Blinatumomab vs historical standard therapy of adult relapsed/refractory acute lymphoblastic leukemia

Abstract

We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.

Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia: Pathophysiology, Prevention, and Treatment

“…Leukemia relapsing after or unresponsive to initial therapy usually represents chemo-resistant disease, and historically, the response to available salvage conventional chemo-based regimens was disappointing, as only a small fraction of patients were successfully able to proceed to allogeneic hematopoietic cell transplantation (HCT) [1,2]. The management of relapsed and refractory (r/r) B cell ALL has markedly evolved over the last few years with newly approved effective novel therapies, among which are two CD19-targeted immunotherapies, namely, CD19 chimeric antigen receptor (CAR) T cell and CD19 bispecific T cell engager (BiTE®) therapy.…”

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data

“…In total 1139 patients met these criteria, of whom survival data was available from 1112 patients [15]. Two-thirds of patients (67%) were diagnosed after the year 2000.…”

“…Regulatory approval of blinatumomab in the US was based on results from a single-arm phase 2 study in 189 adults with R/R Ph(−) B-precursor ALL [14]. Historical observational data from 1139 patients with R/R Ph(−) B-precursor ALL who received standard of care therapy in Europe and the US provided context for the interpretation of the single-arm clinical study [15]. The single-arm clinical study and the historical observational data have been compared for rates of complete remission (42.9% vs 24%) and overall survival (OS) at 1 (32.0% vs 15.5%) and 3 years (13.8% vs 6.2%) [14, 15].…”

“…Historical observational data from 1139 patients with R/R Ph(−) B-precursor ALL who received standard of care therapy in Europe and the US provided context for the interpretation of the single-arm clinical study [15]. The single-arm clinical study and the historical observational data have been compared for rates of complete remission (42.9% vs 24%) and overall survival (OS) at 1 (32.0% vs 15.5%) and 3 years (13.8% vs 6.2%) [14, 15]. To date, the blinatumomab clinical study includes 3 years of survival follow-up data, after which time 13.8% of patients remained alive [Amgen data on file].…”

Inclusion and response criteria for clinical trials in relapsed/refractory acute lymphoblastic leukemia and usefulness of historical control trials

“…In other words, for a comparison of real-world data with clinical trial data, principally the disease-specific inclusion criteria should match; we tried to come as close as possible to this approach in our comparative analysis. 17 Nevertheless, we have addressed this limitation of our analysis very clearly in the discussion.…”