Biomarkers associated with blinatumomab outcomes in acute lymphoblastic leukemia

Abstract

This study aimed to identify biomarkers for clinical outcomes in a phase 3 clinical study of blinatumomab or chemotherapy in adults with Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Patients were randomized 2:1 to receive blinatumomab, a BiTE® therapy, for 4 weeks (9 μg/day cycle 1 week 1, 28 μg/day thereafter) every 6 weeks, or chemotherapy. Baseline blood samples were evaluated to identify biomarkers prognostic (both treatment groups) or predictive (either treatment groups) for overall survival, event-free survival, hematologic remission, minimal residual disease (MRD) response, duration of response, or adverse events. Baseline values were balanced between treatment groups. Prognostic biomarkers were platelets, tumor burden, and percentage of T cells: each 1-log increase in platelets at baseline was prognostic for improved 6-month survival; lower tumor burden was prognostic for hematologic remission; and a higher percentage of CD3+ T-cells was prognostic for MRD response. Consistent with the BiTE mechanism of action, higher percentage of CD45+ CD3+ CD8+ T cells was associated with hematologic remission following blinatumomab. No examined biomarkers were significant for the risk of grade ≥3 adverse events. Incorporating baseline biomarkers into future studies may help to identify subgroups most likely to benefit from blinatumomab.

Trial registration: ClinicalTrials.gov NCT02013167.

Conflict of interest statement

AW has received honoraria from and has served on an advisory board for Amgen. J-MR has received research funding from and has served on speakers’ bureaus for Amgen, Pfizer, Incyte, and Ariad Pharmaceuticals. RAL has received research funding and honoraria from Amgen. DR has received honoraria from Amgen. AG has served on an advisory board for Amgen. YC, AA, CEDS, and JF are employees and stock holders of Amgen. HK has received research funding and honoraria from Amgen, Ariad Pharmaceuticals, Astex Pharmaceuticals, Bristol-Myers Squibb, Novartis, Pfizer, AbbVie, Actinium Pharmaceuticals, Immunogen, and Orsenix.

© 2021. The Author(s).

Figures

Fig. 1. Baseline biomarkers evaluated for association with overall survival, event-free survival, and duration of response.

a Overall survival. b Event-free survival. c Duration of response. For overall survival, a hazard ratio of <1 indicates that higher levels of the biomarker were prognostic or predictive for improved overall survival. aLOG10 transformed. CD45+ CD3− CD19+ B cells are expressed as a percentage of circulating lymphocytes. Bone marrow blasts are a percentage of all nucleated marrow cells. CI confidence interval.

Fig. 2. Baseline biomarkers and 6-month survival probabilities.

a A lower percentage of CD45+ CD3− CD19+ B lymphocytes at baseline was associated with higher 6-month survival probability in the blinatumomab group; this association was less pronounced in the chemotherapy (SOC) group. b For both treatment groups combined, higher platelet counts at baseline were associated with higher 6-month survival probability. aLOG10 transformed.

Fig. 3. Relationship between baseline biomarkers and hematologic remission during blinatumomab (BLIN) or chemotherapy (SOC).

Percentage of (a) bone marrow (BM) blasts, (b) CD3+ CD4+ T cells, (c) CD3+ CD8+ T cells, (d) CD19+ B cells, and (e) CD3+ T cells at baseline in patients with (CR+) or without (Non CR+) hematologic remission (CR, CRh, and CRi). f Baseline CD3+:CD19+ (E:T) ratio in patients with or without hematologic remission. The red horizontal line indicates the median value and the box includes the 25th and 75th percentile values. CR complete remission with full hematologic recovery, CRh complete remission with partial hematologic recovery, CRi complete remission with incomplete hematologic recovery, SOC standard of care.

Fig. 4. Relationship between baseline biomarkers and hematologic remission during blinatumomab (BLIN) or chemotherapy (SOC) as first salvage therapy or as second or later salvage therapy.

Percentage of (a) bone marrow (BM) blasts, (b) CD3+ CD4+ T cells, (c) CD3+ CD8+ T cells, (d) CD19+ B cells, and (e) CD3+ T cells at baseline in patients with (CR+) or without (Non CR+) hematologic remission (CR, CRh, and CRi). f Baseline CD3+:CD19+ (E:T) ratio in patients with or without hematologic remission. The red horizontal line indicates the median value and the box includes the 25th and 75th percentile values. CR complete remission with full hematologic recovery, CRh complete remission with partial hematologic recovery, CRi complete remission with incomplete hematologic recovery, SOC standard of care.

Fig. 5. Baseline biomarkers evaluated for association with hematologic remission and minimal residual disease.

a Hematologic remission. b minimal residual disease (MRD) response. When the odds ratio was >1, the biomarker was prognostic or predictive for increased likelihood of hematologic remission or MRD response. CR/CRh/CRi = complete remission with full (CR), partial (CRh), or incomplete (CRi) recovery of peripheral blood counts. MRD response = an MRD level below 10−4 (by PCR or flow cytometry). aLOG10 transformed. T cells are expressed as a percentage of circulating lymphocytes. Bone marrow blasts are a percentage of all nucleated marrow cells. CI confidence interval, PCR polymerase chain reaction.