The FDA has granted accelerated approval to blinatumomab to treat adults and children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) who are in remission but still have minimal residual disease (MRD).
"This is the first FDA-approved treatment for patients with MRD-positive ALL," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Because patients who have MRD are more likely to relapse, having a treatment option that eliminates even very low amounts of residual leukemia cells may help keep the cancer in remission longer. We look forward to furthering our understanding about the reduction in MRD after treatment with [blinatumomab]. Studies are being conducted to assess how [blinatumomab] affects long-term survival outcomes in patients with MRD."
BCP-ALL is a rapidly progressing type of cancer in which the bone marrow makes too many B-cell lymphocytes, an immature type of white blood cell. The NCI estimates that approximately 5,960 people in the U.S. will be diagnosed with ALL this year and approximately 1,470 will die from the disease.
Blinatumomab works by attaching to CD19 protein on the leukemia cells and CD3 protein found on certain immune system cells. Bringing the immune cell close to the leukemia cell allows the immune cells to attack the leukemia cells better. The FDA first approved blinatumomab under accelerated approval in December 2014 for the treatment of Philadelphia chromosome (Ph)-negative relapsed or refractory positive BCP-ALL. Full approval for this indication was granted in July 2017 and, at that time, the indication was also expanded to include patients with Ph-positive ALL.
The efficacy of blinatumomab in MRD-positive ALL was shown in a single-arm clinical trial that included 86 patients in first or second complete remission who had detectable MRD in at least one out of 1,000 cells in their bone marrow. Efficacy was based on achievement of undetectable MRD in an assay that could detect at least one cancer cell in 10,000 cells after one cycle of blinatumomab treatment, in addition to the length of time that the patients remained alive and in remission (hematological relapse-free survival). Overall, undetectable MRD was achieved by 70 patients. Over half of the patients remained alive and in remission for at least 22.3 months.
The side effects of blinatumomab when used to treat MRD-positive BCP-ALL are consistent with those seen in other uses of the drug. Common side effects include infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, neutropenia, anemia, febrile neutropenia, and thrombocytopenia.
Blinatumomab carries a boxed warning alerting patients and health care professionals that some clinical trial participants had problems with low blood pressure and cytokine release syndrome at the start of the first treatment, and experienced a short period of encephalopathy or other side effects in the nervous system. Serious risks include infections, effects on the ability to drive and use machines, pancreatitis, and preparation and administration errors-instructions for preparation and administration should be closely followed. There is a risk of serious adverse reactions in pediatric patients due to benzyl alcohol preservative; therefore, the drug prepared with preservative-free saline should be used for patients weighing less than 22 kilograms.
This new indication for blinatumomab was approved under the accelerated approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further study in randomized controlled trials is required to verify that achieving undetectable MRD with blinatumomab improves survival or disease-free survival in patients with ALL.
The FDA granted this application Priority Review and it received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.