Measuring Therapeutic Response in Chronic Graft-versus-Host Disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group Report

Skin and skin appendages 

Skin is the most frequently affected organ in chronic GVHD, and manifestations are highly variable. Skin assessments are structured to reflect 4 anatomic levels of skin involvement: (1) erythematous rash (epidermal involvement); (2) movable sclerosis (dermal involvement); (3) nonmoveable sclerosis, hidebound skin, or involvement of subcutaneous tissue and fascia (subcutaneous involvement); and (4) ulceration (full thickness loss of epidermal tissue) (Figure 1). Abnormalities for the first 3 points are each assessed separately according to the percent of body surface area (BSA) involved as estimated by the rule of nines for adults. A worksheet for recording the BSA involved for each of 8 skin regions is provided at: http://www.asbmt.org/GvHDForms (Attachment 3). Ulcer size is assessed by measuring the largest diameter of the largest ulcer.

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Figure 1. Skin manifestations assessed for response in chronic GVHD. A, Erythematous papular rash. B, Erythematous rash with papules and small scaly plaques. C, Dermal sclerosis. Skin is thickened, with decreased mobility to pinching but without adherence to underlying tissues. D, Subcutaneous sclerosis. Skin is hidebound, fixed to underlying tissues and cannot be pinched. Ulcers are present.

The term “erythematous rash of any sort” is used as an inclusive reference to the many superficial skin eruptions of chronic cutaneous GVHD including papular, lichen planus-like, papulosquamous, poikiloderma, and keratosis pilaris-like rashes. The term “lichenoid” is not used, because this is a histopathologic diagnosis, not a clinical descriptive term.

Likewise, the term “sclerosis” or “sclerotic” is used to represent the general category of cutaneous GVHD findings associated with skin fibrosis, and to avoid confusion with the autoimmune disorder scleroderma. Superficial sclerosis (moveable) includes both lichen sclerosus-like and morphea-like lesions. Deep sclerosis includes diffuse, immovable (hidebound) sclerosis involving a wide area of skin, fibrosis of subcutaneous fat septae (rippling), and fasciitis (groove sign). Sclerotic skin manifestations may be as variable as the superficial form of the disease and are difficult to measure reliably. Sclerotic changes respond slowly to therapy and progression or regression of sclerotic lesions ideally should be assessed not only according to the total surface area involved but also according to the depth of involvement at any given site.

Because quantitative methods to measure the depth of sclerotic involvement are not available in a general oncology practice, these changes have been described in more qualitative terms related to thickening, pliability, adherence to underlying tissues, or changes in joint mobility. No validated scale exists for assessing sclerotic skin changes of chronic GVHD. Measures such as the Rodnan score for assessment of systemic sclerosis might be helpful for clinical evaluation of chronic GVHD, but this scale does not measure lichen sclerosus-like changes, subcutaneous involvement without overlying skin thickening, or fascial involvement. For this reason, the Rodnan score is not suitable for use in clinical trials. More sophisticated skin-specific scores are being developed for use by trained assessors in selected clinical trials (R. Knobler, MD, and H. Greinix, MD, oral communication, December 2005). There is an urgent need for the development of more quantifiable and reproducible measurements or imaging methods that could be used in patients with sclerotic skin manifestations of chronic GVHD [30, 31, 32, 33, 34].

Pigmentary changes do not indicate activity in chronic GVHD disease per se. Moreover, changes in pigmentation occur gradually and are perceptible only across long time intervals. Nonetheless, these changes should be recorded in the assessment forms, as described in the Diagnosis and Staging document [9], because they indicate the extent of previous skin involvement. Individuals who assess chronic GVHD of the skin should consult a picture atlas that is available for training and standardization (http://www.asbmt.org/GvHDForms).

The patient symptom intensity self-report profile includes the most severe itching during the past week, rated according to a 1-to-10 scale, because itching is the most frequent cutaneous symptom of chronic GVHD.

The rule of nines as an estimate of BSA involvement is intended for use in adults and is less accurate in children, particularly young children. For the sake of simplicity, we recommend using the rule of nines for all children, except for those younger than 1 year. A BSA grid for children younger than 1 year can be found at: http://www.asbmt.org/GvHDForms (Attachment 4).

Eyes 

Dry eyes reflect either lacrimal dysfunction or destruction. The primary measure of lacrimal gland function in chronic GVHD is the Schirmer’s test (to be performed without anesthesia) for each eye separately, as recommended by the Sjögren’s syndrome consensus group [45]. Objective improvement would not be expected in cases where dry eyes and abnormal Schirmer’s test result from complete lacrimal destruction. Instructions for administration of the Schirmer’s test are provided with the instructional manual at: http://www.asbmt.org/GvHDForms.

The patient symptom intensity self-report profile includes the chief eye complaint rated according to a 1-to-10 scale for peak severity during the past week. The complaint can change from visit to visit, but only one chief eye complaint is graded. This method is simple to use but may impose undesirable limitations in patients with multiple complaints. In addition, ocular symptoms in patients with chronic GVHD can have causes other than chronic GHVD.

Schirmer’s test without anesthesia is not recommended for children younger than 9 years, and evaluation by an ophthalmologist may be needed for objective scoring in younger children.

Mouth 

Mouth assessments are conducted by using the newly proposed modification of the Schubert Oral Mucositis Rating Scale that scores oral surfaces from 0 to 15, with higher scores indicating more severe involvement. The 4 chronic GVHD manifestations assessed in this scale include: (1) mucosal erythema (0-3) grading based on the color intensity; (2) lichen-type hyperkeratosis (percent of oral surface area); (3) ulcerations (percent of oral surface area); and (4) presence of mucoceles (total number) (Figure 2). Instructions for these assessments and a photo dictionary are provided in the instructional manual on the World Wide Web: http://www.asbmt.org/GvHDForms.

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Figure 2. Oral manifestations assessed for response in chronic GVHD. A, Moderate erythema of vermilion lip. Labial mucosa shows severe erythema. B, Area of sheetlike lichenoid hyperkeratosis is present inside commissure. C, Ulcer with pseudomembranous fibrin exudates surrounded by severe erythema. D, Numerous vesicle-like mucoceles are seen at center of the palate, with patches of lichenoid hyperkeratosis and moderate erythematous changes.

The patient self-report symptom intensity profile includes dry mouth (subjective decrease in oral wetness), mouth pain in the absence of stimulation, and mouth sensitivity (irritation resulting form normally tolerated spices, foods, liquids, or flavors), each rated according to a 1-to-10 scale for peak severity during the past week.

Hematopoietic 

Parameters to be evaluated for response assessments are absolute platelet count [46] and absolute eosinophil count [47]. Total white count and percent eosinophils are also recorded on the form at the time of the clinic visit.

Gastrointestinal tract 

Gastrointestinal (GI) symptoms are difficult to measure in the outpatient setting. For this reason, GI symptoms during the preceding week are graded not through patient self-report forms but through interview by the examining clinician according to 0-to-3 severity scales. For upper GI symptoms of early satiety, anorexia, nausea, and vomiting, a score of 1 indicates mild, occasional symptoms, with little reduction in oral intake. A score of 2 indicates moderate, intermittent symptoms, with some reduction in oral intake, and a score of 3 indicates more severe or persistent symptoms throughout the day, with marked reduction in oral intake on most days. For esophageal symptoms of dysphagia or odynophagia, a score of 1 indicates occasionally difficult or painful swallowing of solid foods or pills. A score of 2 indicates intermittent dysphagia or odynophagia with solid foods and pills, but not for liquids or soft foods, and a score of 3 indicates dysphagia or odynophagia for almost all oral intakes on most days. Finally, for lower GI symptoms, a score of 1 indicates occasional loose or liquid stools, on some days. A score of 2 indicates intermittent loose or liquid stools throughout the day without requiring intervention to prevent or correct volume depletion, and a score of 3 indicates voluminous diarrhea requiring intervention to prevent or correct volume depletion.

Patients with chronic GVHD often have weight loss that is not always explained by GI symptoms [48]. Although the exact relationship between weight loss and chronic GVHD activity is not clear, patient weight should be recorded at each scheduled evaluation, given the simplicity of this measure and its potential importance for monitoring the success of therapy.

Liver 

Liver injury should be assessed according to the most recent laboratory results for total serum bilirubin (mg/dL), alanine aminotransferase (U/L), and alkaline phosphatase (U/L). Laboratory upper limits of normal should also be recorded.

Lung 

Measures that can be used to evaluate the response of bronchiolitis obliterans syndrome (BOS) after therapy are forced expiratory volume in the first second (FEV1) and single breath diffusion lung capacity for carbon monoxide (DLCO) adjusted for hemoglobin, both of which are included in standard pulmonary function testing [49]. These two parameters are also included as components of the lung function score (LFS) that was recently developed as a predictor of respiratory failure and mortality after allogeneic hematopoietic stem cell transplantation [50]. A modified LFS is proposed as a simple measure of changes in the lung function in patients with BOS (see Table 3). Pulmonary function tests should be performed in children who are older than 5 years.

Table 3. Categories of the Lung Function Score

	Category	Lung Function	LFS
	I	Normal	2
	II	Mild decrease	3-5
	III	Moderate decrease	6-9
	IV	Severe decrease	10-12

The LFS is computed according to FEV1 and DLCO measurements compromise (>80% of predicted = 1, 70%-79% = 2, 60%-69% = 3, 50%-59% = 4, 40%-49% = 5, <40% = 6). The scores for FEV1 and DLCO are then added together, and the sum is reduced to an overall category according to Table 3.

It is important to emphasize that the LFS has never been used in chronic GVHD response assessments, and its exact role in this setting needs to be determined. To allow validation in trials, absolute values of both FEV1 and DLCO should be recorded on the data collection forms.

Vulva and vagina 

Women should be asked specific questions relating to vulvar and vaginal symptoms, such as burning, pain, discomfort, or dyspareunia. Patients who report problems should be referred to a gynecologist. Because such symptoms could be caused by conditions other than chronic GVHD, and because proper evaluation requires a specialist examination, this information should be recorded but not scored for response assessment. Academic gynecologists interested in chronic GVHD are developing precise vulvovaginal assessment scales. These scales will be useful in selected trials where vulvar and vaginal changes are the primary end points of interest [39, 40].

Musculoskeletal connective tissue 

Active-assisted range of joint motion could potentially serve as a very useful objective measure of chronic GVHD tissue response in patients with sclerotic changes involving large joints or the trunk. The main limitation of this tool, however, is the need for an adequately trained professional (usually a physical therapist) who can conduct the range-of-motion measurements in a standardized and reproducible fashion. If such a trained professional is available, pertinent range-of-motion measurements should be recorded sequentially, and for this purpose, trained clinicians should also be able to make serial measurements of selected sentinel joints for routine assessment purposes. Normal levels are available for adults and for children [51].

Clinician perceptions 

Physicians, nurse practitioners, or physician assistants should provide an assessment of current overall chronic GVHD severity on a 4-point scale (none, mild, moderate, severe) [12] and they can also provide an assessment of current overall chronic GVHD severity on an 11-point numeric scale (0 indicates no GVHD manifestations; 10 indicates most severe chronic GVHD symptoms possible). The categories of mild, moderate, and severe have been used in previous studies for patient and clinician assessment, where they were undefined but showed good prognostic characteristics [12, 54]. Clinicians should also provide their assessments of patient chronic GVHD changes during the past month scored on a 7-point scale (very much better, moderately better, a little better, about the same, a little worse, moderately worse, very much worse) [14].

Patient perceptions 

Similarly, at each patient self-assessment, patients should score their perceptions of overall chronic GVHD severity, overall severity of symptoms, and change in symptom severity compared with 1 month ago, using the same response options used by clinicians.

The exact role of global scales in chronic GVHD response assessments and their appropriate use as outcome measures in clinical trials remains to be determined. These scales could be sensitive to qualitative changes that might otherwise escape detection if the assessments were limited to quantitative measures.

HAP 

Recommended patient-reported measures of functional status include the HAP questionnaire (for adults) and the Activities Scale for Kids questionnaire (for children age 5-15 years) [19, 23, 24, 25]. The HAP is a measure of physical activity. The 94 questions are ranked hierarchically in ascending order according to the metabolic equivalents of oxygen consumption required to perform each activity [19]. The HAP, therefore, provides a survey of the activities the patient performs independently across a wide range of metabolic demand, beginning with getting out of bed, bathing, dressing, walking using public transit, performing a series of progressively more physically demanding household chores, and ending with running or jogging 3 miles in 30 minutes or less. The recommended corollary instrument to measure self-reported function in children is the Activities Scale for Kids [23, 24, 25].

Performance scales 

The Karnofsky Performance Scale is commonly used in clinical assessments of chronic GVHD and has prognostic value for survival [60]. Whether a clinician assessment that combines performance, health status, and impairment is a valid, reliable, or sensitive tool to gauge response after therapy for chronic GVHD remains to be determined. Performance scores should nonetheless be recorded as part of each assessment. Lansky Play Performance Scale scores should be recorded for children younger than 16 years [26].

Complete organ response 

The term “complete organ response” indicates resolution of all reversible manifestations related to chronic GVHD in a specific organ.

Partial organ response 

The proposed general guideline for defining partial response in specific organ requires at least 50% improvement in the scale used to measure disease manifestations related to chronic GVHD. This guideline was selected as unequivocally indicating genuine clinical benefit. The criterion of 50% improvement requires some adjustment in cases where the extent of abnormality at the baseline measurement is low. For example, there would be no question that a 50% decrease in rash from 80% of BSA to 40% represents genuine clinical improvement. On the other hand, the same 50% decrease from 5% of BSA to 2.5% would represent a much less compelling clinical improvement. For this reason, when the extent of abnormality at the baseline measurement is lower than the midpoint on the scale, the minimum criterion for response should be defined as percentage (eg, 25%) of the full scale as opposed to a percentage of the starting value. To be consistent, if the extent of abnormality at the baseline measurement is lower than the minimum percent of full-scale change needed to define a partial response (eg, 25% of the full scale), then the only possible response would be a complete response.

Organ progression 

Criteria for progression in each organ must be defined, because the overall category of partial response requires the absence of progression in any organ (see below). For an organ affected by chronic GVHD at the baseline evaluation, the proposed general guideline for defining progression specifies an absolute increase of at least 25% in the scale used to measure disease manifestations related to chronic GVHD. Progression cannot be scored for manifestations with baseline values that are within 25% of the full-scale value. When baseline measures of chronic GVHD severity are 50% to 75% of full scale at baseline, the criteria for improvement require more than a 50% change from baseline (which produces more than a 25% of full-scale change), whereas a 25% of full-scale change is sufficient for progression. This asymmetry in the minimal criteria for improvement and progression is intended to ensure a high level of confidence that any improvement is clinically meaningful and to ensure early detection of any deterioration.

Proposed guidelines for calculating partial response and progression and instructions for use by study coordinating centers are available on the World Wide Web at: http://www.asbmt.org/GvHDForms.htm (Appendices C and D). The criteria proposed in these guidelines are admittedly arbitrary, because in most cases, they have never been validated for patients with chronic GVHD, and the distribution of baseline scores is unknown. For these reasons, the proposed criteria are provisional and subject to change with further clinical experience. Also, depending on the stringency of response definitions required by the specific study, these general guidelines could be modified to fit the needs of a particular protocol. Because the criteria are subject to change, we strongly recommend that data report forms should always record the actual numeric values for any measurement.

Limitations in measurement of organ responses 

The response criteria in Appendix C do not account for qualitative changes. Clinical experience indicates that clinically important qualitative improvement often occurs before improvement in the measures summarized in Appendix C. For this reason, the response criteria in Appendix C should not be used as the primary guide for clinical decisions. Certain organs are not considered in Appendix C because quantitative assessments are not feasible. The response criteria also do not account for the prior trajectory of abnormalities. For example, stable disease might be considered a response when the prior trajectory was clear progression, as indicated, for example, by serial pulmonary function tests. Stable disease after prior improvement could not be considered a favorable outcome, and stable disease after prior stability cannot be considered a response.

Standardized response criteria for BOS associated with chronic GVHD have never been investigated. The hallmark of response to therapy for BOS is stabilization of lung function with no further decrease in FEV1 during a 3-month period. A few cases of improved FEV1 after therapy for BOS have been reported, but these outcomes could reflect disease misclassification or very early treatment.

Definitions of overall response 

Three general overall categories of response are proposed: complete response, partial response, and other. Although the group recognizes the complete and partial responses as the categories of greatest interest, other summary outcomes such as stable disease or mixed response can be also included in clinical trials. Complete overall response is defined as resolution of all reversible manifestations in each organ or site, and partial overall response is defined as improvement in a measure for at least one organ or site without progression in measures for any other organ or site. We do not propose the routine use of the term “stable disease” because the interpretation depends too heavily on the prior trajectory of the disease, as discussed above.