Newswise — December 1, 2021 - Seattle Children’s today announced seven oral presentations at the American Society of Hematology (ASH) annual meeting, the world’s premier event in malignant and non-malignant hematology set to take place from Dec. 11-14.
These studies demonstrate the depth and breadth of research in pediatric blood cancer within Seattle Children’s. The organization, internationally recognized for its work in pediatric cancer and blood disorders, is committed to helping prevent, diagnose, treat and pioneer cures for children with these conditions.
“We are on a major, upward curve when it comes to understanding the biology of cancer. This could lead to improved outcomes and reduced toxicity in children with cancer and blood disorders,” said Dr. Todd Cooper, Director of the Pediatric Leukemia/Lymphoma Program and Co-Director of the High-Risk Leukemia Program at Seattle Children’s. “We are proud of the research our investigators are doing to revolutionize the treatment of pediatric cancer and provide individualized care for children and young adults with the disease.”
The oral presentations include:
470 SCRI-CAR19x22v2 T Cell Product Demonstrates Bispecific Activity in B-ALL; presented by Dr. Colleen Annesley, attending physician at Seattle Children’s
This study builds on the findings from PLAT-05, one of the first-in-the-nation pediatric phase 1 trials that tests the safety and feasibility of CAR T-cells that have been reprogrammed to target CD19 and CD22 proteins simultaneously. 14 subjects enrolled onto PLAT-05 for the SCRI-CAR19x22xv2 dose escalation. In contrast to v1 products, the CAR composition of v2 products was skewed in favor of CD22 CAR expression. The study demonstrated enhanced activity of SCRI-CCAR19x22v2 compared to v1, with dual activity against both CD19 and CD22 demonstrated by elimination of ALL with single antigen expression.
168 Poor Clinical Outcome in Pediatric Immunotherapy is Mediated By a Pre-Existing Overactive IL-18-IFNy Immune Phenotype; presented by Dr. Heather Gustafson, Assistant Professor in the Ben Towne Center for Childhood Cancer Research at Seattle Children’s
This study examined the potential role of the patient’s pre-CAR immunophenotype beyond T-cells in driving therapeutic response and toxicity to CAR T-cell therapy. In patients with no response to CAR-T therapy as well as patients who experienced high levels of toxicity and diminished long-term survival, the study found evidence of a pre-existing overactive HLH-like axis. The study also highlighted the need to study patient-specific immune characteristics prior to CAR therapy, as these may be predictive of CAR success and failure.
256 KMTA2A Rearrangements Are Associated with Lineage Switch Following CD19 Targeting CAR T-Cell Therapy; presented by Dr. Adam Lamble, Attending Physician, Cancer and Blood Disorders Center
This study conducted a retrospective review of 420 pediatric patients treated with CAR T-cell therapy at seven different centers across the U.S. and found lineage switch (LS) occurs in 2.9% of children. The presence of a KMT2Ar was the biggest risk factor. Given the predisposition to LS, the role for consolidative HSCT in KMT2Ar patients warrants further study, but the study further supports the long-term safety of CAR T-cells in children with B-ALL.
403 CD22 CAR Optimization for Improved in-Human Activity Following Inadequate CD22 CAR Activity in Phase 1 Clinical Trial PLAT-04; presented by Dr. Corinne Summers, Clinical Investigator at Seattle Children’s and Assistant Member of Fred Hutchinson Cancer Research Center
This study built upon the findings in PLAT-04, a phase 1 study of CD22-CAR T Cell immunotherapy for CD22+ leukemia. While the CD22 CAR T-cell product (SCRI-CAR22v1) was successfully manufactured, subjects had minimal CAR T-cell expansion. As a result, SCRI-CAR22v2 was designed and based on promising preclinical data, PLAT-07 opened for enrollment. In PLAT-07, the CAR T-cells are reprogrammed to recognize and target the CD22 protein on leukemia and lymphoma. The study showed minor CAR alterations produced encouraging results in early clinical findings.
519 Significant Improvements in Survival for Patients with t(6;9)(p23;q34)/DEK-NUP214 in Contemporary Trials with Intensification of Therapy: A Report from the Children’s Oncology Group; presented by Dr. Katherine. G. Tarlock, Assistant Professor of Pediatrics at the University of Washington and Seattle Children’s
This study sought to investigate the outcome of children with t(6;9) AML to determine if intensification of therapy, specifically the use of hematopoietic stem cell transplant (HSCT) in CR1, and FLT3 inhibitors for ITD+ patients, may have improved outcomes for this high risk group of patients. While outcomes have improved significantly over the past three decades, the study found the intensification of upfront therapy with HSCT, which occurred for many t(6;9) patients due to their co-occurrence with FLT3-ITD, was critical to these improvements. This suggests outcomes for t(6;9) patients can be significantly improved with an intensified upfront therapeutic approach.
KMT2A Partial Tandem Duplications (KMT2A-PTD) Is a Rare, but Recurrent Genomic Event in Childhood AML and Associated with High Rate of Co-Occurring FLT3 Mutations; Presented by: Dr. Danielle Kirkey, pediatric hematology/oncology fellow at Seattle Children’s
This study interrogated the transcriptome and associated clinical and genomic data from pediatric AML patients treated on COG AAML1031 to define the prevalence of KMT2A-PTD, frequency of co-occurring genetic mutations and outcomes associated with this variant. The team evaluated the significance of KMT2A-PTD on clinical outcome. Patients with KMT2A-PTD had a poor response to induction therapy with a morphologic CR rate of 45% and rate of residual disease (MRD) positivity by flow cytometry after initial course of therapy was 40%. Additionally, high rates of relapse were noted for patients with KMT2A-PTD with a RR of 53%. Event-free survival (EFS) for patients with and without KMT2A-PTD was 39% vs. 46%, respectively (p=0.54) with a corresponding overall survival of 58% and 64% (p=0.61). In this large cohort of childhood AML patients treated on AAML1031, the team identified a small subset of patients with KMT2A-PTD and show the high prevalence of co-occurring FLT3 mutations. Further research into KMT2A-PTD in pediatric AML will guide future risk-adapted therapy and enhance understanding of biologic implications of this lesion, including whether altered KMT2A may serve as a therapeutic target as it may for KMT2A-r AML.
Access to CAR-T Cell Therapy in Underrepresented Populations: A Multicenter Cohort Study of Pediatric and Young Adult ALL Patients; Presented by Dr. Anurekha Hall, physician and pediatric hematologist-oncologist at Seattle Children’s
This study aimed to evaluate how sociodemographic characteristics of patients referred for CAR-T from outside institutions (referred CAR-T) differed from r/r patients referred for CAR-T at their home institution (local CAR-T), r/r patients not referred for CAR-T at their home institution (other relapse), and patients without r/r disease (without relapse). It was hypothesized that there would be a higher proportion of non-Latinx White patients and patients with higher socioeconomic status among referred CAR-T patients. In a large multicenter cohort of B-ALL pediatric and young adult patients, the demographics of referred CAR-T patients were notably different than local CAR-T patients. Latinx patients are at increased risk of relapse, making access to CAR-T all the more essential; however, it was found that less than one-third of patients referred from outside institutions for CAR-T cell therapy were Latinx, while a majority of patients receiving CAR-T cell therapy locally were Latinx. This association suggests that barriers to access such as distance and need for travel may differentially impact Latinx patients due to structural racism. Spanish-speaking patients and patients with public insurance were also underrepresented in referrals from outside institutions. Future work will involve additional analysis to identify non-clinical factors that may influence referral and enrollment rates on CAR-T clinical trials.
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Ranked as one of the top children’s hospitals in the country by U.S. News & World Report, Seattle Children’s serves as the pediatric and adolescent academic medical center for Washington, Alaska, Montana and Idaho – the largest region of any children’s hospital in the country. As one of the nation’s top five pediatric research centers, Seattle Children’s Research Institute is internationally recognized for its work in neurosciences, immunology, cancer, infectious disease, injury prevention and much more. Seattle Children’s Foundation works with the Seattle Children’s Guild Association, the largest all-volunteer fundraising network for any hospital in the country, to gather community support and raise funds for uncompensated care and research.
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