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Targeted Therapy for Children with Leukemia Can Provide Substantial Benefit, Study Finds


  • Genomic testing of patient leukemia cells uncovers genetic alterations that can be targeted by drug therapies in many patients
  • Genomic testing impacts care in numerous patients in clinical trial

Testing tumor tissue for genetic alterations that can be targeted by drugs, a mainstay of treatment in a variety of cancers, can benefit many children with leukemia, investigators at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center report in a new study. In some cases, such therapy can be lifesaving.

Of the 153 children with relapsed, treatment-resistant, or high-risk leukemia who participated in the study, 18% were found to have genetic alterations that can be targeted with currently available therapies. Fourteen percent of participants were treated with drugs directed at specific alterations in their cancer, resulting in remission of the leukemia in some cases. One patient, a girl who was in intensive care after relapsing from multiple treatments including a stem cell transplant and CAR T-cell therapy, was found to have a targetable abnormality in her leukemia. Treated with the targeted drug imatinib, she has now been in remission for more than two years.

Yana Pikman, MDYana Pikman, MD

“Research has yielded an enormous amount of information about the genetic alterations associated with different types of cancer, including pediatric leukemia, but efforts to use that information to improve treatment have lagged behind,” says Yana Pikman, MD, of Dana-Farber and Boston Children’s Hospital (BCH), the first author of the study, posted online today by the journal Cancer Discovery. “This study shows that, for many patients whose leukemia has a cancer-promoting alteration, treatment that targets that alteration can have a major impact on the course of their disease.”

A variety of factors have hindered the use of genetic information in treating pediatric leukemia, researchers say. One is that some of the genetic alterations associated with the disease result in abnormal proteins that have been difficult to target with drugs. Another is that the disease advances so quickly that genetic profiling of tumor tissue – which traditionally took weeks to complete – wasn’t thought to provide results in time to be used in developing a treatment plan.

The new study set out to explore whether rapid testing for alterations was feasible and whether targeted treatment based on genetic testing could be integrated into patient care.

The 153 patients who joined the study were treated at 15 major U.S. pediatric cancer institutions belonging to the Leukemia Precision-based Therapy (LEAP) Consortium. Upon enrollment, clinicians collected a bone marrow sample – or blood sample if it contained at least 20% leukemia cells – for analysis. The samples were genetically sequenced – their genetic code read letter by letter – using a DNA- and an RNA-based technique. The DNA technique returned results in an average of five days, the RNA technique in an average of 17 days.

Twenty-one patients were found to have high-confidence, actionable alterations – that is, genetic abnormalities for which there is substantial evidence of susceptibility to a targeted drug. Seventeen patients received the targeted drug matched to the alteration in their leukemia; 11 of them had targetable alterations that would not have been identified with standard testing at most institutions. Some of the patients experienced remissions after receiving the targeted drug, which was given in combination with chemotherapy when possible.

“In some cases, the molecular data on the leukemia prompted the patient’s diagnosis to be revised, which led to a change in the therapy they were receiving,” says the study’s senior author, Kimberly Stegmaier, MD, of Dana-Farber and BCH. “The study results also suggest that even when a young patient has already begun receiving chemotherapy for leukemia, adding a targeted therapy to the regimen can be beneficial when testing shows a specific genetic alteration is present,” she says.

The most common genetic alterations in the leukemia samples tested were mutations activating the Ras/MAPK pathway, which can be inhibited by a number of existing drugs. Sequencing also turned up dozens of alterations classified as “variants of unknown significance” (VUS) – DNA changes whose role in driving cancer growth is unknown. Follow-up experiments showed for the first time that one such VUS, a mutation in the FLT3 gene, does in fact contribute to the growth of pediatric leukemia. Several existing drugs target the gene.

“These findings underscore the need to continue to probe pediatric leukemia for genetic alterations associated with the disease, and to develop therapies that target them,” Pikman says. “More needs to be done to bring novel agents under development in labs into the clinic.”

The co-authors of the study are: Kristen Stevenson, MS, Traci M. Blonquist, MS, Asmani A. Adhav, Catherine M. Clinton, Nicole Ocasio-Martinez, Giacomo Gotti, MD, Yuting Li, Shan Lin, PhD, Amanda L. Robichaud, and Amy Saur Conway, of Dana-Farber; Andrew E. Place, MD, PhDKatherine A. Janeway, MD, MMSc, and Lewis B. Silverman, MD, of Dana-Farber and BCH; Neekesh V. Dharia, MD, PhD, of Dana-Farber, BCH, and the Broad Institute of Massachusetts Institute of Technology and Harvard University; Anjali Cremer, MD, of Dana-Farber and University Hospital Frankfurt, Frankfurt, Germany; Marian H. Harris, MD, PhD, of BCH; Sarah K. Tasian, MD, Stephen P. Hunger, MD, Tasleema Patel, Haley L. Faust, and Cristina F. Contreras, of Children’s Hospital of Philadelphia; Justine M. Kahn, MD, MS, of Columbia University Irving Medical Center; Maria Luisa Sulis, MD, of Columbia University Irving Medical Center and Memorial Sloan Kettering Cancer Center; Jing Chen, MD, of Columbia University Irving Medical Center and Children’s Cancer Institute and Joseph M. Sanzari Children’s Hospital, Hackensack, N.J.; Neerav N. Shukla, MD, of Memorial Sloan Kettering Cancer Center; Beth Apsel Winger, MD, PhD, Elliot Stieglitz, MD, and Mignon L. Loh, MD, of Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco; Todd M. Cooper, DO, and Katherine Tarlock, MD, of Seattle Children’s Hospital; Melinda Pauly, MD, of Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta; Kelly W. Maloney, MD, and Lia Gore, MD, of Children’s Hospital Colorado; Michael J. Burke, MD, of Children’s Hospital of Wisconsin; Patrick A. Brown, MD, of Johns Hopkins Kimmel Cancer Center; Nathan Gossai, MD, of Children's Minnesota; Jennifer L. McNeer, MD, MS, of Comer Children’s Hospital, Chicago, Ill.; Lisa Gennarini, MD, of Children’s Hospital at Montefiore, Bronx, N.Y.; Peter D. Cole, MD, of Children’s Hospital at Montefiore, and Rutgers Cancer Institute of New Jersey; Matthew J. Barth, MD, of Roswell Park Comprehensive Cancer Center, Buffalo, N.Y.; Jeffrey A. Magee, MD, PhD, of Washington University/St. Louis Children’s Hospital; Alma Imamovic, MS, of the Broad Institute; Cristina E. Tognon, PhD, and Jeffrey W. Tyner, PhD, of Knight Cancer Institute, Oregon Health & Science University, Portland, Ore.; Wilian A. Cortopassi, PhD, Diego Garrido Ruiz, PhD, and Matthew P. Jacobson, PhD, of University of California San Francisco; Angela Su, and Alexandre Puissant, PhD, of St Louis Hospital, Paris, France; and Annette S. Kim, MD, PhD, and Neal I. Lindeman, MD, of Brigham and Women’s Hospital.

The research was supported by a St. Baldrick’s Foundation Consortium grant and Hannah’s Heroes. Additional supported was provided by the Wong Family Fund for Translational Research; grants R35 CA210030, K08 CA222684, 1K08CA184418, 1U01CA232486, P30 CA046934, and 1R01CA214428-01A1; Alex’s Lemonade Stand Foundation; the Children’s Leukemia Research Foundation; Pan-Mass Challenge Team Crank; and the 4C’s Fund.