ORLANDO, Fla.—The appropriate selection of treatment modalities for children with hematologic malignancies and a careful understanding of the biology of each disorder and the results of each therapy are key to treating these conditions in the pediatric population, according to three presenters who spoke at the Pediatric Malignancies education program at the 52nd American Society of Hematology Meeting and Exposition.

Childhood cancer provides a paradigm for how clinical trials and research studies may be able to improve hematologic malignancies. Certain types of these disorders are unique to children such as juvenile myelomonocytic leukemia (JMML) while others are also possible in adults, such as acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). The presenters covered a wide range of topics related to new research about these conditions during the presentation, including the challenges to overcome, treatment modalities, and use of pediatric transplantation.

Mignon L. Loh, MD, of the Division of Pediatric Hematology/Oncology, University of California – San Francisco, San Francisco, California, talked about new developments in the way JMML is understood and how this information may lead to new therapies for the disorder that occurs primarily in young children in her presentation, “Pediatric Myeloproliferative Disorders.”

There are two challenges that researchers and clinicians face when trying to better understand pediatric malignancies. First, JMML is difficult to diagnose. Second, once the disease is diagnosed, it is also difficult to treat.

Ninety percent of patients with JMML can now be diagnosed with alterations in the PTPN11, NRAS, KRAS, CBL, and NF1 genes. Patients who have JMML have mutations in their genes that signal through the Ras/MAPK pathways (NF1, NRAS, KRAS, PTPN11, and CBL). The disease is diagnosed by detecting the genetic mutations, and Ras is the gene that best makes the diagnosis, according to Dr. Loh. She noted that many children have germline mutations that predispose them to JMML; these include neurofibromatosis (type I) and a new syndrome associated with germline CBL mutations. Based on these results, targeted therapies may have the ability to cytoreduce patients before they undergo allogeneic stem cell transplantation (SCT) or stress the need for SCT in some children with JMML.

“Improving our ability to accurately genotype these patients will help us continue to unravel the signaling consequences of these genetic lesions and hopefully help us to develop new targeted therapies for JMML,” said Dr. Loh.

Dr. Loh also noted that donor source for transplantation does not seem to matter and that mutations may be predictive of patient outcomes. For example, patients with mutations in PTPN11 and NF1 generally present sicker and require swift transplant; patients with mutations in CML either resolve spontaneously or require prompt HSCT; and the predicted course of patients with mutations in Ras remains controversial.

Meinolf Suttorp, MD, of the Schwerpunkt Haematologie/Onkologie, Universitätsklinikum Carl Gustav Carus, Dresden, Germany, discussed the presentation and treatment of pediatric CML.

In the past, allogeneic SCT was the unanimous treatment choice used to treat children with CML. Recently, new first (imatinib) and second (dasatinib and nilotinib) BCR-ABL1 tyrosine kinase inhibitors (TKI) were developed, thus providing more successful options and revolutionizing the way the disease is treated.

However, Dr. Suttorp noted, not many randomized controlled trials on TKI therapy have been conducted using the pediatric population, thus drastically limiting the amount of data that is available about the treatment. Factors that may influence the low number of such trials include the low number of cases in children, the use of heterogeneous biological therapy, and the existing advantages of data from observational databases such as a larger sample size.

Dr. Suttorp noted that transplantation still should be used in children to treat pediatric malignancies despite the apparent uncertainty that surrounds the use of this procedure. The key is to embrace the uncertainty, study each child’s individual risk factors, and adjust treatment recommendations as new research becomes available.  Research has found that clinicians should not hesitate to proceed with transplantation in this population if there is indication that it should be done, especially in children with late-stage disease.

He added that specific criteria have been identified that can predict the risk factors for survival in patients who undergo transplantation and have an initial relapse, including the following: age greater than 10 years, NCI high risk classification, CNS3 at diagnosis, male sex, and T-lineage.

Using this information to provide the best treatment, clinicians should “continually watch the goalposts and know what we’re defining” in order to optimally treat pediatric malignancies now and in the future, concluded Dr. Suttorp.