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Expert Discusses Strategies for Advancing Pediatric ALL Care

Published: Wednesday, Sep 20, 2017

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At the 2017 Society of Hematology Oncology Annual Meeting, pediatric hematologist Ching-Hon Pui, MD, said the effort to improve outcomes in pediatric acute lymphoblastic leukemia (ALL) should follow insight provided by next-generation sequencing (NGS) and appropriate use of minimal residual disease (MRD) criteria.

Research using NGS indicates that pediatric B-cell ALL (B-ALL) may differ from ALL in adults, at least in terms of the frequency of alterations associated with ALL. MRD has proven to be prognostic, but questions remain about the timing of assessment, leukemia subtype, and type of treatment used, said Pui, the chair of the Oncology Department and co-leader of the Hematological Malignancies Program at St. Jude Children’s Hospital in Memphis, Tennessee. Pui reviewed findings from recent studies that informed associations between specific alterations and outcomes in ALL, in order to illustrate the role that NGS can play in guiding clinical management.

Compared to adult patients, MEF2D-related gene fusions occurred about half as often in pediatric B-ALL patients (3.5% vs 6.8%), and children with the alterations tended to be older (median age, 12.1 years).1 MEF2D gene fusions are associated with upregulation of pre-B-cell receptor signaling and downregulation of JAK-STAT signaling.

In pediatric B-ALL MEF2D gene fusions are prognostically adverse, including a 5-year survival of 33% compared with 71% for pediatric patients without the gene fusions. The gene fusions also confer a worse prognosis in adults with B-ALL (5-year survival of 16% vs 31% for patients without the gene fusions). Several studies have confirmed the association between MEF2D gene fusions and poor outcomes in both children and adults and in geography-defined populations, said Pui.

As opposed to MEF2D gene fusions, ZNF384 gene fusions confer a more favorable prognosis. The 5-year survival in pediatric patients with ZNF384 gene fusion–positive B-ALL is 75% as compared with 69% for pediatric patients with other forms of B-ALL. The gene fusions also confer a worse prognosis for adults, associated with a 5-year survival of 40% compared with 30% for patients with other subtypes of B-ALL.

Like MEF2D gene fusions, ZNF384 fusions occur less often in pediatric patients with B-ALL than in adults (4.0% vs 7.3%). Patients with ZNF384-related gene fusions are more likely to have a CD10-negative phenotype (19% vs 3% in other pediatric B-ALL and 16% vs 5% in adults).

As compared with other forms of B-ALL, ZNF384 gene fusions are associated with increased expression of the myeloid-associated antigens CD13 and CD33 (12% vs 2% in pediatric patients and 13% vs 0% in adults). Additionally, MEF2D fusions are associated with high expression of GATA3, CEBPA, and CEBPB, as well as upregulation of the JAK-STAT pathway. Pui noted, “Some patients do well with therapy and some do not. We need an international study to [figure] out who are the good players and who are the bad players.”

For the time being, leukemia specialists have used MRD to identify poor responders who require intensified therapy, he continued. MRD provides a wealth of information about disease status to inform treatment and clinical management, including the tumor microenvironment, host-specific factors, leukemic cell factors, and therapy-related factors. However, application of the information to clinical management has been suboptimal.

“Until recently, we did not know how to use MRD optimally,” said Pui.

Several factors affect the predictive value of MRD, including the timing of measurement, the leukemia subtype, and the treatment used, he continued. Negative MRD during early remission induction reflects sensitive disease, and treatment intensity can be reduced with the subsequent treatment of patients with favorable genetics (such as TEL-AML or hyperdiploid ALL).

High-level or persistent MRD after consolidation therapy indicates drug-resistant leukemia. Effective postremission therapy may still cure certain patients without transplant, such as high-dose methotrexate for hyperdiploid >50 ALL and the combination of cyclophosphamide, cytarabine, and mercaptopurine for early T-cell precursor ALL.

Illustrating the lack of understanding about MRD, Pui reviewed a large European study that involved more than 4700 pediatric patients with standard-risk ALL and negative MRD on days 33 and 78 after initiation reduction was begun. Investigators in Germany and Italy compared standard therapy with reduced-intensity treatment.

The 4-year results showed a cumulative relapse risk of 3.2% with standard therapy versus 6.3% with the deintensified treatment.2 The 8-year disease-free survival was 92.3% with standard therapy and 89.2% with deintensified therapy. The 8-year overall survival was 98.0% and 96.1% for standard and less-intense therapy, respectively.


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