Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy

Marlon Wendell Athaydes Kerr; Fábio Magalhães-Gama; Hiochelson Najibe Santos Ibiapina; Fabíola Silva Alves Hanna; Lilyane Amorim Xabregas; Eliana Brasil Alves; João Paulo Diniz Pimentel; Maria Perpétuo Socorro Sampaio Carvalho; Andréa Monteiro Tarragô; Andréa Teixeira-Carvalho; Olindo Assis Martins-Filho; Allyson Guimarães da Costa; Adriana Malheiro

doi:10.3389/fonc.2021.696032

Bone Marrow Soluble Immunological Mediators as Clinical Prognosis Biomarkers in B-Cell Acute Lymphoblastic Leukemia Patients Undergoing Induction Therapy

Front Oncol. 2021 Sep 27:11:696032. doi: 10.3389/fonc.2021.696032. eCollection 2021.

Authors

Marlon Wendell Athaydes Kerr^{1

2}, Fábio Magalhães-Gama^{2

3

4

5}, Hiochelson Najibe Santos Ibiapina^{6

7}, Fabíola Silva Alves Hanna^{1

2

3}, Lilyane Amorim Xabregas^{1

2}, Eliana Brasil Alves², João Paulo Diniz Pimentel², Maria Perpétuo Socorro Sampaio Carvalho^{1

2}, Andréa Monteiro Tarragô^{1

2

3}, Andréa Teixeira-Carvalho^{1

4

5}, Olindo Assis Martins-Filho^{1

4

5}, Allyson Guimarães da Costa^{1

2

3

6

7

8}, Adriana Malheiro^{1

2

3}

Affiliations

¹ Programa de Pós-Graduação em Ciências Aplicadas à Hematologia, Universidade do Estado do Amazonas (UEA), Manaus, Brazil.
² Diretoria de Ensino e Pesquisa, Fundação Hospitalar de Hematologia e Hemoterapia do Amazonas (HEMOAM), Manaus, Brazil.
³ Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas (UFAM), Manaus, Brazil.
⁴ Programa de Pós-Graduação em Ciências da Saúde, Instituto René Rachou - Fundação Oswaldo Cruz (FIOCRUZ) Minas, Belo Horizonte, Brazil.
⁵ Grupo Integrado de Pesquisas em Biomarcadores de Diagnóstico e Monitoração, Instituto René Rachou - FIOCRUZ Minas, Belo Horizonte, Brazil.
⁶ Programa de Pós-Graduação em Medicina Tropical, UEA, Manaus, Brazil.
⁷ Instituto de Pesquisa Clínica Carlos Borborema, Fundação de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), Manaus, Brazil.
⁸ Escola de Enfermagem de Manaus, UFAM, Manaus, Brazil.

Abstract

Different factors are used as predictors of unfavorable clinical outcomes in B-Cell Acute Lymphoblastic Leukemia (B-ALL) patients. However, new prognostic markers are needed in order to allow treatment to be more accurate, providing better results and an improved quality of life. In the present study, we have characterized the profile of bone marrow soluble mediators as possible biomarkers for risk group stratification and minimal residual disease (MRD) detection during induction therapy. The study featured 47 newly-diagnosed B-cell acute lymphoblastic leukemia (B-ALL) patients that were categorized into subgroups during induction therapy according to risk stratification at day 15 [Low Risk (LR), Low Risk increasing to High Risk (LR→HR) and High Risk (HR)] and the MRD detection on day 35 (MRD^(-) and MRD⁽⁺⁾). Soluble immunological mediators (CXCL8, CCL2, CXCL9, CCL5, CXCL10, IL-1β, IL-6, TNF, IFN-γ, IL-17A, IL-4, IL-5, IL-10 and IL-2) were quantified by cytometric bead array and ELISA. Our findings demonstrated that increased levels of CCL5, IFN-γ and IL-2 at baseline appeared as putative candidates of good prognosis in LR and MRD^(-) subgroups, while CCL2 was identified as a consistent late biomarker associated with poor prognosis, which was observed on D35 in HR and MRD⁽⁺⁾ subgroups. Furthermore, apparently controversial data regarding IL-17A and TNF did not allow the definition of these molecules as either positive or negative biomarkers. These results contribute to the search for novel prognostic indicators, and indicate the potential of bone marrow soluble mediators in prognosis and follow-up of B-ALL patients during induction therapy.

Keywords: biomarkers; bone marrow microenvironment; chemokines; cytokines; leukemia.