Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for a variety of hematologic malignancies and disorders. Unfortunately, acute graft-versus-host disease (GVHD) is a frequent complication of HCT. While substantial research has identified clinical, genetic and proteomic risk factors for acute GVHD, few studies have sought to develop risk prediction tools that quantify absolute risk. Such tools would be useful for: optimizing donor selection; guiding GVHD prophylaxis, post-transplant treatment and monitoring strategies; and, recruitment of patients into clinical trials. Using data on 9,651 patients who underwent first allogeneic HLA-identical sibling or unrelated donor HCT between 01/1999-12/2011 for treatment of a hematologic malignancy, we developed and evaluated a suite of risk prediction tools for: (i) acute GVHD within 100 days post-transplant and (ii) a composite endpoint of acute GVHD or death within 100 days post-transplant. We considered two sets of inputs: (i) clinical factors that are typically readily-available, included as main effects; and, (ii) main effects combined with a selection of a priori specified two-way interactions. To build the prediction tools we used the super learner, a recently developed ensemble learning statistical framework that combines results from multiple other algorithms/methods to construct a single, optimal prediction tool. Across the final super learner prediction tools, the area-under-the curve (AUC) ranged from 0.613–0.640. Improving the performance of risk prediction tools will likely require extension beyond clinical factors to include biological variables such as genetic and proteomic biomarkers, although the measurement of these factors may currently not be practical in standard clinical settings.
Highlights
Allogeneic hematopoietic cell transplantation (HCT) is currently the treatment of choice for a variety of hematologic malignancies and disorders[1, 2]
Acute graft-versushost disease (GVHD), a debilitating condition associated with significant morbidity, compromised quality of life and mortality remains a frequent complication of HCT[3,4,5,6,7,8]
To-date, substantial effort has been directed towards identifying factors known before transplant that are associated with increased relative risk of acute GVHD including: patient and donor characteristics, such as the indication for transplant[9], patient age[10] and comorbidities[11], use of an unrelated donor[12], and gender disparity[10]; graft properties, including human leukocyte antigens (HLA) mismatch[13] and immunophenotypic makeup[10]; clinical factors, including transplant conditioning, GVHD prophylaxis strategies[13, 14] and post-transplant infectious events such as cytomegalovirus (CMV) reactivation; genetic factors, including variants of the nucleotide-binding oligomerization domain containing protein 2 (NOD2)[15] and polymorphisms of genes related to interleukin-1 (IL-1)[16]; and plasma protein profiles, including those based on TNF-α[17]
Summary
Allogeneic hematopoietic cell transplantation (HCT) is currently the treatment of choice for a variety of hematologic malignancies and disorders[1, 2]. Estimating the absolute risk of acute GVHD as a function of the interplay between the characteristics of the patient and potential unrelated donors could help inform decisions about whether to pursue transplantation, which donor to select, and how to perform the transplant. Patients at high risk for severe acute GVHD and early mortality may be more circumspect about pursuing transplantation in first remission, or they may be select transplant approaches designed to minimize GVHD, potentially at the cost of greater immunosuppression and higher risk of infections. They may be more interested in clinical trials of novel approaches to prevent GVHD. The quantification of absolute risk could be used as an inclusion criterion for clinical trials to select appropriate participants based on risk profile
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