Certain children with acute megakaryoblastic leukemia (AMKL) and GATA1 mutations may benefit from allogeneic stem cell transplants (SCT), according to a new study.

"Historically, long-term survival for pediatric AMKL patients without Down syndrome is poor, so the standard recommendation by many pediatric oncologists has been to treat all patients with allogeneic stem cell transplantation during their first remission," explained Tanja A. Gruber of St Jude Children's Research Hospital in Memphis, Tennessee.

Specifically, there are three recurrent alterations that confer a poor prognosis

"By doing a comprehensive genomic analysis combined with outcome data," she told, "we were able to not only discover new mutations that cause the cancer but to identify which genetic alterations are important predictors of treatment success as well. Specifically, there are three recurrent alterations that confer a poor prognosis."

In a paper in Nature Genetics, Dr Gruber and colleagues note that the genetic basis of AMKL in children with Down syndrome has been identified, but the cause is unknown in 30 per cent to 40 per cent of other pediatric cases.

To investigate further, the researchers performed RNA and exome sequencing on specimens from 75 pediatric and 24 adult patients. These data combined with those from 14 previously described patients yielded a total of 89 pediatric cases, which, say the researchers, is "the largest (cohort) of this rare malignancy to undergo next generation sequencing to date."

The team established that AMKL is a "heterogeneous malignancy that can be divided into seven subgroups with varying outcomes. These subgroups are characterised by chimeric oncogenes with cooperating mutations in epigenetic and kinase signalling genes."

Among these were the fusion genes CBFA2T3-GLIS2, KMT2A and NUP98-KDM5A, which are all associated with reduced survival compared to other pediatric AMKL subtypes.

"Therefore," say the researchers, "patients carrying CBFA2T3-GLIS2 or KMT2Ar that have inferior outcomes may benefit from allogeneic SCT in first complete remission. While NUP98-KDM5A outcomes did not reach statistical significance, their (survival outcomes) warrant close monitoring and consideration of allogeneic SCT as well."

The researchers also note that the chimeric oncogenes that define CBFA2T3-GLIS2 and NUP98-KDM5A "are missed by conventional karyotyping and therefore require split-signal FISH or RT-PCR for detection."

In a statement Dr Gruber said, "the results raise the possibility that paediatric AMKL patients without Down syndrome who have mutations in GATA1 may benefit from the same reduced chemotherapy used to treat the leukaemia in patients with Down syndrome."

She added: "We recommend that all newly identified paediatric AMKL patients without Down syndrome should be screened for these prognostic indicators at diagnosis. The results will help identify which patients need allogeneic stem cell transplants during their first remission and which do not."