Expert Discusses Strategies for Advancing Pediatric ALL Care

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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.

Pui and colleagues recently reported findings from an analysis of patients who achieved MRD-negative status on day 19. The results showed that only patients with translocation 12;21 and hyperdiploid >50 status were good candidates for reduced-intensity therapy.³

At Pui’s center, patients identified as having a poor prognosis by MRD proceed to transplant, and results have improved dramatically, he said.

Addressing efforts to improve outcomes in T-cell ALL (T-ALL), Pui said several genomics-guided strategies have proven effective. Specifically, dasatinib (Sprycel) has demonstrated efficacy in ABL1-class fusions, ruxolitinib (Jakafi) for ETP-ALL and JAK-STAT alterations, and bortezomib (Velcade) for patients who have day 15 MRD of ≥5% and no targetable lesions.

Treatment to reduce CNS recurrence remains a major need in pediatric ALL. Pui cited 3 promising strategies: triple intrathecal therapy beginning with the first dose of treatment, continuing for 13 to 21 doses for patients with low-risk disease and 16 to 27 doses for patients with standard- and high-risk disease; early intensive triple intrathecal therapy (twice weekly for 2 weeks, then weekly for 2 weeks during induction) for patients at high risk of CNS relapse; and intrathecal therapy performed by an experienced clinician with pencil-point spinal needle under sedation and with leucovorin rescue.

Pui concluded by reviewing 2 approaches to treatment of pediatric patients with relapsed or refractory ALL. A phase I/II trial of the anti-CD19 antibody blinatumomab (Blincyto) led to complete responses (CRs) within the first 2 cycles in 27 of 70 patients (39%), 14 (52%) of whom achieved MRD-negative status.⁴ The most common grade ≥3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Cytokine release syndrome occurred in 5% of patients, and 2 patients had grade 2 seizures. Pui said 13 of the 27 patients who achieved a CR subsequently went on to transplant.

The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) led to CRs in 83% of 63 evaluable children and young adults with relapsed/refractory ALL, a study that supported FDA approval of the therapy. All responding patients attained MRD-negative status within 3 months of the single infusion of CAR T-cells. The patients had a median survival of 16.6 months compared with 7.5 months in the study of blinatumomab and 3 months with standard treatment with clofarabine

Eighty-eight patients were enrolled, but 16 did not receive treatment. Seven patients did not receive treatment because of manufacturing problems, 6 patients died before receiving treatment, and 3 patients discontinued because of adverse events before receiving the CAR T-cell infusion.

References

1. Liu YF, Wang BY, Zhang WN, et al. Genomic profiling of adult and pediatric B-cell acute lymphoblastic leukemia. EBioMedicine. 2016;8:173-183. doi: 10.1016/j.ebiom.2016.04.038.
2. Schrappe M, Zimmermann M, Möricke A, et al. Reduced intensity delayed intensification in standard-risk patients defined by minimal residual disease in childhood acute lymphoblastic leukemia: results of an international randomized trial in 1164 patient (trial AIEOP-BFM ALL 2000). Blood. 2016;128(22):4.
3. Pui CH, Pei D, Raimondi SC, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia. 2017;31(2):333-339. doi: 10.1038/leu.2016.234.
4. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol.2016;34(36):4381-4389. doi: 10.1200/JCO.2016.67.3301.