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Explore our cutting edge research, world-class patient care, career opportunities and more.
St. Jude Children's Research Hospital Home
- Fundraising
St. Jude innovated the “total therapy” combination of chemotherapy, which forms the backbone of modern treatment for pediatric acute lymphoblastic leukemia (ALL).
While many children have benefited from the approach, researchers continue to investigate how to de-intensify treatment for those who respond well to prevent adverse late effects, and to improve treatments for those who do not respond well.
With INITIALL, we are building on what we learned about improving the outcome for children with ALL and moving to a new approach to treatment and a new trial design.
Department of Oncology
“We’re approaching an upper limit to what giving a single therapy regimen to all patients can do to improve overall survival,” said Seth Karol, MD, MSCI, Department of Oncology. Karol is the principal investigator of a new clinical trial for ALL called INITIALL. “St. Jude created Total Therapy, and now, with INITIALL, we are building on what we learned about improving the outcome for children with ALL and moving to a new approach to treatment and a new trial design.”
Stratifying by susceptibility
St. Jude scientists have collected a wealth of genetic and epigenetic information, clinical features, and outcomes on pediatric cancers. That information enabled researchers to classify ALL into distinct subtypes and identify features that predict susceptibility or resistance to current therapies, including targetable vulnerabilities. INITIALL aims to leverage these insights.
“What makes INITIALL’s design special is combining the knowledge of specific genomic alterations and tumor characteristics, then separating patients into a standard of care or an experimental treatment group based on their specific cancer’s risk profile and likelihood of response to therapy,” Karol explained. “The use of cancer genomics to dramatically change induction therapy is unique and allows us to offer new treatments only to those patients most likely to benefit from it, while offering standard treatment to those least likely to need newer therapies to be cured.”
Instead of testing a single treatment for all participants, INITIALL stratifies patients based on the features of their cancer to different treatment arms that are likely to provide the most benefit. Most patients will have low-or standard-risk B-cell ALL (B-ALL) or B-cell lymphoblastic lymphoma and will receive therapy intended to minimize adverse late effects based on Total Therapy’s most recent iteration, Total 17. The almost 40% of children with either T-cell ALL (T-ALL) or high-risk B-ALL will receive a new therapy combination changing the current standard mix of chemotherapy drugs used in the first month of treatment. Most notably, patients with B-ALL will receive inotuzumab and blinatumomab during induction, moving these forward into the earliest parts of therapy. If any patients in the standard risk group have a slow response, they can be transferred to the experimental combination and receive these agents on the trial after induction.
Experimental combinations
The drugs inotuzumab and blinatumomab in the experimental combination are antibody-based treatments that have been approved by the Food and Drug Administration (FDA) for relapsed disease, but this is their first use in the early induction phase of treatment for pediatric cancer. Inotuzumab is an antibody-chemotherapy drug conjugate, with the antibody binding to a cancer-specific protein to bring the drug close enough to kill the cancer cells, enabling a lower dose of the drug to reduce unwanted side effects. Blinatumomab also binds to a cancer-specific protein, but it acts as a bridge for anticancer T cells to find and destroy malignant cells.
In contrast to B-ALL, most patients with T-ALL will receive an experimental combination, venetoclax or dasatinib, added to standard therapy. Both have already been FDA–approved for use in adults; this will be the first time venetoclax and dasatinib will be tested in pediatric T-ALL.
Based on previous work from St. Jude, patients will receive therapy targeting nearly mutually exclusive sensitivity to venetoclax, which counters anti-apoptotic BCL-2 signaling, or dasatinib, which counters prosurvival T-cell receptor signaling, in combination with other chemotherapies.
“INITIALL builds on the strength of fundamental and clinical research at St. Jude to test whether a treatment works or not and understand why it performed the way it did, from characterizing the genomics of unexpected toxicities to navigating logistical challenges, while being nimble enough to come up with solutions,” said Karol. “That expansive view is what will enable us to continue improving therapy for every child with ALL by providing a platform for comprehensive patient-centered assessments regardless of the therapy selected.”