Baseline Biomarkers Influencing Clinical Outcomes in Adults with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (R/R ALL) Treated with Blinatumomab Versus Standard-of-Care Chemotherapy (SOC) from a Randomized Phase 3 Study

Introduction: Blinatumomab, an anti-CD3/CD19 bispecific T-cell engager antibody construct, showed antileukemic activity and significantly longer overall survival (OS) vs SOC in adults with advanced Philadelphia chromosome-negative R/R ALL (median OS 7.7 vs 4.0 months; P=0.01) (N Engl J Med 2017;376:836−847). Here we aimed to identify baseline biomarkers that were prognostic (disease-related) or predictive (treatment-related) of clinical outcomes.

Methods: Adults with R/R ALL (refractory to primary induction therapy or salvage therapy, first relapse <1 year, second or later relapse, or relapse after allogeneic hematopoietic cell transplantation [alloHCT]) were randomized to receive either blinatumomab or SOC. Blinatumomab was given by continuous infusion (4 wks on/2 wks off) for up to 5 cycles (9 μg/d on d1‒7 of cycle 1 and 28 μg/d thereafter). Up to 4 additional maintenance cycles (4 wks on/8 wks off) were allowed for up to 1 year. Evaluated biomarkers included leukocytes, monocytes, lymphocytes, granulocytes, platelets, neutrophils, CD45⁺ CD3⁺ CD4⁺ T cells, CD45⁺ CD3⁺ CD8⁺ T cells, CD45⁺ CD3^- CD19⁺ B cells, CD3^- CD16⁺ CD56⁺ cells, bone marrow (BM) blasts, CD3⁺ T cells, CD19⁺ cells, and ratios of CD3⁺/CD19⁺ and CD3⁺%/BM blast%. A multivariate model was used to select potential biomarkers associated with treatment outcomes. Effect on outcome was determined if either the main effect or interaction term between the biomarker and treatment had a P value ≤0.3. Prognostic and predictive associations of baseline biomarkers with OS, hematologic response (complete remission [CR] or CR with full, partial, or incomplete hematologic recovery [CR/CRh/CRi]) within the first 12 wks, and minimal residual disease (MRD) response were assessed by Cox regression for OS and multivariate logistic regression for hematologic response and MRD response. Predictive biomarkers were identified using interaction tests with treatment group.

Results: A total of 405 patients received blinatumomab (n=271) or SOC (n=134). Baseline characteristics including age, prior alloHCT, salvage status, granulocytes, platelets, and lymphocyte subpopulations (CD45⁺ CD3⁺ CD8⁺, CD45⁺ CD3^- CD19⁺, and CD3⁺) were generally balanced between treatment arms. Associations of baseline biomarkers with clinical outcomes are presented in the table. Higher platelet counts were associated with decreased risk of death (HR 0.43; 95% CI 0.29-0.65) and increased CR (odds ratio [OR] 4.12; 95% CI 2.04-8.33) and CR/CRh/CRi (HR 1.64; 95% CI 0.90-2.99). Higher granulocyte counts were associated with decreased risk of death (HR 0.75; 95% CI 0.57-0.99), whereas total leukocyte counts were not (HR 1.04; 95% CI 0.70-1.54). Lower BM blast percentage was associated with increased CR (OR 0.90; 95% CI 0.82-0.97) and CR/CRh/CRi (OR 0.87; 95% CI 0.80-0.95) but not OS (HR 1.04; 95% CI 0.98-1.09). Higher CD3⁺ T cells were associated with increased MRD response (OR 1.75; 95% CI 0.99-3.08). Higher counts of CD45⁺ CD3^- CD19⁺ cells increased the risk of death for blinatumomab patients (HR 1.19; 95% CI 1.09-1.29) but also was not associated with a survival advantage for SOC patients (HR 1.03; 95% CI 0.93-1.15). Higher CD45⁺ CD3⁺ CD8⁺ T cells were associated with increased CR (OR 1.39; 95% CI 1.18-1.65) and CR/CRh/CRi (OR 1.44; 95% CI 1.22-1.70) in patients treated with blinatumomab but did not correlate with increased hematologic response in SOC patients. Multiple logistic regression modeling for adverse events (AEs) of interest showed that BM blasts and lymphocyte markers (CD3⁺ and CD45⁺ CD3⁺ CD8⁺) were not associated with grade ≥3 neurologic events, infections, or cytokine release syndrome.

Conclusions: Higher platelet and granulocyte counts, lower BM blasts, and higher numbers of CD3⁺ T cells were prognostic for improved OS, hematologic response, and MRD response, respectively, in patients with R/R ALL who received blinatumomab vs SOC. A higher frequency of CD45⁺ CD3⁺ CD8⁺ cells was predictive of increased hematologic response to blinatumomab, whereas a higher frequency of CD45⁺ CD3^- CD19⁺ cells was predictive of decreased OS. BM blast percentage and lymphocyte markers were not associated with AEs of interest. Overall, these data demonstrate that responses to blinatumomab can be seen across a variety of subgroups, including those expressing specific baseline biomarkers. Further study is needed to identify subgroups most likely to benefit from blinatumomab.

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