Pediatric hematology

The EHA congress offered a diversity of studies that were designed for better treatment and survival of children with hematologic diseases. In one of these studies, important novel chromosomal SPI1 (PU.1) aberrations were identified that associated with very poor survival rates in hematological malignancies. Also, progress has been made regarding the role of infections causing leukemia. Furthermore, data of a clinical phase 2 trial with dasatinib showed encouraging results for treatment of pediatric CML. During an educational session, the role of next-generation sequencing for an appropriate diagnosis in bone marrow failure and myelodysplastic syndromes was discussed.

Novel poor prognostic PU.1 fusions in T-ALL

The picture of genetic aberrations and their concomitant expression profiles in children with T cell acute leukemia (T-ALL) starts to settle, yet much is left unknown. Important driver mutations for pediatric T-ALL globally subdivide patients into the TLX-related cluster, TAL1 clusters and early T cell progenitor (ETP) cluster. In order to discover new driver mutations or oncogenic fusion genes and to identify new prognostic markers in T-ALL, Dr Masafumi Seki (University of Tokyo Hospital, Tokyo, Japan) utilized RNA-seq as well as target capture sequencing of 158 genes on 121 patient samples and validated this in a separate cohort.1

Using this strategy, known chromosomal aberrations were identified, but also novel in-frame fusions involving the SPI1 gene (PU.1) in 3.9% of patients. Seki said “The hematopoietic transcription factor PU.1, encoded by SPI1, plays a central role in developing several blood lineages encoding T cells.” The fusions placed SPI1 under control of the strong STMN1 or TCF7 promoters with subsequent very high expression of PU.1 RNA in these patients. In vitro assays confirmed the oncogenic potential of these fusions and fused cells arrested in immature stage. Interestingly, clustering or RNA expression revealed that SPI1 fusions/overexpression formed a separate T-ALL cluster and these patients had an extremely poor survival compared to others (HR 8.66, 95% CI 2.60-28.78, P=4.28*10-4). Therefore, Seki stresses that “patients with SPI1 fusions seem to be incurable with current standard chemotherapy, which underscores the importance of detecting this subset of patients for more intensive or alternative therapies.”


Infections contribute to leukemia development in mice

There are many hypotheses regarding the specific peak of developing leukemia in children between 2-6 years of age. One is the exposure to infections as a trigger to leukemia. “However”, Dr Julia Hauer (Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Düsseldorf, Germany) said, “the mechanism how exposure to infections causes leukemia is not yet known, and on the other hand, knowing how infections can trigger leukemia would offer a lot more options for prevention”.

Hauer hypothesized that infections only trigger leukemia development on a susceptible genetic background, so in “children who carry a genetic predisposition, meaning a germline predisposition that is inherited from their parents or may be a durable acquired early genetic lesion”, Hauer said.2 She proved this by using two different mouse models harboring either a rare or common leukemic aberration. These mice only developed leukemia upon exposure to common specific infections. She emphasized that “mice were not infected with a specific pathogen, they only transferred from a very clean environment to a common infection environment.” In these mice, the leukemia mimicked the phenotype of human leukemia, but the mechanisms of development were different in both genetic models and “is therefore dependent on the genetic predisposition that is present from the beginning”, Hauer said. “However”, she added “this predisposition is definitely needed in order to give exposure to infections a chance to trigger leukemia.”


Interested in the webcast of Dr Hauer's presentation on childhood leukemia?


Dasatinib as alternative treatment for pediatric CML-CP

Chronic myeloid leukemia (CML) is rare in children and this translates into slow generation of new clinical study results. Nonetheless, improved treatment regimens are important, as options are limited in children, particularly for those intolerant or resistant (I/R) to imatinib. Therefore, based on prior adult CML study results, Dr Michel Zwaan (Erasmus MC-Sophia Children’s Hospital, Rotterdam, The Netherlands) tested whether dasatinib could serve as an alternative.3,4

Zwaan presented results of this open-label phase 2 CA180-226 study, in which pediatric imatinib I/R CML patients received tablets of 60 or 80 mg/m2 QD dasatinib, and newly-diagnosed patients either received 60 mg/m2 tablets or 72 mg/m2 QD powder for oral suspension.4

Zwaan said the data showed a “very good and fast result”; the primary objective of major cytogenetic response of at least 30% was already reached at 3 months in imatinib I/R CML chronic phase (CP) patients, which increased to >80% at 1 year. In newly-diagnosed patients a complete cytogenetic response of at least 55% was reached at 6 months and also increased to >80% at 1 year.

It is important to mention that the safety profile is comparable to that of adults. Zwaan also found that those with less than 10% of BCR-ABL1 transcripts survived significantly better and he therefore agreed that “early clinical response, in terms of BCR-ABL1 transcript levels, is important also when using dasatinib in a newly-diagnosed cohort in children with CML.” The positive results of this trial nominees dasatinib as a new standard of care for pediatric patients with CML-CP, “with the additional benefit that it concerns only a once-daily dose with or without food thereby potentially increasing adherence in children.”


Interested in the webcast of Dr Zwaan's presentation on peidatric CML-CP?


Next generation sequencing improves precision medicine in BMF/MDS

A good diagnosis is critical in multiple aspects of precision medicine in bone marrow failure (BMF) and myelodysplastic syndromes (MDS), explained Dr Akiko Shimamura (Boston Children's Hospital, Boston, USA) during an educational session. She demonstrated how next-generation sequencing (NGS) techniques can add to a correct diagnosis of heritable BMF/MDS in children5.

“Trying to get at the specific diagnosis for BMF and MDS is critical in terms of precise delineation of treatment selection”, said Shimamura. Patients do not always follow the text book and an appropriate diagnosis can offer life-changing therapies. In addition, Shimamura said, “knowing your diagnosis ahead of time allows you to choose the appropriate transplant regime to best benefit your patient”. In line with this, selection of a proper donor is critical and according to Shimamura it is therefore “important to really understand, particularly with family donors, whether you are dealing with an inherited disorder, so you avoid transplanting the patient back with the same disorder”. Furthermore, a diagnosis enables cancer surveillance “to catch leukemia before they develop” and improve outcome, said Shimamura. This not only applies to the patient, but also to family members.

According to Shimamura NGS is indispensable in BMF/MDS diagnostics, since family history data is often lacking or limited. NGS is worth performing as it will benefit many patients; heritable BMF/MDS is not as rare as is generally thought. BMF/MDS becomes much more prominent when all diseases that involve BMF/MDS are regarded as a whole, instead of as single entities.

Integration of NGS in BMF/MDS diagnostic procedures requires selection of patients for NGS testing and therefore a careful investigation of signs, symptoms and family history. Moreover, for correct interpretation of NGS data, a thorough cooperation between specialized doctors is indispensable as well as between different lab tests.


Interested in the webcast of Dr Shimamura's presentation on precision medicine in BMF/MDS?



  1. Seki M, et al. EHA 2017: abstract S799.
  2. Hauer J, et al, EHA 2017: abstract S148, presidential symposium.
  3. Shah NP, et al. Haematologica 2010;95:232-240
  4. Zwaan CM, et al, EHA 2017: abstract S422.
  5. Shimamura A, et al, EHA 2017: educational session.