This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that describes the extent and severity of chronic GVHD for each organ or site at any given time, taking functional impact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity that are based on the number of organs or sites involved and the degree of involvement in affected organs (mild, moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical sign of chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation (e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond 100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1) classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of moderate to severe global severity.

The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and scoring the severity of chronic GVHD. The 2014 NIH consensus maintains the framework of the prior consensus with further refinement based on new evidence. Revisions have been made to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes, genitalia, and lungs have been revised. Categories of chronic GVHD should be defined in ways that indicate prognosis, guide treatment, and define eligibility for clinical trials. Revisions have been made to focus attention on the causes of organ-specific abnormalities. Attribution of organ-specific abnormalities to chronic GVHD has been addressed. This paradigm shift provides greater specificity, more accurately measures the global burden of disease attributed to GVHD, and will facilitate biomarker association studies.

Risk factors for grades 2-4 acute graftversus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD. (Blood. 2011;117(11):3214-3219) IntroductionDuring the past 3 decades, several studies have identified risk factors associated with the development of acute and chronic graft-versus-host disease (GVHD). 1 In these studies, acute GVHD generally referred to disease manifestations that occurred within the first 100 days after hematopoietic cell transplantation (HCT), [2][3][4] and chronic GVHD referred to disease manifestations that were present after day 100. 5 The most consistently reported factors significantly associated with an increased risk of grades 2-4 acute GVHD were recipient human leukocyte antigen (HLA) mismatching with the donor, 6-8 alloimmunization of the donor, 9-12 the use of a female donor for male recipients, 9,11-13 and older patient age. 11,13,14 Less consistently reported risk factors have included prior cytomegalovirus infection in the recipient, 14,15 higher intensity of the conditioning regimen (irradiation), 12,14 donor age, 16 and grafting with growth factor-mobilized blood cells. 14,17 For chronic GVHD, the most consistently reported risk factors include prior acute GVHD, 18-20 grafting with growth factor-mobilized blood cells, 17,21,22 the use of a female donor for male recipients, 19,20,23 older patient age, 18-20,23 and mismatched and unrelated donors. 20,24 The objective of the current study was to compare risk factor profiles for grades 2-4 acute and chronic GVHD. For this purpose, we used diagnostic criteria recommended by the National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease. 25 According to these criteria, acute and chronic GVHD are distinguished by differences in clinical manifestations and...

The lack of standardized criteria for quantitative measurement of therapeutic response in clinical trials poses a major obstacle for the development of new agents in chronic graft-versus-host disease (GVHD). This consensus document was developed to address several objectives for response criteria to be used in chronic GVHD-related clinical trials. The proposed measures should be practical for use both by transplantation and nontransplantation medical providers, adaptable for use in adults and in children, and focused on the most important chronic GVHD manifestations. The measures should also give preference to quantitative, rather than semiquantitative, measures; capture information regarding signs, symptoms, and function separately from each other; and use validated scales whenever possible to demonstrate improved patient outcomes and meet requirements for regulatory approval of novel agents. Based on these criteria, we propose a set of measures to be considered for use in clinical trials, and forms for data collection are provided (). Measures should be made at 3-month intervals and whenever major changes are made in treatment. Provisional definitions of complete response, partial response, and progression are proposed for each organ and for overall outcomes. The proposed response criteria are based on current expert consensus opinion and are intended to improve consistency in the conduct and reporting of chronic GVHD trials, but their use remains to be demonstrated in practice.

In 2005, the NIH Chronic GVHD Consensus Response Criteria Working Group recommended several measures to document serial evaluations of chronic GVHD organ involvement. Provisional definitions of complete response, partial response, and progression were proposed for each organ and for overall outcome. Based on publications over the last nine years, the 2014 Working Group has updated its recommendations for measures and interpretation of organ and overall responses. Major changes include elimination of several clinical parameters from the determination of response, updates to or addition of new organ scales to assess response, and the recognition that progression excludes minimal, clinically insignificant worsening that does not usually warrant a change in therapy. The response definitions have been revised to reflect these changes and are expected to enhance reliability and practical utility of these measures in clinical trials. Clarification is provided about response assessment after the addition of topical or organ-targeted treatment. Ancillary measures are strongly encouraged in clinical trials. Areas suggested for additional research include criteria to identify irreversible organ damage and validation of the modified response criteria, including in the pediatric population.

Key Points High-resolution matching for HLA-A, -B, -C, and -DRB1 is required for optimal survival in myeloablative-unrelated donor transplantation. HLA-DPB1 nonpermissive mismatches should be avoided in otherwise matched transplants to minimize overall mortality.

Although transplant practices have changed over the last decades there is no information on trends in incidence and outcome of cGVHD over time. This study utilized the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe the time trends for cGVHD incidence, non-relapse mortality, and the risk factors for cGVHD. The 12-year period was divided into three intervals: 1995-1999, 2000-2003, 2004-2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia and myelodysplastic syndrome. In the multivariate analysis, the incidence of cGVHD was shown to be increased in more recent years (odds ratio= 1.19, p<0.0001) and this trend was still seen when adjusting for donor type, graft type, or conditioning intensity. In patients with cGVHD, non-relapse mortality has decreased over time, but at 5-years there were no significant differences among different time periods. Risk factors for cGVHD were in line with previous studies. This is the first comprehensive characterization of the trends in cGVHD incidence and underscores the mounting need for addressing this major late complication of transplantation in future research.

• In combination with cyclophosphamide, intravenous busulfan is associated with better leukemia-free and overall survival in AML than TBI.Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] 5 0.58; 95% confidence interval [CI]: 0.39-0.86; P 5 .007), and relapse after, but not before, 1 year posttransplant (RR 5 0.23; 95% CI: 0.08-0.65; P 5 .006), and better leukemia-free survival (RR 5 0.70; 95% CI: 0.55-0.88; P 5 .003) and survival (RR 5 0.68; 95% CI: 0.52-0.88; P 5 .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first