Improving Outcomes for Philadelphia-Positive and Philadelphia-Like Acute Lymphoblastic Leukemia
Identifying genomic lesions that increase the risk of relapse in Ph+ and Ph-like ALL with identification of new therapeutic targets
Technology Overview
Dr. Mignon Loh
Leukemia is the most common type of cancer in children. Standard treatment for acute lymphoblastic leukemia (ALL) in children is chemotherapy, immunotherapy and, when possible, targeted agents such as tyrosine kinase inhibitors (TKIs). A major issue with chemotherapy is toxicity, which can have long-term effects on patients and is of particular concern in children.
Pediatric hematologist-oncologist Mignon Lee-Cheun Loh, MD, is investigating how and why specific forms of leukemias relapse in order to identify new agents to improve outcomes. Her translational research in genomics has created better diagnostics and identified novel therapeutics that are effective and less toxic for children, adolescents and young adults with leukemia. One area of Dr. Loh’s research focuses on ALL, which is the most common childhood cancer.
Some subtypes of ALL develop when cancer cells undergo a genetic mutation that fuses two genes to create an oncofusion protein, which then activates a kinase with constitutive signaling that drives white blood cells to become cancerous. Examples include the fusion gene BCR::ABL1, leading to Philadelphia (Ph) chromosome-positive ALL, as well as other fusions that involve ABL1, ABL2, PDGFRb and CSFR1, leading to ABL-class Ph-like ALL. Importantly, many of these fusions can be targeted with TKIs, and studies have shown that adding TKIs to chemotherapy benefits patients with these types of leukemias. The addition of these targeted therapies has doubled long-term survival rates to 75%-80%.
A major obstacle to long-term survival, however, is the lack of predictors for leukemia relapse. More than 90% of relapses occur in patients who respond well to treatment and test negative for circulating cancer cells (i.e., no measurable residual disease) at the end of induction chemotherapy.
Dr. Loh and team are analyzing genomic data from pediatric patients with Ph+ or ABL-class Ph-like ALL who were enrolled in the largest-ever international phase 3 trial (Children’s Oncology Group AALL1631 Study). This clinical trial tested imatinib in combination with two different cytotoxic chemotherapies. Using primary patient samples from the AALL1631 trial, the Loh Lab and their collaborators are doing a large genomic screen to identify additional genetic events (e.g., secondary or passenger mutations) that are more frequent in patients diagnosed with Ph+ or Ph-like ALL who relapse. Mutations that rise to the top as poor prognostic indicators are being modeled in cell lines.
Dr. Loh and team will screen drugs using the engineered cell lines and patient-derived xenograft animal models to identify new therapies for patients with additional mutations that are associated with an increased risk of relapse.
Other collaborators on this large genomics project include researchers at Fred Hutch Cancer Center, Saint Jude Children’s Research Hospital, the University of Montreal and Children’s Hospital of Philadelphia. This effort to identify inhibitors of cell proliferation and better markers of relapse can inform precision medicine approaches.
The Loh Lab’s isogenic cell line models and engrafted immunogenic animal models could become available to industry partners as a valuable resource for drug development.
Dr. Loh, who is director of the Ben Towne Center for Childhood Cancer and Blood Disorders Research at Seattle Children’s Research Institute, is a clinician and translational researcher with extensive expertise in pediatric leukemias and multisite clinical trials. She is interested in partnering to identify new therapeutic targets to improve treatment response and predict relapse in pediatric patients diagnosed with Ph+ or Ph-like ALL.
Stage of Development
- Preclinical in vitro
- Preclinical in vivo
- Clinical trials
Partnering Opportunities
- Collaborative research and development
- Sponsored research agreement
- Consultation agreement
- Licensing
- Clinical trial collaboration
- Investigator-initiated clinical trials
- Data access
Publications
Ligon JA, Ji L, Dang A, … Loh M, et al. Role of race and ethnicity in survival among children/young adults with relapsed ALL: a Children’s Oncology Group report. Blood Adv. 2025;9(22):5738–5751.
Hogan LE, Bhatla T, Xu X, Loh M, et al. Severe toxicity and poor efficacy of reinduction chemotherapy are associated with overall poor outcomes in relapsed B-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group AALL1331 trial. Haematologica. 2025:287386.
Wang’ondu RW, Ashcraft E, Chang TC, Loh M, et al. Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Leukemia. 2025;39(7):1595-1606.
Chen W, Chang TC, Rabin KR, Loh M, et al. Performance of two-phase designs for the time-to-event outcome and a case study assessing the relapse risk associated with B-ALL subtypes. JCO Clin Cancer Inform. 2025;9:e2400223.
Tasian SK, Loh ML, Hunger SP. Philadelphia chromosome-like acute lymphoblastic leukemia. Blood. 2017;130(19):2064-2072.
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