Lewis B. Silverman, MD
Director of Clinical Research and Clinical Care, Department of Pediatric Oncology
Professor of Pediatrics, Harvard Medical School
Acute lymphoblastic leukemia (ALL)
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
Pediatric Hematology/Oncology, 1998
Boston Children's Hospital/Dana-Farber Cancer Institute, Pediatric Hematology/Oncology, 1996
Boston Combined Residency Program, Boston Children's Hospital/Boston Medical Center, Pediatrics
Children's Hospital Boston
Harvard Medical School, 1991
Dr. Silverman received his MD from Harvard Medical School in 1991 and training in pediatrics at Children's Hospital Boston in 1994. He subsequently completed a fellowship in pediatric hematology-oncology at Children's Hospital and DFCI. In 1997, he became an attending physician in pediatric oncology at Children's Hospital and DFCI, where he currently is medical director of the Inpatient Oncology Serive and chief of the Pediatric Hematologic Malignancy Service. He is the principal investigator of the DFCI ALL Consortium, a multi-institutional group conducting clinical trials in children with newly diagnosed and relapsed ALL.
Childhood Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Fifty years ago, childhood ALL was universally fatal, but today long-term event-free survival rates are nearly 80%. Despite this improved outcome, therapy remains nonspecific and toxic.The Dana-Farber Cancer Institute ALL Consortium has been conducting clinical trials in childhood ALL for over 30 years, with a focus on improving survival while minimizing toxicity. A major focus of our research has been to improve the tolerability of the drug asparaginase. Asparaginase is an important agent used to treat children with ALL, but up to one-third of patients experience significant side effects from it, and those who are unable to receive all of the intended asparaginase doses have a higher relapse rate. We are currently conducting a trial comparing intravenous PEG-asparaginase with intramuscular E. coli asparaginase to determine if the former is associated with less toxicity. We also have attempted to minimize the cardiac toxicity related to another drug, doxorubicin. In a randomized trial, patients received doxorubicin either with or without dexrazoxane, a potential cardioprotectant agent. Significantly fewer patients treated with dexrazoxane had elevations of troponin T (a serum marker of cardiac injury), and those who did had notably lower elevations, suggesting that dexrazoxane prevented doxorubicin-induced cardiac damage. We continue to monitor long-term cardiac function, and are investigating pharmacogenomic predictors of late cardiac toxicity. We also continue to study and test strategies to minimize other potential late effects in long-term survivors, including neurocognitive late effects and bony morbidity (such as osteonecrosis). Importantly, we have recently identified a new prognostic factor: minimal residual disease (MRD) levels. Molecular techniques can be used to measure levels of residual leukemia in patients who, by microscopic evaluation, are in complete remission. We found that patients with relatively high MRD levels at the end of one month of treatment had a much higher risk of relapse than those with lower MRD levels. In our current clinical trial, we are intensifying therapy for patients with high MRD levels in an attempt to improve their outcome. We continue to pursue the development of targeted therapies that are more leukemia-specific and less toxic. Areas of interest include Notch 1 inhibitors (for patients with T-cell ALL), mTOR pathway inhibitors (to reverse corticosteroid resistance) and flt-3 inhibitors (for patients with MLL gene rearrangements). Because of our unique adult-pediatric consortium, we will be able to test these and other novel targeted agents in patients regardless of age.
Video: Meet Video 1