On March 29, 2018, the Food and Drug Administration (FDA) approved a new drug for the treatment of precursor B-cell acute lymphoblastic leukemia (B-cell precursor acute lymphoblastic The FDA approved a new drug for the treatment of B-cell precursor acute lymphoblastic leukemia, bona fide monotherapy (trade name Blincyto, manufactured by Amgen). The drug is administered intravenously to treat adults and children with B-cell precursor acute lymphoblastic leukemia who have achieved remission after initial therapy but still have minimal residual disease (MRD).
Minimal residual disease refers to the presence of cancer cells despite the fact that they are not found under the microscope. Once microscopic residual disease is present, there is an increased risk of cancer recurrence.
Bonatumumab was approved by the FDA back in December 2014 for the treatment of relapsed or refractory positive B-cell precursor acute lymphoblastic leukemia in Philadelphia chromosome (Ph chromosome)-negative patients. Subsequently, in 2017, the drug was approved by the FDA for an expanded indication for patients with Ph chromosome positivity. With this further expansion, bona tumor monotherapy has become the first drug approved for the treatment of microsomal residual disease-positive acute lymphoblastic leukemia.
What is precursor B-cell acute lymphoblastic leukemia?
Precursor B-cell acute lymphoblastic leukemia is a rapidly progressive cancer with an excess of B-cell lymphocytes in the bone marrow, which are immature white blood cells, also called precursor B cells.
According to the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues, acute lymphoblastic leukemia and precursor B-cell acute lymphoblastic leukemia are the same disease, except that they represent different clinical presentations –Naive cells in the bone marrow >25% in acute lymphoblastic leukemia and ≤25% in precursor B-cell acute lymphoblastic leukemia.
On the surface of precursor B cells, antigens such as CD19, CyCD79a, CyCD22, and sometimes CD24, PAX5, TdT, etc. are expressed positively. These antigens, on the one hand, can be used as targets for therapeutic targeting bridging and, on the other hand, as biomarkers to screen for suitability for therapy.
What is Bona tumor monoclonal antibody?
Bonatumumab is a bispecific T-cell engager (BiTE) antibody drug that targets both the CD19 antigen on the surface of B cells and the CD3 antigen on the surface of T cells. To use an analogy, bona fide monoclonal antibody is like a bridge that connects the CD19 protein on one end to the leukemia cells (precursor B-cell acute lymphoblastic leukemia cells) and the CD3 protein on the T cells on the other end to act to bring the T cells closer to the leukemia cells to better attack.
By acting as described above, bona tumor monoclonal antibody not only helps immune cells recognize and kill leukemia cells, but also eliminates very small amounts of residual leukemia cells, helping to prolong remission of the cancer. It is important to note, however, that the efficacy of the drug depends on the presence of functional T cells, and if there is a lack of killer T cells, then the drug will have difficulty working. In addition, bonatumumab needs to be given by continuous infusion.
Evidence of efficacy: 85% of patients in remission had undetectable microscopic residual disease
Bonatumumab was approved primarily based on a single-arm clinical trial (BLAST trial) that enrolled 86 patients in first or second remission who had at least 1 cell with detectable microscopic residual disease (MRD ≥0.1%) in the bone marrow.
Allogeneic HSCT was performed in 45 patients in CR1 (74%) and 14 patients in CR2 (56%) in continuous hematologic complete remission after bona fide monotherapy. Patients were considered in complete hematologic remission when they had primitive cells in the bone marrow <5%, an absolute neutrophil count >1 Gi/L, and platelets >100 Gi/L.
MRD was undetectable in 52 patients (85%) in 1st remission (CR1) and 18 patients (72%) in 2nd remission (CR2). for CR1 patients, the hematologic median relapse-free survival (RFS) for most transplant patients was expected to be For CR1 patients, the hematologic median relapse-free survival (RFS) was estimated to be 35.2 months for most transplant patients and 12.3 months for CR2 patients, and overall, more than half of the patients remained alive and in remission for at least 22.3 months.
Black box warning: Be wary of cytokine release syndrome
Common adverse reactions to bonatumumab include mainly infections (bacterial and unexplained), fever, headache, infusion-related reactions, neutropenia, anemia, and thrombocytopenia.
It should be noted that the instructions for bonatumumab include a black box warning reminding that the drug caused hypotension and dyspnea, transient encephalopathy, or other neurologic side effects in a subset of patients in the study at the start of their first treatment, considered cytokine release syndrome.
Serious side effects of bonatumumab include infection, pancreatitis. The instructions state that preparation and dosing instructions should be followed closely to prevent injury from misuse of the drug. In addition, because the drug may cause serious adverse reactions in pediatric patients, care should be taken to prepare the drug in preservative-free saline for patients weighing less than 22 kg.
How do I use Bonaftumomab?
According to the approved product insert, the recommended use and dosage of Bonatumumab against microscopic residual disease-positive precursor B-cell acute lymphoblastic leukemia is as follows:
- Recommended duration of therapy: 1 course of induction and 3 courses of consolidation, with a single cycle of induction or consolidation consisting of 28 days of continuous intravenous infusion followed by 14 days of no therapy (42 days total).
- Recommended dose: For induction and consolidation therapy, the recommended fixed dose is 28 mcg per day if the patient weighs more than 45 kg and 15 mcg/m per day if the patient weighs less than 45 kg.
- Glucocorticoids may be given prior to each intravenous injection.
It is important to note that the above recommended doses are for microresidue-positive precursor B-cell acute lymphoblastic leukemia and are not the same for relapsed or refractory positive B-cell precursor acute lymphoblastic leukemia that is Ph chromosome negative/positive.
Bonatumumab has been approved for marketing in China, and the approved indications do not currently include treatment of microscopic residual disease-positive precursor B-cell acute lymphoblastic leukemia; hopefully, as more trial evidence becomes available, the drug will help more patients delay relapse and achieve longer survival.