Zachary Zimmerman

Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3‐positive T cells to recognize and eliminate CD19‐positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B‐cell precursor ALL on the basis of single‐group trials that showed efficacy and manageable toxic effects. Methods In this multi‐institutional phase 3 trial, we randomly assigned adults with heavily pretreated B‐cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard‐of‐care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event‐free survival than that with chemotherapy (6‐month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem‐cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B‐cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167.)

Unleashing the clinical power of T cells: CD19/CD3 bi-specific T cell engager (BiTE®) antibody construct blinatumomab as a potential therapy

Multi-agent chemotherapy is the standard treatment for most B cell malignancies. Since chemotherapy can be associated with significant toxicity and since relapses resistant to chemotherapy often develop, new therapies are needed. Blinatumomab (AMG 103 or MT103) is a late-stage candidate in clinical development, which belongs to a novel class of antibody constructs termed bi-specific T cell engager antibodies. This antibody construct has dual specificity for CD19 and CD3 and can re-direct polyclonal cytotoxic T lymphocytes toward the tumor. This review focuses on the pre-clinical and clinical development of blinatumomab as a powerful new tool in the treatment of B cell malignancies.

Cost-effectiveness of blinatumomab versus salvage chemotherapy in relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia from a US payer perspective

Abstract Objective: To evaluate the cost-effectiveness of blinatumomab (Blincyto) vs standard of care (SOC) chemotherapy in adults with relapsed or refractory (R/R) Philadelphia-chromosome-negative (Ph−) B-precursor acute lymphoblastic leukemia (ALL) based on the results of the phase 3 TOWER study from a US healthcare payer perspective. Methods: The Blincyto Global Economic Model (B-GEM), a partitioned survival model, was used to estimate the incremental cost-effectiveness ratio (ICER) of blinatumomab vs SOC. Response rates, event-free survival (EFS), overall survival (OS), numbers of cycles of blinatumomab and SOC, and transplant rates were estimated from TOWER. EFS and OS were estimated by fitting parametric survival distributions to failure-time data from TOWER. Utility values were based on EORTC-8D derived from EORTC QLQ-C30 assessments in TOWER. A 50-year lifetime horizon and US payer perspective were employed. Costs and outcomes were discounted at 3% per year. Results: The B-GEM projected blinatumomab to yield 1.92 additional life years and 1.64 additional quality-adjusted life years (QALYs) compared with SOC at an incremental cost of

Exposure-adjusted adverse events comparing blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia

180,642. The ICER for blinatumomab vs SOC was estimated to be

Health-related quality of life in adults with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab

110,108/QALY gained in the base case. Cost-effectiveness was sensitive to the number and cost of inpatient days for administration of blinatumomab and SOC, and was more favorable in the sub-group of patients who had received no prior salvage therapy. At an ICER threshold of

Correction regarding data on blinatumomab-associated seizures

150,000/QALY gained, the probability that blinatumomab is cost-effective was estimated to be 74%. Limitations: The study does not explicitly consider the impact of adverse events of the treatment; no adjustments for long-term transplant rates were made. Conclusions: Compared with SOC, blinatumomab is a cost-effective treatment option for adults with R/R Ph − B-precursor ALL from the US healthcare perspective at an ICER threshold of

Treatment with Anti-CD19 BiTE ® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation

150,000 per QALY gained. The value of blinatumomab is derived from its incremental survival and health-related quality-of-life (HRQoL) benefit over SOC.

Indirect treatment comparison of blinatumomab versus inotuzumab ozogamicin for the treatment of adult patients with relapsed or refractory acute lymphoblastic leukemia receiving zero or one prior salvage therapy.

In the phase 3 TOWER study, blinatumomab demonstrated an overall survival benefit over standard-of-care chemotherapy (SOC) in adults with relapsed or refractory (r/r) Philadelphia chromosome-negative (Ph-) B-precursor acute lymphoblastic leukemia (ALL). Nearly all patients in both treatment arms experienced an adverse event (AE), and the incidence rate of serious AEs was higher for blinatumomab. However, as treatment exposure differed between the 2 arms, we conducted an exploratory safety analysis comparing exposure-adjusted event rates (EAERs) of blinatumomab vs SOC. Analyses were conducted for all patients who received therapy (safety population). Patients received a median (range) of 2 cycles (1-9) of blinatumomab (N = 267) vs 1 cycle (1-4) of SOC (N = 109). Grade ≥3 AE rates were generally higher in cycle 1 of blinatumomab than in cycle 2 (76% vs 37%). After adjusting for time on treatment, EAERs of grade ≥3 were significantly lower for blinatumomab vs SOC overall (10.73 vs 45.27 events per patient-year; P < .001) and for events of clinical interest, including infections (1.63 vs 6.49 events per patient-year; P < .001), cytopenias (3.64 vs 20.07 events per patient-year; P < .001), and neurologic events (0.38 vs 0.95 events per patient-year; P = .008). The EAER of grade ≥3 cytokine-release syndrome was higher for blinatumomab than for SOC (0.16 vs 0 events per patient-year; P = .038). These data further support the role of blinatumomab as an efficacious and well-tolerated treatment option for patients with r/r Ph- ALL. This trial was registered at www.clinicaltrials.gov as #NCT02013167.

Allo-HSCT in Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia Treated with Blinatumomab vs Standard-of-Care Chemotherapy From a Randomized Phase 3 Study

In the phase 3 TOWER study, blinatumomab significantly improved overall survival in adults with relapsed or refractory (R/R) Philadelphia chromosome-negative (Ph-) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) relative to standard-of-care chemotherapy. A secondary objective of this study was to assess the impact of blinatumomab on health-related quality of life (HRQL) as measured by the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30). This analysis included the 342 of 405 randomized patients for whom baseline and ≥1 postbaseline result were available in any EORTC multi-item scale or single-item measure. In general, patients receiving blinatumomab (n = 247) reported better posttreatment HRQL across all QLQ-C30 subscales, based on descriptive mean change from baseline, than did those receiving chemotherapy (n = 95). The hazard ratios for time to deterioration (TTD) of ≥10 points from baseline in HRQL or death ranged from 0.42 to 0.81 in favor of blinatumomab, with the upper bounds of the 95% confidence interval <1.0 across all measures, except insomnia, social functioning, and financial difficulties; sensitivity analysis of TTD in HRQL without the event of death were consistent with these findings. When treatment effect over time was tested using a restricted maximum likelihood-based mixed model for repeated measures analysis, P < .05 was reached for blinatumomab vs chemotherapy for all subscale measures except financial difficulties. The clinically meaningful benefits in overall survival and HRQL support the clinical value of blinatumomab in patients with R/R Ph- BCP-ALL when compared with chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT02013167.

Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors

With regard to the Review article by Stone and DeAngelis, published in the February 2016 issue of this journal (Cancer-treatmentinduced neurotoxicity — focus on newer treatments. Nat. Rev. Clin. Oncol. 13, 92–105 (2016))1, we wish to address an erroneous statement made by the authors that blinatumomab treatment “causes seizures in 15–20% of treated patients” (REF. 1). According to the reference cited to support this statement within the Review2, and the published clinicaltrial literature on blinatumomab3–5, this range refers to the total frequencies of all grade ≥3 neurological adverse events combined, including not only seizures, but also encephalopathy, confusion, and cerebellar symptoms. Across several studies involving adults with relapsed and/or refractory B-cell acute lymphoblastic leukaemia (B-ALL) who received blinatumomab, seizures of any grade were reported in 2.1–8.3% of 246 patients in total: one of 21 patients with persistence or relapse of minimal residual disease (4.8%) had a grade 3 seizure in an early phase II trial3; three of 36 patients (8.3%) had epileptic seizures or convulsions leading to treatment interruption in the dose-finding phase II study4; and four of 189 patients (2.1%) had convulsions in the confirmatory multicentre phase II trial5. Among the patients treated with blinatumomab in clinical trials, most of the neurological adverse events observed have been low-grade tremors and dizziness3–5. More-serious neurological events, such as seizures and encephalopathy, have been the most-common reasons for treatment interruptions (frequency of 15–17%) and discontinuations (frequency of 4.8%)3–5, but patients have generally responded well to interventional therapy for these toxicities. Indeed, these adverse events have predominantly been limi ted in duration and primarily resolved with treatment interruption and/or standard anticonvulsive therapies, and most of the patients were subsequently able to resume blinatumomab therapy3–5. Given the few treatment options currently available for relapsed and/or refractory B-ALL, we feel that accurately reporting the blinatumomab-related seizure rate is pertinent, in order to better inform appropriate treatment decisions. Max S. Topp is at the Department of Internal Medicine II, Division of Hematology and Medical Oncology, Würzburg University Medical Centre, Oberdürrbacher Strasse 6, Würzburg 97080, Germany.