Findings

For the ALL study, Dr Fioretos and colleagues examined the presence of fusion genes in 195 pediatric patients with BCP ALL. The patients had previously undergone G-banding, fluorescent in situ hybridization, and molecular analyses to detect established genetic BCP ALL mutations as part of their routine clinical diagnosis. In addition, 49 pediatric patients with BCP ALL were studied as a validation cohort.

The team found that 65% of the primary cohort had an in-frame fusion gene, including 82% of "B-other" cases previously described as lacking specific genetic changes. A further 10% of patients were found to have out-of-frame fusions.

The results showed that 4% of overall BCL ALL cases, and 16% of those described as B-other, had gene rearrangements involving the DUX4 gene, resulting in fusions between IGH and DUX4 or, less frequently, ERG and DUX4, leading to DUX4 overexpression.

Noting that DUX4 encodes for a transcription factor normally expressed in germ cells, the team says that "it is tempting to speculate that the aberrant expression of DUX4 in the rearranged cases causes activation of transcriptional programmes that normally are expressed during early stem cell development."

The team also identified a subgroup that had an ETV6-RUNX1–like gene expression profile, without gene fusion but with coexisting ETV6 and IKZF1 gene alterations. This was found in 3% of the overall cohort and 14% of B-other cases. In all, 98% of cases could be classified into distinct genetic subtypes with a known underlying driver mutation or an in-frame gene fusion.

Dr Florets commented in a release: "Like all types of cancer, childhood leukaemia is caused by genetic mutations in normal cells, which are then transformed into cancer cells. Finding the critical mutations in the diseased cells is an important condition for understanding the mechanisms of the disease and ultimately discovering new therapies."