A supplemental biologics license application has been submitted to the FDA for the full regulatory approval of blinatumomab as a treatment for patients with Philadelphia chromosome-negative relapsed/refractory B-precursor acute lymphoblastic leukemia.
Sean E. Harper, MD
A supplemental biologics license application (sBLA) has been submitted to the FDA for the full regulatory approval of blinatumomab (Blincyto) as a treatment for patients with Philadelphia chromosome-negative (Ph-) relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL), according to the developer of the anti-CD19 immunotherapy, Amgen.
The sBLA was based on data from the phase III TOWER study, in which the median overall survival (OS) with blinatumomab was 7.7 months versus 4 months with standard chemotherapy. The application also provides data supporting the use of blinatumomab in patients with Philadelphia chromosome-positive (Ph+) relapsed/refractory B-cell precursor ALL.
"Acute lymphoblastic leukemia is one of the most aggressive B-cell malignancies, and adult patients who relapse or are refractory to treatment often go through multiple lines of therapy," Sean E. Harper, MD, executive vice president of Research and Development at Amgen, said in a statement. "We are excited to potentially receive full approval for Blincyto, the first immunotherapy to demonstrate an overall survival benefit versus standard of care chemotherapy in patients with relapsed or refractory Ph- B-cell precursor ALL, and bring a much needed new treatment option to those who are Ph+."
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 = .001).
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).
The FDA granted an accelerated approval to blinatumomab in 2014 as a treatment for patients with Ph- relapsed/refractory B-precursor ALL, based on findings from a phase II trial.
According to Amgen, the BLINCYTO label includes a Boxed Warning regarding cytokine release syndrome and neurological toxicities.
Topp MS, Stein A, 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.