Max S. Topp, MD
Treatment with blinatumomab (Blincyto) led to a median overall survival (OS) of 7.7 months versus 4 months with standard chemotherapy in patients with Philadelphia chromosome–negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to results from the phase III TOWER study published in The New England Journal of Medicine
The FDA granted an accelerated approval to the anti-CD19 immunotherapy blinatumomab in December 2014 based on phase II data showing strong activity with the treatment in ALL. The accelerated approval was contingent on outcomes from the confirmatory TOWER trial.
"Historically, patients with relapsed or refractory ALL have a poor prognosis, with an overall survival of just 4 months on standard of care chemotherapy," study author Max S. Topp, MD, professor and head of Hematology, University Hospital of Wuerzburg, Germany, said in a statement. "Findings from this head-to-head study showed that Blincyto almost doubled the median overall survival from four to 7.7 months, offering these high-risk patients a much needed alternative to chemotherapy that is both innovative and effective."
The open-label phase III TOWER trial randomized 405 patients in a 2:1 ratio to blinatumomab (n = 271) or investigator’s choice of 1 of 4 standard chemotherapy regimens (n = 134). The median patient age was 37 years in both arms. Other baseline characteristics were also well balanced in the blinatumomab versus the standard chemotherapy arm, including median bone marrow blasts (80% vs 79%), prior salvage therapy (56% vs 52%), and prior allogeneic stem cell transplant (alloSCT; 35% vs 34%).
Blinatumomab was administered in 6-week cycles of 4 weeks on (continuous infusion of 9 µg/d in week 1 of cycle 1, then 28 µg/d) and 2 weeks off. Patients received dexamethasone prior to blinatumomab to prevent cytokine release syndrome. If remission was reached following 2 induction cycles, patients were allowed to receive treatment until relapse. OS was the primary efficacy endpoint. Complete remission (CR) and combined CR or CR with partial or incomplete hematologic recovery (CR/CRh/CRi) were secondary outcome measures.
Treatment with blinatumomab reduced the risk of death by 29% versus standard chemotherapy (HR, 0.71; 95% CI, 0.55-0.93; P
= .012). The OS benefit with blinatumomab was observed across prespecified patient subgroups based on age, prior salvage therapy, or alloSCT. The study was halted early for efficacy based on the recommendation of an an independent data monitoring committee.
The CR rate with blinatumomab was 34% versus 16% with standard chemotherapy (P
<.001). The combined CR/CRh/CRi rates were 44% versus 25%, respectively (P
<.001). Among the overall population of patients achieving a CR/CRh/CRi, minimal residual disease–negative status was achieved by 76% of patients receiving blinatumomab versus 48% of patients receiving standard of care. The 6-month estimated event-free survival rates were 30.7% versus 12.5%, respectively (HR, 0.55; 95% CI, 0.43-0.71).
"Adults with Ph- relapsed or refractory B-cell precursor ALL are in critical need of new treatment options," lead study author Hagop M. Kantarjian, MD, professor and chair of the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a statement. "Results from the TOWER study reinforce the potential of this single agent bispecific T cell engager immunotherapy, which helped a higher percentage of patients achieve minimal residual disease response versus standard of care chemotherapy, highlighting the depth and quality of remissions achieved."
The safety analysis for TOWER was based on 376 patients who received at least 1 dose of blinatumomab (n = 267) or standard chemotherapy (n = 109). Of these patients, 57% and 25%, in the blinatumomab and chemotherapy arms, respectively, started ≥2 cycles.
The adverse event (AE) profile was similar between the 2 arms and consistent with previous studies of blinatumomab. The incidence of all-grade AEs was 99% in both treatment arms. Grade 3 AEs occurred in 37% of the blinatumomab arm and 30% of the standard chemotherapy arm. The rates of grade 4 AEs were 31% and 44%, respectively. Grade 5/fatal AEs occurred in 19% of the blinatumomab arm versus 17% of the chemotherapy arm, including grade 5 infection rates of 11% and 12%, respectively.
Grade ≥3 AEs of interest included neutropenia (38% in the blinatumomab arm vs 58% in the standard chemotherapy arm), infection (34% vs 52%), neurologic events (9% vs 8%), and cytokine release syndrome (5% vs 0).
"As the first study of an immunotherapy to demonstrate overall survival benefit in adult patients with Ph- relapsed or refractory B-cell precursor ALL, TOWER represents an important advance in the understanding of this aggressive, ultra-orphan disease," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the developer of blinatumomab, said in a statement. "As demonstrated by the data published in The New England Journal of Medicine
, Blincyto has proven to improve overall survival, extend remission rates, and reduce minimal residual disease in these high-risk patients who previously have had limited effective options."
- Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783.
- Topp MS, Stein A, Nicola Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER). Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract S149.