Max S. Topp, MD
The median overall survival (OS) with the anti-CD19 immunotherapy blinatumomab (Blincyto) was 7.7 months versus 4 months with standard chemotherapy in patients with Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), according to results from the phase III TOWER study presented at the 2016 European Hematology Association (EHA) Congress.
The TOWER study is the confirmatory study for the accelerated approval of blinatumomab, which the FDA granted in December 2014 based on phase II data demonstrating strong clinical activity with the agent in ALL.
“Blinatumomab is the first immunotherapy to demonstrate an overall survival benefit when compared to chemotherapy in relapsed/refractory adult lymphoblastic leukemia patients. There was an almost two-fold increase in overall survival compared to standard of care,” lead study author Max S. Topp, MD, professor and head of Haematology, University Hospital of Wuerzburg, Germany, said when presenting the data at EHA.
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 39% versus 19% with standard chemotherapy (P
<.001). The combined CR/CRh/CRi rates were 46% versus 28%, respectively (P
The safety analysis 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).
In the phase II study that led to the approval of the drug, intravenous blinatumomab was administered for 4 weeks followed by a 2-week resting period for up to 5 cycles to 189 patients with Ph- ALL. The median age of patients was 39 and 34.1% had undergone a hematopoietic stem cell transplantation (HSCT) prior to entering the trial. The primary endpoint of the study was CR or CR with partial hematological recovery (CRh), with secondary endpoints focused on CR, CRh, relapse-free survival, and OS.
According to the FDA label for the drug, the CR rate was 32.4% (95% CI, 25.7-39.7), the CRh rate was 9.2% (95% CI, 5.4-14.3), and the combined CR/CRh rate was 41.6% (95% CI, 34.4-49.1). Approximately 39% of patients who achieved a CR/CRh went on to receive a HSCT.
Commenting on the TOWER results, Sean E. Harper, MD, executive vice president of Research and Development at Amgen, the developer of blinatumomab said, “This is the first study of an immunotherapy to demonstrate overall survival benefit in adult patients with Ph-negative B-cell precursor relapsed or refractory ALL, a very complex-to-treat disease with limited treatment options. Blincyto is currently approved for the treatment of Ph-negative B-cell precursor relapsed or refractory ALL under accelerated approval, and we look forward to working with regulatory authorities for a full approval for Blincyto in this patient population."
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.
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