Taking a BiTE out of Relapsed or Refractory Acute Lymphocytic Leukaemia

Chemotherapy has revolutionized the treatment of acute lymphoblastic leukemia (ALL), but despite 50 years of progress, the aspiration of achieving cure for all patients remains stubbornly out of reach. The outlook is particularly poor for adults, for whom, despite a complete remission rate approaching 90 percent, only around 40 percent achieve long-term survival. As such, there is a need to develop new approaches for the management of relapsed disease, where salvage chemotherapy achieves remission in only 18 to 44 percent of cases. Moreover, refractory or relapsed disease has a median overall survival of between two to six months and a five-year survival that remains below 10 percent.

It is against this sobering backdrop that the immunotherapy agent blinatumomab has been compared directly with chemotherapy. Blinatumomab is a “bispecific T-cell engager” (BiTE) antibody construct that binds simultaneously to CD19 on B cells and CD3 on T cells, thereby bringing effector T cells into close contact with ALL tumour cells, which are then killed.

Relatively small clinical studies had identified the potential of blinatumomab in ALL but this phase III randomized trial sought to define the magnitude of this effect. The TOWER trial was an impressive multinational study involving 101 centers from 21 countries. Investigators randomly assigned 405 patients to receive either blinatumomab or investigator’s choice of chemotherapy in a 2:1 randomization. The most popular chemotherapy was FLAG, chosen in 45 percent of cases, with additional regimens based on clofarabine, high-dose cytarabine, or high-dose methotrexate. A key feature of the study was that patients were very heavily pretreated. Entry criteria included patients refractory to primary induction or salvage, first relapse within 12 months, second or greater relapse, or relapse after allogeneic stem-cell transplantation. Indeed, 35 percent of patients had undergone previous transplantation, and 25 percent of patients received blinatumomab as third or later salvage therapy.

Blinatumomab was administered as a continuous infusion every six weeks with “four weeks on” and “two weeks off.” The protocol included two cycles of induction therapy, after which patients could proceed to consolidation treatment if they achieved morphological remission. In reality, the median number of treatment cycles was two in the blinatumomab arm and one in the chemotherapy arm. Only 3 percent of chemotherapy patients proceeded to consolidation, whereas this was achieved by 32 percent of blinatumomab-treated patients. Both treatments were used as a bridge to allogeneic stem-cell transplantation; ultimately 24 percent of patients in both arms proceeded to this high-intensity treatment modality.

The primary outcome was overall survival, and the headline result was that this was increased from four months in the chemotherapy group to 7.7 months in the blinatumomab arm (HR, 0.71; p=0.01). Complete remission with full hematologic recovery within 12 weeks was seen in 34 percent of blinatumomab patients compared with only 16 percent of chemotherapy patients (p<0.001). Moreover, event-free survival (defined as time from randomization until relapse after achieving a complete remission, or death) at six months was 31 percent for blinatumomab patients compared with 12 percent for the chemotherapy arm. Quality of life was also improved in the blinatumomab cohort.

Blinatumomab has previously been associated with characteristic adverse effects that include cytokine release syndrome (CRS) and neurotoxicity. These are becoming less of a concern as experience with this agent accumulates. Dexamethasone was given prior to infusion, and CRS did not usually require treatment discontinuation. Intrathecal prophylaxis was also given according to local guidelines. The rate of neurologic grade ≥3 adverse events was 9 percent in both arms of the study.