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.

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.

Importance Cancer is caused by a diverse array of somatic and germline genomic aberrations. Advances in genomic sequencing technologies have improved the ability to detect these molecular aberrations with greater sensitivity. However, integrating them into clinical management in an individualized manner has proven challenging. Objective To evaluate the use of integrative clinical sequencing and genetic counseling in the assessment and treatment of children and young adults with cancer. Design, Settings and Participants An observational, consecutive case series (May 2012–October 2014) of 102 children and young adults (mean age, 10.6; median age, 11.5, range: 0–22 years) with relapsed, refractory, or rare cancer at a single major academic medical center. Exposures Each participant underwent integrative clinical exome (tumor and germline DNA) and transcriptome (tumor RNA) sequencing along with genetic counseling. Results were discussed in a multi-disciplinary Precision Medicine Tumor Board (PMTB) and recommendations were reported to treating physicians and families. Main Outcomes and Measures Proportion of patients with potentially actionable findings (PAF), results of clinical actions based on integrative clinical sequencing (ICS), and estimated proportion of patients or their families at risk for future cancer. PAF was defined as any genomic findings discovered during sequencing analysis that could lead to a 1) change in patient management by providing a targetable molecular aberration, 2) change in diagnosis or risk stratification or 3) provides cancer-related germline findings, which inform patients/families about a potential future risk of various cancers; Results We screened 104 patients and enrolled 102 patients of which 91 (89%) had adequate tumor tissue available to complete sequencing and only these patients were included in all subsequent calculations, including 28 (31%) with hematological malignancies and 63 (69%) with solid tumors. Overall, 42 (46%) patients had PAFs which changed patient management including, 54% (15/28) with hematological malignancies and 43% (27/63) with solid tumors. Overall, individualized actions were taken in 23 of the 91 (25%) patients and families based on actionable ICS findings, including change in treatment in 14 (15%) and genetic counseling for future cancer risk in 9 (10%) patients. 9/91 (10%) of these personalized clinical interventions resulted in ongoing partial clinical remission of 8–16 months duration or help sustain complete clinical remission of 6–21 months duration. All 9 (10%) patients and families with actionable incidental genetic findings agreed to formal genetic counseling and screening. Conclusions and Relevance In this single center case series of children and young adults with relapsed or refractory cancer, incorporation of data from integrative clinical sequencing into clinical management was feasible, revealed potentially actionable findings in 46% of patients, and was associated with change in treatment and family genetic counseling in a s...