B-ALL and Therapies Available
Approximately 3,500 cases of childhood leukemia are diagnosed each year, making it the most common cancer among children. However, despite excellent therapies, it is still the second most frequent cause of death from cancer before 20 years of age 4-6. Pediatric B-ALL has provided a model for improvement of survival among patients with cancer by progressive improvements in the efficacy of multiagent chemotherapy in large, randomized clinical trials. Such advances have led to an increase in survival rate from less than 10% in the 1960s to greater than 90% today 5,7. Where we are today has been a triumph of clinical trial development and multicenter patient enrollment by cooperative groups, both in the US and abroad, but, despite these improvements, relapse occurs in 15-20% of patients8.
By contrast to the steadily improved outcome of patients with newly diagnosed B-ALL, less progress has been made in the treatment of r/r B-ALL. Several factors contribute to the prognosis after relapse, including time to relapse, immunophenotype, and site of relapse5. Medullary relapse within 36 months of initial diagnosis portends the worst prognosis with a 5-year overall survival rate of only 10-20% 9-11. General treatment algorithms for relapsed B-ALL include multi-agent chemotherapy followed by haemopoietic stem cell transplantation (HSCT) for patients stratified as high-risk, and approximately 2 years of chemotherapy for those with lower or standard risk features. Radiation is often incorporated into regimens for patients who relapse with leukemia in the central nervous system (CNS). Toxicities from such treatment regimens are significant, including, but not limited to, metabolic syndrome and obesity, increased risk for secondary malignancy, and long-term impairment of cardiovascular, cerebrovascular, and peripheral nervous systems5. In addition, limited information on the long-term cognitive effects of intrathecal chemotherapy, used universally as CNS prophylaxis, exists. Few new agents have been FDA-approved for relapsed B-ALL, with clofarabine and vincristine sulfate liposomal injection approved by the FDA in 2004 and 2012, respectively12,13, based on complete remission rates of 20 to 30%14-16.
Since the 1950s, there have been three established pillars of cancer therapy: surgery, radiation therapy, and chemotherapy. To this list, a fourth pillar can now be added: immunotherapy. Immunotherapies provide an alternative mechanism of action and, in the case of CAR T, selective targeting of antigens on cancer cells, often limiting unwanted “off target” side effects. From 2014 to 2017, three novel and distinct immunotherapy drugs were approved by the FDA for the treatment of r/r B-ALL, a feat that was unprecedented in the prior 25 years17. (1) Blinatumomab, a bi-specific T cell engager (BiTE) designed to link CD19+ B cells with CD3+ T cells, (2) Inotuzumab ozogamicin, an anti-CD22 antibody conjugated to a calicheamicin-class cytotoxic drug (3), and most recently, in August 2017, the FDA granted full approval to tisagenlecleucel, a CD19-directed CAR T cell product, which will be the focus of this review.