Novel Relapse Markers Identified in Pediatric ALL

MedicalResearch.com Interview with:
Jason Saliba PhD

Perlmutter Cancer Center
New York University Langone Medical Center
New York, NY

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically over the last four decades, but the prognosis for those who relapse remains dismal, especially for those who relapse while on therapy. In fact, relapsed disease remains a leading cause of cancer related mortality in children. To date, various studies have discovered a number of somatic alterations that contribute to driving relapse and have provided profound insight into the selective forces that lead to clonal outgrowth of drug resistant populations. However, the timing of the initial emergence of the driving mutations along with the speed of clonal outgrowth is unknown.

Whole exome sequencing (WES) was run on available diagnosis, germline (remission), and relapse samples collected from thirteen pediatric ALL patients treated according to Nordic NOPHO ALL protocols. Analyses were then performed to find somatic missense mutations enriched in the relapse samples versus their patient matched diagnosis and/or germline samples. Candidate relapse driving missense mutations were identified as present at high levels (>20%) in the relapse sample, but were undetectable in germline or low to absent in the diagnosis sample. Eight of the thirteen patients contained mutations in genes previously reported to be enriched at relapse. Interestingly, a majority of the patients contained novel candidate relapse specific genes involved in a wide array of cellular processes such as cell adhesion/migration, RNA polymerase II/transcription, circadian rhythm, the unfolded protein response, RNA transport, epigenetic regulation, DNA methylation, and kinases.

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Germline Genetic Variation in IKZF1 and Predisposition to Childhood ALL

MedicalResearch.com Interview with:

Michelle Churchman, PhD Scientific Manager of Charles Mullighan's laboratory Department of Pathology St Jude Children's Research Hospital

Dr. Michelle Churchman

Michelle Churchman, PhD
Scientific Manager of Charles Mullighan’s laboratory
Department of Pathology
St Jude Children’s Research Hospital

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The role of IKZF1 alterations in the development of B-progenitor acute lymphoblastic leukemia (B-ALL) and their role in determining poor outcome of treatment has been a long-term focus of our groups. We had previously identified somatic (tumor-acquired) IKZF1 deletions and mutations in high-risk leukemia, and identified several mechanisms by which these mutations drive high-risk leukemia. We also have a long-standing interest in studying inherited genetic risk factors of childhood ALL. In this latest study, our research team identified a family in Germany with a history of B-cell deficiency and B-ALL that had a germline IKZF1 mutation, prompting us to investigate whether inherited IKZF1 variants are related to predisposition to ALL in general. To investigate this, the IKZF1 gene was sequenced from the germline DNA of nearly 5000 patients enrolled on St. Jude Children’s Research Hospital and Children’s Oncology Group front-line ALL trials. We identified 27 unique inherited (germline) IKZF1 variants in 44 patients and found that most of them perturbed the normal functions of the encoded Ikaros transcription factor. Particularly, several of the variants lost the ability to bind DNA and regulate expression of transcriptional targets.

We know from previous studies that genes involved in differentiation and adhesion are overexpressed in IKZF1-altered leukemic cells, which results in abnormal adhesion between cells and components of the bone marrow.

Many of the variants resulted in increased adhesion. We show that several of these germline variants caused leukemic cells to be less sensitive to drugs.

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Tocilizumab High Active For Refractory Graft vs Host Disease

MedicalResearch.com Interview with:

Dr. Alex Ganetsky

Dr. Alex Ganetsky

Alex Ganetsky, PharmD, BCOP
Clinical Pharmacy Specialist – Hematology/BMT
Hospital of the University of Pennsylvania

MedicalResearch.com: What is the background for this study? What are the main findings?

• Allogeneic hematopoietic cell transplant (HCT) recipients with steroid-refractory gastrointestinal acute graft-versus-host disease (GI-GVHD) have poor outcomes.
• There is no consensus for optimal treatment of these patients.
• We retrospectively evaluated the efficacy of tocilizumab, an interleukin-6 receptor monoclonal antibody, for the treatment of steroid-refractory GI-GVHD.
• 10/11 (91%) patients achieved a complete response after a median time of 11 days (range, 2 – 18) from tocilizumab initiation.
• The median time to response onset, defined as improvement in GVHD stage by at least 1, was 1 day (range, 1 – 6).
• At a median follow-up of 3 months (range, 1.1 – 12.8) from tocilizumab initiation, 8 of 11 patients are alive and free of the their underlying hematologic malignancy.
• No associations between serum levels of IL-6 and tocilizumab response could be identified.
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