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.