In the JournalsPerspective

Propensity score analysis supports blinatumomab vs. standard of care for relapsed/refractory ALL subset

Blinatumomab appeared to confer better outcomes than standard of care among adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, according to results of a propensity score analysis published in Cancer.

“The standard of care for de novo Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is induction with conventional or attenuated chemotherapy in combination with a tyrosine kinase inhibitor. Most patients achieve complete remission and proceed to allogeneic hematopoietic stem cell transplantation. However, relapse can occur and is most commonly associated with TKI-resistant mutations in the kinase domain of the BCR-ABL1 oncogene,” Alessandro Rambaldi, MD, researcher in the department of oncology and hematology at University of Milan in Italy, and colleagues wrote. “There is no definitive evidence of a sustained response or long-term survival with TKIs after a relapse, with OS ranging from approximately 4 to 6 months. Compounding these challenges, Ph+ ALL is rare, and this limits most clinical trials evaluating new treatments to single-arm studies.”

One such study assessed blinatumomab (Blincyto, Amgen), a bispecific T-cell engaging antibody construct, among 45 patients (median age, 55 years; range, 23-78; 53% men) treated with at least one second-generation TKI for relapsed or refractory Ph+ ALL.

Rambaldi and colleagues compared data from that prospective phase 2 trial with data from a historical cohort of 55 similar patients (median age, 53 years; range, 20-82; 51% men) treated with standard-of-care chemotherapy and included in two clinical databases from centers in Italy and Spain.

A larger proportion of patients in the blinatumomab group had no prior salvage therapy (31% vs. 13%), had not received prior treatment with three or more TKIs (38% vs. 16%) and did not have prior allogeneic HSCT (44% vs. 33%).

Investigators compared the two groups using a propensity score analysis with Bayesian augmentation — a technique that aims to reduce bias that may exist between groups due to disease characteristics, treatment factors or other known predictors of outcome. Researchers improved statistical power of the analysis to 80% by applying Bayesian data augmentation with data from a phase 3 trial of blinatumomab vs. standard of care among patients with relapsed or refractory Philadelphia-negative B-cell precursor ALL.

Results showed a complete remission rate of 27% in the standard-of-care cohort compared with 36% in the blinatumomab cohort. This resulted in a non-Bayesian-data augmented OR (65% power) of 1.54 (95% CI, 0.61-3.89) and a Bayesian-augmented OR (80% power) of 1.7 (95% credible interval, 0.94-2.94).

Median OS was 6 months (95% CI, 4.4-9.2) with standard of care vs. 7.1 months (95% CI, 5.6-not estimable) with blinatumomab.

The Bayesian-augmented HR comparing OS of blinatumomab vs. standard of care was 0.77 (95% credible interval, 0.61-0.96). This correlated to a 23% reduction in the risk for death with blinatumomab compared with standard of care.

Common grade 3 or higher adverse events associated with blinatumomab included febrile neutropenia (27%), thrombocytopenia (22%) and anemia (16%).

Photo of Ryan Cassaday
Ryan D. Cassaday

The propensity score analysis provides important comparisons between blinatumomab and standard of care in the absence of a rigorous randomized trial, Ryan D. Cassaday, MD, physician in the division of hematology in the department of medicine at University of Washington School of Medicine in Seattle, wrote in an accompanying editorial.

“For now, and perhaps forever, these data are the best available to support the conclusion that outcomes with blinatumomab are at least as good, if not better, for patients with relapsed/refractory Ph+ B-cell ALL,” Cassaday wrote. “Results from ongoing trials will help us to understand better ways of using this effective agent in both the front-line and salvage settings. As we await these data, the routine and investigational use of blinatumomab in patients with Ph+ B-cell ALL is well-founded.” – by Jennifer Southall

Disclosures: The study was funded by Amgen. Rambaldi reports consultant roles with or travel support from Amgen, Celgene, Gilead, Italfarmaco, Novartis, Omeros, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures. Cassaday reports grants from Amgen, Incyte, Kite/Gilead, Merck, Pfizer, Seattle Genetics and Vanda Pharmaceuticals; advisory board roles with Amgen and Adaptive Biotechnologies; honoraria from Pfizer; and that his spouse is a paid employee of Seattle Genetics and owns stock.

Blinatumomab appeared to confer better outcomes than standard of care among adults with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia, according to results of a propensity score analysis published in Cancer.

“The standard of care for de novo Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is induction with conventional or attenuated chemotherapy in combination with a tyrosine kinase inhibitor. Most patients achieve complete remission and proceed to allogeneic hematopoietic stem cell transplantation. However, relapse can occur and is most commonly associated with TKI-resistant mutations in the kinase domain of the BCR-ABL1 oncogene,” Alessandro Rambaldi, MD, researcher in the department of oncology and hematology at University of Milan in Italy, and colleagues wrote. “There is no definitive evidence of a sustained response or long-term survival with TKIs after a relapse, with OS ranging from approximately 4 to 6 months. Compounding these challenges, Ph+ ALL is rare, and this limits most clinical trials evaluating new treatments to single-arm studies.”

One such study assessed blinatumomab (Blincyto, Amgen), a bispecific T-cell engaging antibody construct, among 45 patients (median age, 55 years; range, 23-78; 53% men) treated with at least one second-generation TKI for relapsed or refractory Ph+ ALL.

Rambaldi and colleagues compared data from that prospective phase 2 trial with data from a historical cohort of 55 similar patients (median age, 53 years; range, 20-82; 51% men) treated with standard-of-care chemotherapy and included in two clinical databases from centers in Italy and Spain.

A larger proportion of patients in the blinatumomab group had no prior salvage therapy (31% vs. 13%), had not received prior treatment with three or more TKIs (38% vs. 16%) and did not have prior allogeneic HSCT (44% vs. 33%).

Investigators compared the two groups using a propensity score analysis with Bayesian augmentation — a technique that aims to reduce bias that may exist between groups due to disease characteristics, treatment factors or other known predictors of outcome. Researchers improved statistical power of the analysis to 80% by applying Bayesian data augmentation with data from a phase 3 trial of blinatumomab vs. standard of care among patients with relapsed or refractory Philadelphia-negative B-cell precursor ALL.

Results showed a complete remission rate of 27% in the standard-of-care cohort compared with 36% in the blinatumomab cohort. This resulted in a non-Bayesian-data augmented OR (65% power) of 1.54 (95% CI, 0.61-3.89) and a Bayesian-augmented OR (80% power) of 1.7 (95% credible interval, 0.94-2.94).

PAGE BREAK

Median OS was 6 months (95% CI, 4.4-9.2) with standard of care vs. 7.1 months (95% CI, 5.6-not estimable) with blinatumomab.

The Bayesian-augmented HR comparing OS of blinatumomab vs. standard of care was 0.77 (95% credible interval, 0.61-0.96). This correlated to a 23% reduction in the risk for death with blinatumomab compared with standard of care.

Common grade 3 or higher adverse events associated with blinatumomab included febrile neutropenia (27%), thrombocytopenia (22%) and anemia (16%).

Photo of Ryan Cassaday
Ryan D. Cassaday

The propensity score analysis provides important comparisons between blinatumomab and standard of care in the absence of a rigorous randomized trial, Ryan D. Cassaday, MD, physician in the division of hematology in the department of medicine at University of Washington School of Medicine in Seattle, wrote in an accompanying editorial.

“For now, and perhaps forever, these data are the best available to support the conclusion that outcomes with blinatumomab are at least as good, if not better, for patients with relapsed/refractory Ph+ B-cell ALL,” Cassaday wrote. “Results from ongoing trials will help us to understand better ways of using this effective agent in both the front-line and salvage settings. As we await these data, the routine and investigational use of blinatumomab in patients with Ph+ B-cell ALL is well-founded.” – by Jennifer Southall

Disclosures: The study was funded by Amgen. Rambaldi reports consultant roles with or travel support from Amgen, Celgene, Gilead, Italfarmaco, Novartis, Omeros, Pfizer and Roche. Please see the study for all other authors’ relevant financial disclosures. Cassaday reports grants from Amgen, Incyte, Kite/Gilead, Merck, Pfizer, Seattle Genetics and Vanda Pharmaceuticals; advisory board roles with Amgen and Adaptive Biotechnologies; honoraria from Pfizer; and that his spouse is a paid employee of Seattle Genetics and owns stock.

    Perspective
    Elizabeth Griffiths

    Elizabeth Griffiths

    In July 2017, the FDA granted full approval to blinatumomab for the management of relapsed or refractory precursor Ph+ or Ph-negative B-cell ALL. A single-arm, phase 2 study that enrolled 45 patients and demonstrated a complete remission rate of 36% served as the basis for this approval among patients with Ph+ disease. Although these numbers — both in terms of enrolled patients and response rate — are soberingly low, this result was dramatic given that it was achieved without the toxicity of chemotherapy, a burden that cannot be overstated.

    For those who remained skeptical of blinatumomab’s relative superiority over salvage chemotherapy in the Ph+ setting, this recent propensity analysis by Rambaldi and colleagues provides additional data affirming its single-agent activity. Although these single-agent response data are perhaps less exciting, we and others have extensively utilized blinatumomab in combination with TKIs in patients with Ph+ ALL and have seen substantially more robust response rates, particularly when used in the setting of relatively early relapse or measurable residual disease.

    A significant body of literature supports this type of combination strategy for our patients outside the context of a clinical trial, and there are ongoing prospective studies in this arena. I would argue, however, that the most clinically important value of novel targeted therapeutics — not only blinatumomab, but also inotuzumab ozogamicin (Besponsa, Pfizer Oncology) and engineered or chimeric cellular therapeutics — lies in their utilization early on for newly diagnosed patients of all ages. In this context, achievement of early minimal residual disease negativity may pave the way toward long-term survival for all our patients with ALL.

    References:

    Assi R, et al. Clin Lymphoma Myeloma Leuk. 2017;doi:10.1016/j.clml.2017.08.101.

    Hanif A, et al. Leuk Lymphoma. 2018;doi:10.1080/10428194.2017.1411595. 

    King AC, et al. Leuk Res. 2019;doi:10.1016/j.leukres.2019.02.009. 

    Martinelli G, et al. J Clin Oncol2017;doi:10.1200/JCO.2016.69.3531.

    Pulte ED, et al. Oncologist. 2018;doi:10.1634/theoncologist.2018-0179.

    Stock W, et al. Blood. 2019;doi:10.1182/blood-2018-10-881961. 

    Wieduwilt MJ, et al. Blood. 2018;132(Supplement 1):309.

    • Elizabeth Griffiths, MD
    • HemOnc Today Next Gen Innovator
      Roswell Park Comprehensive Cancer Center

    Disclosures: Griffiths reports no relevant financial disclosures.

    See more from Immuno-Oncology Resource Center