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. Author manuscript; available in PMC: 2022 Jul 22.
Published in final edited form as: Expert Rev Hematol. 2021 Sep 8;14(10):883–885. doi: 10.1080/17474086.2021.1977117

Strategies to improve pharmacogenomic-guided treatment options for patients with β-hemoglobinopathies

George P Patrinos 1,2,3,*, David H K Chui 4, Ross C Hardison 5,6, Martin H Steinberg 4
PMCID: PMC9306350  NIHMSID: NIHMS1823066  PMID: 34490838

Abstract

Drug efficacy and toxicity are closely related to the unique genetic profile of individuals, or pharmacogenomics. Despite the fact that cardiology, psychiatry and oncology are among the clinical specialties in which pharmacogenomics has become a clinical reality, the utility of pharmacogenomics has yet to be demonstrated for several other medical specialties. Over the last 15 years, genomic variants in a number of loci have been shown to be significantly associated with the fetal hemoglobin (HbF) response to hydroxyurea, the only approved drug for HbF induction for sickle cell disease. Here, we provide an update and discuss future challenges to the application of pharmacogenomics to improve therapies for β-hemoglobinopathies in relation to the current pharmacological treatment modalities for those disorders.

Keywords: β-hemoglobinopathies, sickle cell disease, therapeutics, pharmacogenomics, genomic variants, clinical trial

Introduction

β-hemoglobinopathies, which include β-thalassemia and sickle cell disease (SCD), comprise a heterogeneous group of disorders of hemoglobin (Hb) synthesis and structure. [reviewed in Patrinos and Antonarakis, 2011]. Around 7% of the world population are carriers of a α- and/or β-globin gene disorders [http://globin.bx.psu.edu/hbvar; Giardine et al, 2021].

In addition to supportive therapy, hematopoietic stem cell transplantation and several different forms of gene therapy are under study. Fetal Hb (HbF) inducing drug treatment with hydroxyurea (HU) is the standard of care in SCD and had been used, albeit less successfully, in β-thalassemia. The response to this drug is highly variable (Patrinos and Grosveld, 2008; Karamperis et al., 2021). Approximately, 25% of patients with β-hemoglobinopathies do not respond to HU (Gravia et al., 2014; Karamperis et al., 2021), suggesting that genomic variants could play role in modulating this variable HbF response. Understanding the pharmacogenomics (PGx), the genetic basis of the interindividual differences in HbF response to HU therapy, could therefore be beneficial in terms of pharmacological treatment for this group of disorders.

Existing evidence to individualize HU treatment response

There are few studies focused on PGx of HbF response to HU in SCD and even fewer in β-thalassemia (Gravia et al., 2014; Karamperis et al., 2021). Genome-wide association studies (GWAS) have revealed strong associations between the quantitative trait loci (QTL) Xmnl-HBG2 within the human β-globin gene cluster and the HBS1L-MYB and BCL11A loci and HbF levels (Karamperis et al., 2021). In a candidate gene-based association study, where the increment in HbF at 2 years after institution of HU in SCD was the outcome measure, Ma and co-workers (2007) showed significant association of variants in the linkage peaks of 6q22.3-23.2 representing the HBS1L-MYB QTL and 8q11-q12, which had previous been associated with HbF levels. Genomic variants in the MAP3K5, TOX, NOS1, NOS2, ARG2 and FLT genes were also associated with HbF response. An association between SAR1 gene promoter variants and response to HU was also demonstrated (Kumkhaek et al., 2008). In 2012, Borg and co-workers showed using whole-transcriptome analysis that genomic variants in the KLF10 gene also modulated HbF levels in response to HU treatment, a finding that has been confirmed in two subsequent retrospective studies (Elfalfy et al., 2017; Kolliopoulou et al., 2019). The latter study also showed that genomic variants within the MAP3K5, NOS2A, ARG2 genes could be also correlated with HU treatment response, confirming previous findings by Ma and co-workers.

These results, although confirmed in different populations and types of hemoglobinopathies, must be considered preliminary. Nonetheless, they provide hope that useful PGx biomarkers for HbF response to HU, HbF inducers yet to be approved and even for newly approved drugs for β-hemoglobinopathies like voxelotor, crizanlizumab and luspatercept could be discovered and validated in a prospective study.

A call for prospective PGx studies for β-hemoglobinopathies

Application of PGx is a rapidly evolving and highly promising approach but is still in its early stage of development for β-hemoglobinopathies. As previously mentioned, apart from HU, there are no PGx data for other drugs used for treating these diseases, while the vast molecular diversity of β-hemoglobinopathies poses yet another challenge for the identification of PGx biomarkers. Also, the effect of hydroxyurea on mortality and morbidity in adult SCD, including the risks and benefits have been well studied and reported previously (Steinberg et al., 2003; 2010).

To proceed beyond this early stage and in order to obtain some meaningful and clinically impactful results to individualize HU treatment for β-hemoglobinopathies, a concerted and well-orchestrated effort among different clinical and research centers in different countries needs to be organized (Fig. 1). In particular, β-hemoglobinopathy patients need to be actively recruited in large numbers and well-characterized at the molecular level, using next-generation sequencing of both the β-globin gene cluster and known modifier genes. To incentivize clinicians to participate in this effort, the microattribution approach (Giardine et al., 2011) could be pursued further and expanded, similar to the CFTR2 Consortium (https://cftr2.org) that has been successfully implemented in a clinical setting (Sosnay et al., 2013), in which a large number of clinical centers and clinicians have participated. Strong commitment from multiple clinical centers is needed in order to collect a large number of patients and cover a wide range of clinical and genetic variability, building on and expanding beyond the published retrospective studies that included a limited number of patients.

Figure 1.

Figure 1

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Overview of the stepwise approach to identify, validate and possibly incorporate PGx biomarkers into routine clinical practice based on individualized HU drug treatment response.

This, coupled with the development of gene-specific next-generation sequencing (NGS) panels (Shang et al., 2017) will allow fine mapping of the genomic variants that contribute not only to the disease molecular heterogeneity but also to HU drug response, which will allow not only proceeding agnostically in the discovery phase but also to establish statistically significant associations with a large study sample. NGS could be performed in a centralized manner (a single or few laboratories) to ensure data homogeneity and consistency.

The on-going whole-genome sequencing and phenotyping consortia such as Trans Omics for Precision Medicine (TOPMed; Taliun et al. 2021) and the UK BioBank (Bycroft et al. 2018) are focused on phenotypes such as commonly measured blood cell parameters. Our proposed PGx consortium potentially could leverage these rich repositories of genotype and phenotype data to improve fine mapping of genomic variants with drug responses.

Creation of a strong consortium of motivated clinicians and laboratory scientists will allow the launch of a multi-site prospective PGx clinical study to confirm part or ideally all of the preliminary findings from the discovery phase and also give the evidence required by regulatory bodies to establish a panel of PGx biomarkers that could be eventually used by clinicians to rationalize HU treatment response. In parallel, a dedicated team of economists would engage to perform economic evaluation of the above therapeutic options to assist decision makers to define whether they can be adopted in healthcare systems to contribute towards reducing the burden of the annual healthcare expenditures (Patrinos and Mitropoulou, 2017) and possibly decide on the reimbursement of those interventions by the payers (Simeonidis et al., 2019). This approach would eventually enable integration of such a PGx biomarker panel for individualizing HU treatment response among β-hemoglobinopathies patients (Fig. 1).

Acknowledgements

GPP is full Member and National Representative at the European Medicines Agency, Committee for Human Medicinal Products (CHMP) – Pharmacogenomics Working Party, Amsterdam, the Netherlands. Support for RCH is from the National Institutes of Health grants R24DK106766, R01CA178393, and R01DK054937.

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