In a multinational, prospective, randomized, phase III study, investigators found that the anti-CD19/CD3 bispecific T-cell engager antibody blinatumomab improved survival outcomes, compared with standard-of-care chemotherapy, for patients with relapsed/refractory, B-cell precursor acute lymphocytic leukemia (ALL). Treatment with blinatumomab also led to longer event-free survival (EFS) and appeared to lower adjusted rates of serious adverse events (AEs), according to an article in the New England Journal of Medicine led by Hagop Kantarjian, MD, chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, and co-authors.
“Most adults with B-cell precursor ALL will relapse and will die from complications of resistant disease or associated treatment,” Dr. Kantarjian and co-authors explained, adding that “more effective treatment is needed” for this patient population.
Patients were enrolled between January 2014 and September 2015. The trial included 405 adult patients with relapsed/refractory, B-cell precursor ALL that was: Refractory to primary induction therapy or to salvage with intensive combination chemotherapy; in first relapse with the first remission lasting <12 months; in second or greater relapse; or in relapse at any time after allogeneic hematopoietic cell transplantation (alloHCT). Other criteria included >5 percent bone marrow (BM) blasts and an Eastern Cooperative Oncology Group performance status score of ≤2. Patients were excluded from the trial if they had other active cancers, had grade ≥2 acute graft-versus-host disease (GVHD) or chronic GVHD, or had received HCT or other active anti-cancer treatment within 4 to 12 weeks prior to randomization.
Patients were randomized 2:1 to receive one of the following:
- blinatumomab administered in 6-week cycles consisting of 4 weeks of treatment (9 μg/day during week 1 of induction and 28 μg/day thereafter) and 2 weeks of no treatment (n=271; mean age = 40.8±17.1 years; range = 18-80 years)
- investigator’s choice of chemotherapy (n=134; mean age = 41.1±17.3 years; range = 18-78 years), including:
- fludarabine, high-dose cytosine arabinoside, and granulocyte colony-stimulating factor with or without anthracycline (45%; n=49)
- a high-dose cytosine arabinoside-based regimen (17%; n=19)
- a high-dose methotrexate-based regimen (20%; n=22)
- a clofarabine-based regimen (17%; n=19)
Protocol-specified therapy could be discontinued at any time after the first treatment cycle and the patient could subsequently undergo HCT if the investigator determined that such actions were in the patient’s best interest.
Patients in morphologic remission (≤5% BM blasts) also received up to three cycles of consolidation therapy, and those who were in continued morphologic remission received up to 12 months of maintenance therapy. In the blinatumomab group, maintenance therapy consisted of a 4-week continuous infusion every 12 weeks, and all patients received dexamethasone prior to blinatumomab dosing to prevent infusion reactions.
Most patients (n=376) received at least one treatment dose. At data cutoff (January 4, 2016), 22 patients (8%) in the blinatumomab cohort and zero in the chemotherapy group were still on treatment. The median number of treatment cycles was two (range = 1-9 cycles) for those in the blinatumomab cohort and one (range = 1-4 cycles) in the chemotherapy cohort. A total of 251 deaths were reported.
Investigators found that overall survival (OS; primary endpoint) was significantly longer with blinatumomab (median OS = 7.7 vs. 4.0 months; hazard ratio [HR] = 0.71; 95% CI 0.55-0.93; p=0.01).
EFS was also longer for patients receiving blinatumomab versus chemotherapy (6-month estimate = 31% vs. 12%; HR=0.55; 95% CI 0.43-0.71; p<0.001), as was the median duration of remission (7.3 vs. 4.6 months; p values not reported). And remission rates (see TABLE).
“Patients in the blinatumomab group who achieved complete remission with full, partial, or incomplete hematologic recovery had a higher incidence of response with respect to minimal residual disease (MRD) than did patients in the chemotherapy group, which highlighted the depth and quality of remissions achieved with blinatumomab,” the authors noted.
Twenty-four percent of patients in both the blinatumomab and chemotherapy groups proceeded to alloHCT, which is “a major goal in this population,” the authors noted.
“AEs that occurred in the blinatumomab group were consistent with those reported in previous trials,” the authors noted. Serious AEs were reported more frequently in the blinatumomab group (62% vs. 45%; p values not reported). However, “after adjustment for differences in treatment exposure between the two groups, the event rate for serious AEs was lower overall in the blinatumomab group than in the chemotherapy group,” the authors wrote.
Grade ≥3 AEs were reported in 87 percent of patients in the blinatumomab group and 92 percent in the chemotherapy group. Treatment discontinuation resulting from AEs occurred in 12 percent of the blinatumomab group and 8 percent of the chemotherapy group, and treatment interruptions occurred in 32 percent of patients in the blinatumomab group because of infections (7%), neurologic events (6%), cytokine release syndrome (5%), infusion reactions (3%), and neutropenia (3%). Treatment interruptions occurred in just 6 percent of patients receiving chemotherapy.
“Given the previous exposure of these patients to myelosuppressive and immunosuppressive treatment, the activity of an immune-based therapy such as blinatumomab … provides encouragement that responses may be further enhanced and made durable with additional immune activation strategies,” the authors concluded.
The trial took place at two central laboratories with different methods for assessing MRD, which may have introduced a variable that could limit the findings. This study also did not have a blinded randomization given the control treatments.
|TABLE. Best Hematologic Response Within 12 Weeks After Treatment Initiation|
|Treatment Difference (%)||P Value|
|Complete remission with full hematologic recovery||
(95% CI 28.0-39.5)
(95% CI 10.0-23.0)
(95% CI 9.6-26.2)
|Complete remission with full, partial, or incomplete hematologic recovery||
(95% CI 37.9-50.0)
(95% CI 17.6-32.8)
(95% CI 9.9-28.7)
|Complete remission with partial hematologic recovery||
(95% CI 5.8-12.9)
(95% CI 1.7-9.5)
|Complete remission with incomplete hematologic recovery||
(95% CI 0.4-3.7)
(95% CI 1.7-9.5)