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

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.

[1]  Rajesh Chopra,et al.  Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. , 2007, Blood.

[2]  Ron Brookmeyer,et al.  A Confidence Interval for the Median Survival Time , 1982 .

[3]  Michael A. Kelsh,et al.  Acute lymphoblastic leukemia: an assessment of international incidence, survival, and disease burden , 2015, Cancer Causes & Control.

[4]  M. Tormo,et al.  Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group , 2010, Haematologica.

[5]  Laurence L. George,et al.  The Statistical Analysis of Failure Time Data , 2003, Technometrics.

[6]  K. Kreuzer,et al.  Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation. , 2012, Blood.

[7]  R. Larson,et al.  Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. , 2015, The Lancet. Oncology.

[8]  H. Kantarjian,et al.  Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration , 2010, Cancer.

[9]  D. Hoelzer,et al.  Modern therapy of acute lymphoblastic leukemia. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  D. Rubin,et al.  Reducing Bias in Observational Studies Using Subclassification on the Propensity Score , 1984 .

[11]  R. Pazdur,et al.  FDA Approval: Blinatumomab , 2015, Clinical Cancer Research.

[12]  Ralph B D'Agostino,et al.  Estimating treatment effects using observational data. , 2007, JAMA.

[13]  J. Robins,et al.  Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. , 2000, Epidemiology.

[14]  P. Rosenbaum.  Model-Based Direct Adjustment , 1987 .

[15]  R. Simon,et al.  The role of nonrandomized trials in the evaluation of oncology drugs , 2015, Clinical pharmacology and therapeutics.

[16]  H. Kantarjian,et al.  The hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia , 1997, Leukemia.

[17]  H. Kantarjian,et al.  Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. , 2012, The Lancet Oncology.

[18]  H. Kantarjian,et al.  Outcome of adults with acute lymphocytic leukemia after second salvage therapy , 2008, Cancer.

[19]  J. Robins,et al.  Marginal Structural Models and Causal Inference in Epidemiology , 2000, Epidemiology.

[20]  Andreas Wolf,et al.  Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab. , 2012, Blood.

[21]  J. Lunceford,et al.  Strati cation and weighting via the propensity score in estimation of causal treatment e ects : a comparative study , 2004 .

[22]  Giovanni Martinelli,et al.  International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia , 2016, Haematologica.

[23]  D. Rubin,et al.  The central role of the propensity score in observational studies for causal effects , 1983 .

[24]  Pamela A Shaw,et al.  Chimeric antigen receptor T cells for sustained remissions in leukemia. , 2014, The New England journal of medicine.

[25]  J. Kalbfleisch,et al.  The Statistical Analysis of Failure Time Data , 1980 .

[26]  Robert Tibshirani,et al.  An Introduction to the Bootstrap , 1994 .

[27]  H. Dombret,et al.  Outcome of treatment after first relapse in adults with acute lymphoblastic leukemia initially treated by the LALA-94 trial , 2007, Leukemia.