Blinatumomab

Blinatumomab binds CD19 on the surface of the tumor cells and CD3 on the surface of any T cell in the vicinity of the tumor cell.

Trade name Blincyto.

T-cell-engaging by specific single-chain antibodies such as CD19 targeted blinatumomab recruit and activate T cells to attack B-ALL cells.

Blinatumomab is highly effective eliminating minimal residual disease as well as relapsed/refractory ALL.

First immunotherapy to demonstrate an overall survival benefit when compared to chemotherapy in relapsed/refractory adult lymphoblastic leukemia.

In a phase 2 study of patients with Philadelphia chromosome negative relapsed or refractory ALL who had relapsed within 12 months of initial therapy received this agent by continuous IV infusion for four weeks, followed by a two week holiday for up to five cycles: response rate 43%, relapse free survival 5.9 months, median overall survival 6.1 months.

Ponatinib in combination with an immunotherapy agent blinatumomab have demonstrated complete molecular response rates of 83% and MRD negativity of 98% with an estimated three year overall survival of 91%, and mostly without subsequent allogeneic stem cell transplant, in patients with Ph+ALL.

In a phase III TOWER study the median overall survival was 7.7 months vs. 4 months with standard chemotherapy in patients with Philadelphia chromosome negative relapsed or refractory acute lymphoblastic leukemia

Adverse effects fever, headache, neutropenic fever.

Approved for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).

The approval was based on the achievement of durable complete remission (CR) and response with a reduction in minimal residual disease (MRD) to less than 10-4 in a multicenter single-arm trial that enrolled 185 patients with R/R ALL.

In the BLAST trial patients with hematologic remission but with persistent minimal residual disease (MRD) received blinatumomab to redirect CD3+ T cells to produce lysis in CD19+ B cells: 78% of patients became MRD-negative.

Blinatumomab was administered by continuous infusion for 4 weeks of a 6-week cycle.

In the study up to two cycles were used for induction and three cycles for consolidation. 32% of patients with R/R ALL attained CR with 2 cycles of treatment with single-agent blinatumomab, and the response was durable at a median 6.7 months.

31% of the patients in the study had a CR with or without complete hematological recovery but with reduction in MRD to <10-4.

The most common adverse reactions were fever (62%), headache (36%), peripheral edema (25%), febrile neutropenia (25%), nausea (25%), hypokalemia (23%), rash (21%), tremor (20%), and constipation (20%).

Does not cause myelosuppression, although some cases of thrombocytopenia have been seen.

Neurological toxicity occurred in approximately 50% of patients and was a frequent reason for interrupting therapy.

Neurological toxicity median time to onset is 7 days.

Neurological toxicity of grade 3 or higher occurs in 15% of patients and includes encephalopathy, seizures, speech disorders, tremors, impaired consciousness, disorientation and balance disorders.

It is a bispecific CD19-directed CD3 T-cell engager that activates endogenous T cells when bound to the CD19-expressing target cell.

Activation of the immune system in this fashion results in release of inflammatory cytokines.

Cytokine release syndrome, including life-threatening or fatal events, occurred in 11% of the patients.

Side effects are easily alleviated by pausing the infusion because it has a very short half-life as a continuous infusion.

For patients weighing at least 45 kg, the recommended dose and schedule for blinatumomab is 9 mcg/day on days 1-7 and at 28 mcg/day on days 8-28 of the first 42-day cycle, and 28 mcg/day on days 1-28 in later cycles.

Blinatumomab in elderly patients followed by 18 months of maintenance therapy with prednisone, vincristine oral methotrexate and 6MP  had an overall survival rate at six months of 79% and overall response rate after the first cycle was 66%.

It is safe and has the potential to induce sustained remissions in relapsed/refractory B-cell non-Hodgkin lymphoma.

The maximum tolerated daily dose of blinatumomab is 60 µg/m2.

Adverse events: neurologic symptoms and cytokine release syndrome.

The median overall survival in the entire study population was 4.6 years.

Patients who had received blinatumomab ≥60 µg/m2 daily and achieved a response had a median OS of 7.7 years.

Of the surviving patients treated at the maximum tolerated dose of blinatumomab have been treatment-free for >7 years.