Trial Aims to Match Pediatric Patients With More Precise Leukemia Therapy

Yana Pikman, MD

An advanced understanding of the biology of hematologic malignancies has significantly improved survival outcomes. However, in pediatric acute leukemias, said Yana Pikman, MD, the integration of real-time genomic sequencing data into clinical practice has fallen behind.

“With increased availability of molecularly targeted therapies, the promise of matching genetic lesions in patients’ leukemia cells to treatment has not yet been fully realized,” said Pikman, a physician in the Cancer and Blood Disorders Center at Dana-Farber Cancer Institute and instructor of pediatrics at Harvard Medical School.

Community oncologists established the first pediatric leukemia clinical genomics consortium in the United States, known as the Leukemia Precision-based Therapy (LEAP) Consortium, to conduct the first precision oncology clinical trial in pediatric leukemia, said Pikman. To date, the consortium comprises 13 major pediatric cancer institutions.

For the trial, the group theorized that it is feasible to identify and match—in real-time—actionable alterations with a targeted therapy for pediatric patients with different forms of leukemia. To test their hypothesis, the group is using a DNA-based next-generation sequencing panel in combination with RNA-based gene fusion testing, followed by data review by a multidisciplinary tumor board. Recent data from the trial were presented at the 2018 ASH Annual Meeting.

To date, the group has enrolled and reviewed data from 143 patients who were stratified by disease status. Cohort 1 consists of 93 patients with relapsed or refractory leukemias, while cohort 2 includes 50 patients with de novo high-risk leukemias or myelodysplastic syndrome (MDS).

A matched targeted therapy (MTT) recommendation has been made for 72% (n = 103) of patients, tiered based on the level of evidence linking the mutation to potential activity of targeted therapy in the context of each participant’s disease (Tier 1, 11%; Tier 2, 4%; Tier 3, 41%; Tier 4, 6%; Tier 5, 10%). Of the 44 patients in cohort 1 for which there were clinical follow-up data, alterations in therapy were made in 5 patients (11%) based on sequencing results and MTT recommendation. The genomic data helped to refine diagnosis and support additional germline assessment in a subset of participants.

At the same time, the group is also conducting high-throughput drug sensitivity assays to evaluate in vitro antileukemia effects of a panel of up to 120 targeted inhibitors in the context of leukemia-associated genetic alterations. At the 2018 ASH Annual Meeting, data showed that 40 (38%) of the initial 106 accrued patients had adequate amounts of blood or bone marrow for in vitro drug testing. All of the blood samples were tested in the inhibitor panel assay, with 65% of samples yielding interpretable results. The group collected inhibitor screening data for all 12 patients with genetic alterations, which resulted in Tier 1, 2, or 3 MTT recommendations.

OncLive: Please provide some background to this study.

This is the first study of its kind to be conducted in the United States, according to Pikman, and the next step for this research will involve moving these results into therapeutic studies. In an interview with OncLive, Pikman further discussed the clinical implications of using this approach to match targeted therapy to pediatric patients with leukemia.Pikman: Pediatric acute leukemia is the number 1 cause of pediatric cancer. In 2018, it still accounts for a significant number of cancer-related deaths; in fact, it is the number 2 cause of pediatric cancer deaths overall. We need to find a way to provide better treatment for these patients.

What is the design of the trial?

The study we are conducting is evaluating the feasibility of identifying targetable mutations in pediatric patients with relapsed or high-risk leukemia. [Our strategy is to] match these targets with available therapies and create a precision medicine approach in this space.At the time of enrollment, patients have a sample of their leukemia sequenced; those data are then reviewed by a panel comprised of pediatric oncologists, experts in therapeutics, and pathologists. This [process] is to determine if we are able to identify any targetable mutations. If a targetable recommendation is made, we pass that information along. [It is important to remember that] this is not a therapeutic study; it is a feasibility study. Therefore, we are not treating any patient, but we hope this research paves the way for a therapeutic study.

We are discovering several novel genomic alterations that can be of interest and we are now evaluating the significance of these [alterations]. Ongoing work is happening to see if we can tailor our approach to these [alterations].

What are the next steps for this research?

Over the last 5 years, there has been an increase in the availability of technology for sequencing. We are able to conduct these tests in a clinically valid setting. Having the tests available in a rapid turnaround time is also something we have achieved. We are finally moving in the right direction here, because we now have the right technology.To date, we have had almost 150 patients enroll in the trial, and we have seen a significant interest among treating oncologists and families. We have recently received permission to expand the trial, so we plan on doubling the cohort. We have demonstrated the feasibility of doing this, and we have now collected data on whether the targeted therapies being used by the clinicians are effective and what some of the [treatment] barriers are.

What are the clinical implications of this trial?

The obvious next step would be to conduct a therapeutic study as well as basket trials. A patient diagnosed with pediatric acute leukemia will be enrolled, he/she will be sequenced, and then, hopefully, we will have a targeted therapy to put them on. We are seeing similar initiatives happening with adult leukemia.This [research] could be extremely informative for introducing novel drugs into the clinic. Overall, when new drugs are discovered, they are usually tested in adult patients. One thing we have learned from this trial is that pediatric leukemia is different from adult leukemia. Having this genomic characterization in the clinical setting will help inform which drugs are needed in this space and it may shape how we will test novel therapies in the future.

This has been a fantastic collaboration among different oncologists and pathologists, and we have learned some key things. We learned that we can enroll patients and work together, and, most importantly, get genomics turned around quickly. This will all be important for how we treat patients [in the future].

Pikman Y, Tasian SK, Sulis ML, et al. Matched targeted therapy for pediatric patients with relapsed, refractory and high-risk leukemias: a report from the LEAP consortium. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, California. Abstract 261.