The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease

Abstract

Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification.

Keywords: Chronic graft-versus-host disease (cGVHD); allogeneic hematopoietic stem cell transplantation (allo-HSCT); biomarkers; omics; therapy.

Figure 1

Overview of cGVHD biomarkers workflow from discovery to validation studies. Biorepositories of cGVHD patients are used to select cases and controls samples matched at similar time points post-HSCT for the discovery of candidate cGVHD biomarkers. Analytical assays are validated by assessing their accuracy, robustness and cost-effectiveness. Validated assays will move forward for validation in large cGVHD cohorts. Last, after approval from the Food and Drug Administration, tests are used in standard practice in cGVHD clinics.

Figure 2

Predictive biomarker strategy design for newly diagnosed cGVHD. At the onset of cGVHD, biomarkers are measured to stratify patients in low and high risk. Low risk patients on the left, will be randomized to receive either a standard treatment or a reduced toxicity/steroid free treatment. Comparison between A and B will show if steroid free treatment is as efficient as the steroid treatment and if it reduces the risk of relapse and infections rates. On the other hand, high risk patients will receive either a standard treatment or an intensified treatment. Comparison of C and D will show whether intensification of treatment increases the ratio of responders and effectiveness on cGVHD signs without increasing relapse and infections rates.

Figure 3

Prognostic biomarker-based cGVHD preemptive trial design. Before the occurrence of any clinical signs, biomarkers will be measured starting at D100 post-HSCT and repeated every 3 months. Then, biomarkers cutpoints will be used to identify low and high risk patients. Low risk patients, on the left, will receive no intervention or a rapid immunosuppressive (IS) drugs taper. Comparison of A and B will indicate if a rapid taper immunosuppressive drugs regimen is less toxic and lowers infections rates while achieving tolerance sooner (no development of cGVHD). High risk patients, on the right, will be randomized for either no intervention or a preemptive treatment with a steroid-free agent in option 1. In this case, comparison of A and B will show if preemptive intervention before the onset of cGVHD will lower the incidence of cGVHD as compared to no intervention. In option 2, randomization will compare no intervention versus slow immunosuppressive drugs taper. In this case, comparison of C and D will show if the slower taper will decrease the incidence of cGVHD compared to expected incidence.