The birth of the pediatric hematology/oncology specialty can be traced back to the early part of the 20th century, when pediatricians began describing hematologic abnormalities in infants and children. Although hematologic diseases were regularly studied and diagnosed in this era, childhood cancer was still considered a rare phenomenon and received little attention in medicine. The first textbook dedicated to pediatric oncology was published in 1940 and stated that the average survival for a child diagnosed with acute lymphoblastic leukemia (ALL) was shorter than 3 months.1 Seven years later, Sidney Farber, MD, a pathologist at Boston’s Children’s Hospital, founded the Children’s Cancer Research Foundation and set out to cure childhood ALL. At that time, the only therapy available to treat the disease was cortisone, which could offer only a temporary reduction in leukemic cells. Building on the understanding of how folic acid interacts with bone marrow function, Dr Farber began treating children diagnosed with ALL with a purine antagonist. With this approach to treatment, he was able to induce remission in a majority of patients with ALL, but the remissions were not sustainable, and relapse resulting in death was common.2
Dr Farber’s discovery led to the proliferation of anti-leukemic drugs in the 1960s, including vinca alkaloids and cytotoxic agents, which remain the backbone of therapy for ALL. Animal models of leukemia had come into play by this time, with Howard Skipper, MD, showing that combining drugs with different mechanisms of action could theoretically cure leukemia.3 By 1965, the National Institutes of Health reported that the use of multidrug therapy led to superior results in the treatment of patients with ALL.4 During this same time period, the recognition of sanctuary sites and their association with disease relapse was under investigation and ultimately led to the addition of radiation and intrathecal chemotherapy to treatment regimens.5 Survival rates improved dramatically with these comprehensive treatments. By 1990-1994, the 5-year survival rate for childhood ALL reached 83.7%, and in the period 2000-2005, a mere 65 years after ALL was declared a nearly universally fatal disease, the 5-year survival rate was 90.4%.6 As the survival time for childhood ALL began to lengthen, the sequelae of therapy began to surface. By the mid-1970s, late effects of the treatment of childhood cancer began to emerge in the literature. Leukemia researchers began to consider the long-term effects of treatment when designing treatment protocols. For example, crucial research on the impact of cranial radiation on long-term neurocognitive impairment has led to decreasing doses of cranial radiation, from 2400 cGy in early therapies to 1200 to 800 cGy in subsequent cohorts.7
The next challenge for researchers was modifying therapies to lessen the risk of long-term complications while maintaining high cure rates. To achieve this goal, investigators looked to risk factors for resistant disease among patients. The ability to identify those who were at lowest risk of relapse and delivering less intense therapies to this group would decrease the number of survivors with significant late effects. Initial risk factors included the most basic clinical characteristics such as age, white blood cell count, race, and sex. As laboratory research techniques became more sophisticated, it was obvious that there were many more molecular and genetic risk factors associated with poorer outcomes in children with ALL. For example, childhood ALL that is associated with a Philadelphia chromosome mutation has consistently had poor survival and has warranted some of the most intense therapies, including bone marrow transplantation. Currently, the ability to perform whole-genome sequencing of leukemic cells means that nearly every child with ALL has a known, specific genetic abnormality associated with their leukemia, and there are at least 15 genetic abnormalities associated with this disease.8
The most exciting progress that has occurred as a result of advances in genetic classification and diagnosis of childhood ALL is the potential for the development of targeted therapies. Recently, a subpopulation of patients with refractory ALL was found to have mutations of genes encoding cytokine receptors and regulators of kinase signaling.9 Soon there were anecdotal reports in the literature of patients with refractory childhood ALL associated with this mutation who were subsequently treated with tyrosine kinase inhibitor drugs and achieved remission.10,11 This promising, targeted therapy is quickly changing the landscape for children with Philadelphia chromosome–positive ALL. According to a recent report published in the journal Cancer, the 5-year event-free survival rate for children with this mutation treated with a tyrosine kinase inhibitor in addition to traditional chemotherapy was 68.6%, compared with 31.6% for those who did not receive this drug.12
What lies ahead for children diagnosed with ALL? Well, I certainly do not have a crystal ball, but I have to say the future looks quite bright. Clinical trials are abundant, and if the historical pace of advances is any indication, more effective agents and combinations are likely to drive the cure rates of childhood ALL even closer to 100% while decreasing the long-term complications of treatment. Perhaps there will be a day in the not-so-distant future when targeted therapies will be developed for all of the most challenging childhood cancers and we can finally bring this devastating disease to its knees.
- Dargeon HW. Cancer in Children and a Discussion of Certain Benign Tumors. Philadelphia, PA: CV Mosby; 1940.
- Dana-Farber Cancer Institute. History of Dana-Farber Cancer Institute. www.dana-farber.org/About-Us/History-and-Milestones.aspx. Accessed October 24, 2014.
- Skipper HE, Schabel FM Jr, Wilcox WS. Experimental evaluation of potential anticancer agents. XIII. On the criteria and kinetics associated with “curability” of experimental leukemia. Cancer Chemother Rep. 1964;35:1-111.
- Freireich EJ, Karon M, Frei E III. Quadruple combination therapy (VAMP) for acute lymphocytic leukemia of childhood. Proc Am Assoc Cancer Res. 1964;5:20.
- Aur RJ, Simone J, Hustu HO, et al. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood. 1971;37:272-281.
- Hunger SP, Lu X, Devidas M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the Children’s Oncology Group. J Clin Oncol. 2012;30:1663-1669.
- Pui CH. Central nervous system disease in acute lymphoblastic leukemia: prophylaxis and treatment. Hematology Am Soc Hematol Educ Program. 2006:142-146.
- Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29:551-565.
- Roberts KG, Morin RD, Zhang J, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22:153-166.
- Lengline E, Beldjord K, Dombret H, et al. Successful tyrosine kinase inhibitor therapy in a refractory B-cell precursor acute lymphoblastic leukemia with EBF1-PDGFRB fusion. Haematologica. 2013;98:e146-e148.
- Weston BW, Hayden MA, Roberts KG, et al. Tyrosine kinase inhibitor therapy induces remission in a patient with refractory EBF1-PDGFRB-positive acute lymphoblastic leukemia. J Clin Oncol. 2013;31:e413-e416.
- Jeha S, Coustan-Smith E, Pei D, et al. Impact of tyrosine kinase inhibitors on minimal residual disease and outcome in childhood Philadelphia chromosome–positive acute lymphoblastic leukemia. Cancer. 2014;120: