Biology of Blood and Marrow Transplantation 12:252-266 (2006)
`© 2006 American Society for Blood and Marrow Transplantation
`I 083-8791 /06/ I 203-0002$32.00/0
`doi: I 0.10I6/j.bbmt.2006.01.008
`
`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
`
`Steven Z. Pavletic, 1 Paul Martin, 2 Stephanie J. Lee,3 Sandra Mitchell, 1 David Jacobsohn,4
`Edward W Cowen, 1 Maria L. Turner, 1 Gorgun Akpek, s Andrew Gilman, 6 George McDonald, 2
`Mark Schubert, 2 Ann Berger, 7 Peter Bross, 8 Jason W Chien, 2 Daniel Courie!, 9 J. P. Dunn, 10
`Jane Fall-Dickson, 11 Ann Farrell, 8 Mary E. D. Flowers, 2 Hildegard Greinix, 12 Steven Hirschfeld, 8
`Lynn Gerber, 7 Stella Kim,9 Robert Knobler, 12 Peter A. Lachenbruch, 8 Frederick W Miller, 13
`Barbara Mittleman, 14 Esperanza Papadopoulos, 1 s Susan K. Parsons, 16 Donna Przepiorka, 17
`Michael Robinson, 18 Michael Ward, 14 Biyce Reeve, 1 Lisa G. Rider, 13 Howard Shulman, 2
`Kirk R. Schultz, 19 Daniel Weisd01f, 20 Georgia B. Vogelsang1°
`
`1National Cancer Institute, National Institutes of Health, Bethesda, Maryland; 2Fred Hutchinson Cancer Research
`Center, University of Washington School of Medicine, Seattle, Washington; 3Dana-Farber Cancer Institute,
`Boston, Massachusetts; 4Children's Memorial Hospital, Northwestern University School of Medicine, Chicago,
`Illinois; 5University of Maryland School of Medicine, Baltimore, Maryland; 6University of North Carolina School
`of Medicine, Chapel Hill, North Carolina; 7Warren Grant Magnuson Clinical Center, National Institutes of
`Health, Bethesda, Maryland; 8US Food and Drug Administration, Rockville, Maryland; 9University of Texas M.D.
`Anderson Cancer Center, Houston, Texas; 10Johns Hopkins University School of Medicine, Baltimore, Maryland;
`11 National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland; 12Medical University
`of Vienna, Austria; 13National Institute of Environmental Health Sciences, National Institutes of Health, Bethesda,
`Maryland; 14National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland; 15Memorial
`Sloan-Kettering Cancer Center, New York, New York; 16Tufts-New England Medical Center, Boston,
`Massachusetts; 17University of Tennessee, Memphis, Tennessee; 18National Eye Institute; National Institutes of
`Health; Bethesda, Maryland; 19University of British Columbia, British Columbia Children's Hospital, Vancouver,
`British Columbia, Canada; 20University of Minnesota, Minneapolis, Minnesota
`
`Correspondence and reprint requests: Steven Z. Pavletic, MD, Graft-versus-Host and Autoimmunity Unit,
`Experimental Transplantation and Immunology Branch, National Cancer Institute, 9000 Rockville Pike, Bethesda,
`MD 20892-1203 (e-mail: pavletis@mail.nih.gov).
`
`Received January 1 7, 2 006; accepted January 18, 2 006
`
`ABSTRACT
`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 (http://www.asbmt.org/
`GvHDForms). 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
`
`252
`
`Pharmacyclics Exhibit 2048
`Sandoz v. Pharmacyclics
`IPR2019-00865
`
`

`

`Response Criteria in Chronic GVDH
`
`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.
`© 2006 American Society fo1· Blood and Mai7ow Tmnsplantation
`
`KEY WORDS
`Chronic graft-versus-host disease
`sensus
`
`• Allogeneic cell transplantation
`
`• Response criteria
`
`• Con(cid:173)
`
`INTRODUCTION
`
`Overall survival or survival to permanent resolu(cid:173)
`tion of chronic graft-versus-host disease (GVHD) and
`discontinuation of systemic immunosuppression are
`long-term clinical outcomes that are accepted major
`end points in chronic GVHD clinical trials [1-3], but
`these long-term outcomes are not suitable for early(cid:173)
`phase studies. Qualitative assessments of chronic
`GVHD manifestations can guide clinical decisions but
`are not adequate for measuring outcomes in clinical
`trials. To accelerate development of novel therapeutic
`agents in chronic GVHD, quantitative research tools
`are needed to measure short-term responses to treat(cid:173)
`ment and to predict long-term clinical benefit.
`The lack of standardized quantitative response cri(cid:173)
`teria poses one of the major obstacles in pursuing
`therapeutic trials for chronic GVHD [4]. No gener(cid:173)
`ally accepted, much less validated, quantitative criteria
`for organ-specific or overall responses have been de(cid:173)
`veloped previously. The definitions of response typi(cid:173)
`cally used in previous studies have been global and
`qualitative in nature, with considerable variability
`from one study to the next ( extensively reviewed by
`Gorgun Akpek in Attachment 1 at http://www.asbmt.
`org/GvHDForms). In addition, methods have not
`been developed to account for the distinction between
`reversible disease activity and irreversible damage.
`Because no currently available database has infor(cid:173)
`mation from patients with chronic GVHD at a suffi(cid:173)
`cient level of detail, retrospective methods could not
`be used to identify clinical characteristics that are
`sensitive to change and predictive for major outcomes.
`The Working Group began by reviewing instruments
`currently used by hematopoietic stem cell transplan(cid:173)
`tation physicians at Johns Hopkins, Children's Oncol(cid:173)
`ogy Group, Fred Hutchinson Cancer Research Cen(cid:173)
`ter, Harvard University, University of Minnesota, and
`National Institutes of Health. The Working Group
`also included specialists from other fields, including
`rheumatology and gastroenterology, to benefit from
`their experiences in developing and using chronic dis(cid:173)
`ease activity indices and response criteria in clinical
`trials [5-8].
`This document is based on a broad consensus of
`experts and on the use of the best available data. These
`2005 recommendations are intended to advance stan(cid:173)
`dards of chronic GVHD therapeutic trials, but they
`remain provisional and will need to be validated and
`
`refined according to data emerging from prospective
`studies. The Working Group could not entirely re(cid:173)
`solve certain intrinsic tensions between divergent
`goals. On the one hand, the assessments should be as
`simple as possible to facilitate their use by clinicians
`outside the field of hematopoietic cell transplantation,
`but on the other hand, the assessments should contain
`as much information as possible to support research.
`The former goal would require immediate item re(cid:173)
`duction and enforcement of consistency based on ex(cid:173)
`pert opinion, whereas the latter goal would encourage
`further exploration, with deferral of item reduction
`until data are available. For certain organs, the Work(cid:173)
`ing Group could not identify quantitative measures
`that would be suitable for use in clinical trials, even
`though qualitative assessments can be used for clinical
`management. In the end, the Working Group pro(cid:173)
`posed a broad set of assessment measures that should
`be feasible in most academic settings, although some
`simplification might be needed if the assessments are
`to be used by medical providers outside the field of
`hematopoietic cell transplantation.
`The differences between this document and the
`Diagnosis and Staging document should be noted [9].
`Although there is appearance of some overlap, char(cid:173)
`acteristics that could help establish the diagnosis of
`chronic GVHD or to assess the severity of chronic
`GVHD at a single time point might not serve as the
`most appropriate or sensitive measures for chronic
`GVHD disease activity. Conversely, a sensitive mea(cid:173)
`sure of chronic GVHD response might not necessarily
`serve as an appropriate diagnostic and staging tool.
`
`PURPOSE OF THIS DOCUMENT
`
`This document summarizes proposed measures
`and criteria for assessing outcomes in clinical trials
`involving patients with chronic GVHD. The mea(cid:173)
`sures and criteria do not necessarily reflect practices
`that might apply to routine patient care or to trials
`with limited resources. The measures and response
`criteria were developed to meet certain requirements.
`1. The instruments should be easy to use by both transplan(cid:173)
`tation and nontransplantation care providers and should
`be limited to testing methods that are available in the
`outpatient setting.
`2. The criteria should be adaptable for use in adults and in
`children.
`
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`S. Prwletic et nl.
`
`3. The i11strument should focus on the nzost important and
`most comnzo11 manifestations of chronic GVHD and
`should not be designed to chai"acterize all possible clinical
`manifestations.
`4. D evelopment should focus on quantitative measures as
`much as possible.
`5. Measurements of symptoms, signs, global ratings, func(cid:173)
`tion, quality of life, or peifomzance status should be
`made separately, and scales with established psychometric
`characteristics and desirable measurement properties
`should be used whenever possible [10, 11}.
`6. With appropriate refinements and reliability and vali(cid:173)
`dation assessments, these tools should be suitable for use
`in clinical trials where the goals are to improve patient
`outcomes or to obtain regulatory apprnval.
`The Working Group had 3 additional goals: (1) to
`propose provisional definitions of complete response,
`partial response, and disease progression for each or(cid:173)
`gan and for overall response; (2) to suggest appropri(cid:173)
`ate strategies for using short-term end points in ther(cid:173)
`apeutic clinical trials; and (3) to outline future research
`directions.
`
`SUMMARY OF RECOMMENDATIONS
`
`1. Proposed chronic GVHD-specific core measures
`include:
`A. Clinician- or patient-assessed signs and symp(cid:173)
`toms.
`B. The chronic GVHD symptom scale by Lee
`et al [12] .
`C. The clinician- or patient-reported global rating
`scales (Table 1) [12-14] .
`To facilitate validation studies, continuous data
`should be recorded as such and should not be reduced
`to prespecified categories.
`2. Proposed chronic GVHD nonspecific ancillary
`measures for adults include:
`A. Measurement of grip strength [15-1 7] and
`2-minute walk time [18].
`
`B. Patient-reported Human Activity Profile (HAP)
`questionnaire [19] .
`C. Clinician-assessed Karnofsl? performance sta(cid:173)
`tus.
`D . The SF-36 version 2 questionnaire [20,21] and
`FACT-EMT for quality-of-life assessments
`(Table 1) [22] .
`The ancillary chronic GVHD nonspecific mea(cid:173)
`sures are optional and should not be used as primary
`end points in chronic GVHD trials.
`3. Age-appropriate modifications of existing measures
`should be used and explored in children with
`chronic GVHD [23-29] .
`4. Definition of response involves a comparison of
`chronic GVHD activity at two different time
`points. Provisional definitions of complete re(cid:173)
`sponse, partial response, and progression are of(cid:173)
`fered for each organ and for overall outcomes.
`Simple forms to be used for clinician and patient
`assessments are provided in Appendices A and Bat
`http://www.asbmt.org/GvHDForms (Forms A and
`B). In each specific trial, irreversible baseline organ
`damage may be defined initially and tl1en excluded
`in response assessments.
`5. Measures should be made at 3-month intervals and
`whenever a major change is made in treatment.
`Permanent discontinuation of systemic immuno(cid:173)
`suppressive treatment indicates a durable response.
`6. Furtl1er assistance from subspecialists will be
`needed to develop organ- or site-specific measures
`tl1at could improve the sensitivity of chronic
`GVHD assessments. Specific organ or site assess(cid:173)
`ments discussed by the Working Group include tl1e
`following:
`A. Skin: skin-specific scoring systems [30] , durom(cid:173)
`eter [30-32], biopsy [31], or imaging (ultra(cid:173)
`sound, magnetic resonance imaging) [33,34] .
`B. Eyes: corneal staining grading [3 5], conjunc(cid:173)
`[3 6], ocular surface disease
`tival grading
`index [3 7] .
`
`Table I. Pi-oposed Menmres fa,· Assessi11g Respo11ses in Chro11ic GVHD Trinls
`
`Measure
`
`Clinician Assessed
`
`Patient Reported
`
`I. Chronic GVHD-specific core measures
`Signs
`Organ-specific measures
`Symptoms
`Clinician-assessed symptoms
`Global rating
`Mild-moderate-severe [12]
`0-10 severity scale [13]
`7-point change scale [14]
`II. Chronic GVHD-nonspecific ancillary measures
`Function
`Grip strength [ 15-17]
`2-min walk time [ 18]
`Karnofsky or Lansky [26]
`
`Performance status
`Quality of life
`
`N/A
`Patient-reported symptoms Lee symptom scale [ 12]
`Mild-moderate-severe [ 12]
`0-10 severity scale [ 13]
`7-point change scale [14]
`
`HAP [19]
`ASK in children [23-25]
`
`SF-36v.2 [20,21] or
`FACT-BMT [22] in adults
`CHRls in children [27-29]
`
`ASK indicates Activities Scale for Kids; GVHD, graft-versus-host disease; NIA, not applicable; HAP, Human Activity Profile; CHRIS, Child
`Health Ratings Inventories.
`
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`

`Response Criteria in Chronic GVDH
`
`C. Oral: Oral Mucositis Rating Scale [38).
`D. Vulvar-vaginal : organ-specific staging [39,40] .
`E . Function: range of motion, limb volume, fa(cid:173)
`tigue severity scale (41-43].
`
`PROPOSED MEASURES OF CHRONIC GVHD
`RESPONSE ASSESSMENTS
`
`The Working Group distinguished between
`chronic GVHD-specific core measures that directly
`measure organ-specific manifestations of chronic
`GVHD and nonspecific ancillary measures, which
`could reflect the overall impact of chronic GVHD and
`otl1er illness on functioning or quality oflife (Table I).
`In future studies, these measures should be evaluated
`for construct validity (for Glossary see Attachment 2
`at: http://www.asbmt. org/GvHDForms) and potential
`item reduction. In a feasibility study, 8 clinicians who
`had never previously used the assessment forms eval (cid:173)
`uated 4 adults with chronic GVHD (44). The median
`time for each clinician evaluati on was 36 minutes, and
`the median time needed to complete the panel of
`patient self-report items was 14 minutes. Results of
`tl1is evaluation offered preliminary evidence of reli(cid:173)
`ability, feasibility, and acceptability of the newly pro(cid:173)
`posed measures.
`
`PROPOSED CLINICIAN-ASSESSED
`AND PATIENT-REPORTED CHRONIC
`GVHD-SPECIFIC MEASURES
`
`The following sections describe the recommended
`clinician-assessed and patient-reported chronic GVI--ID(cid:173)
`specific measures (Table 2). Specific pediatric consid(cid:173)
`erations for such situations are highlighted where ap(cid:173)
`propriate. For the assessment of symptoms in younger
`children, depending on the child's development, assis(cid:173)
`tance can be provided by tl1e health care provider or
`the parent. The Working Group also recommends
`formal in-person training for all assessments to min(cid:173)
`interobserver variability.
`intraobserver and
`imize
`Instructional manual and slide set to assist wi th
`such training are available at http://www.asbmt.org/
`GvHDForms.
`
`Organ-specific Assessments
`Skin and skin appendages. Skin is tl1e most fre(cid:173)
`quently affected organ in chronic GVHD, and mani(cid:173)
`festations are highly variable. Skin assessments are
`structured to reflect 4 anatomic levels of skin involve(cid:173)
`ment: (I) erytl1ematous rash (epiderma l involvement);
`(2) movable sclerosis (dermal involvement); (3) non(cid:173)
`moveable sclerosis, hidebound skin, or involvement of
`
`Table 2. Proposed Cli11icir111-Assessed mu/ Pntient-Repo1ted Chrnnic GI/HD-Specific Measures
`
`Component
`
`Items Assessed
`
`Measure
`
`Assessor
`
`Skin
`
`Eyes
`
`Mouth
`
`Hematology
`
`GI
`
`Liver
`
`Lungs
`Chronic GVHD symptom scale [ 12]
`Global activity rating
`
`Erythematous rash of any sort
`Movable sclerosis
`Nonmoveable sclerosis or subcutaneous
`sclerosis/fasciitis
`Ulcers
`
`Pruritus or itching
`Bilateral Schirmer's tear test scores without
`anesthesia
`Main ocular symptom at the time of t he visit
`Erythema
`Lichen-type hyperkeratosis
`Ulcerations
`Mucoceles
`Symptoms of o ral pain, dryness, sensitivity
`Platelet count
`Eosinophils
`Upper GI symptoms
`Esophageal symptoms
`Diarrhea
`Total serum bilirubin
`ALT, alkaline phosphatase
`Bronchiolitis obliterans syndrome
`30 items, 7 subscales, I summary scale
`Severity of chronic GVHD symptoms
`Perception of change
`Overall severity of chronic GVHD
`
`% Body surface area
`0%- 1 00% For each feature
`By using rule of nines
`
`Largest dimension (cm) of
`the largest ulcer
`0-10 Scale
`Mean of both eyes, mm
`
`0-10 Scale
`Total score 0-1 5
`
`0-10 Scale
`Number/µL
`Percent
`0-3 Score
`0-3 Score
`0-3 Score
`mg/dL
`U/L
`FEV ,, DLCO
`0- 100
`0- 10
`+3 to -3
`Mild - moderate-severe
`
`C
`C
`C
`
`C
`
`p
`C
`
`p
`C
`C
`C
`C
`p
`C
`C
`C
`C
`C
`C
`C
`C
`p
`C/P
`C/P
`C/P
`
`ALT indicate alanine aminotransferase; C, assessed by the clinician; DLCO, diffusion lung capacity for carbon monoxide; FEV,, forced
`expiratory volw11e in the first second; GI, gastrointestinal; GVHD, graft-versus-host disease; P, reported by the patient.
`Vulvar-va ginal symptoms (yes or no) and patient weight should be recorded at each visi t.
`Range of motion of the most affected joints should be recorded depending on the availabili ty of a physical therapist.
`
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`

`S. Pnvletir et nl.
`
`C
`
`Figure I . Skin manifestations assessed for response in chronic GVHD. A, Erythematous papular rash. B, Erythemarous 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.
`
`subcutaneous tissue and fascia (subcutaneous involve(cid:173)
`ment); and (4) ulceration (full thickness loss of epider(cid:173)
`mal tissue) (Figure 1). Abnormalities for the first 3
`points are each assessed separately according to the
`percent of body surface area (BSA) involved as esti(cid:173)
`mated 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 tl1e largest ulcer.
`The term "erytl1ematous 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, poikilo(cid:173)
`derma, and keratosis pilaris-like rashes. The term "li(cid:173)
`chenoid" is not used, because this is a histopatl1ologic
`diagnosis, not a clinical descriptive term.
`Likewise, me term "sclerosis" or "sclerotic" is used
`to represent me general category of cutaneous GVHD
`findings associated wim skin fibrosis, and to avoid
`confusion with the autoimmune disorder scleroderma.
`Superficial sclerosis (moveable) includes both lichen
`sclerosus-like and morphea-like lesions. Deep sclero(cid:173)
`sis includes diffuse, immovable (hidebound) sclerosis
`involving a wide area of skin, fibrosis of subcutaneous
`fat septae (rippling), and fasciitis (groove sign). Scle(cid:173)
`rotic skin manifestations may be as variable as the
`
`256
`
`superficial form of the disease and are difficult to
`measure reliably. Sclerotic changes respond slowly to
`therapy and progression or regression of sclerotic le(cid:173)
`sions ideally should be assessed not only according to
`the total surface area involved but also according to
`the depm 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 tluckening, pliability,
`adherence to underlying tissues, or changes in joint mo(cid:173)
`bility. No validated scale exists for assessing sclerotic skin
`changes of chronic GVHD. Measures such as the Rod(cid:173)
`nan score for assessment of systenuc sclerosis nught be
`helpful for clinical evaluation of chronic GVHD, but this
`scale does not measure lichen sclerosus-like changes,
`subcutaneous involvement without overlying skin tluck(cid:173)
`ening, or fascial involvement. For this reason, the Rod(cid:173)
`nan score is not suitable for use in clirucal 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 communica(cid:173)
`tion, December 2005). There is an urgent need for the
`development of more quantifiable and reproducible
`measurements or imaging methods mat could be used in
`patients with sclerotic skin manifestations of chrmuc
`GVHD [30-34].
`
`

`

`Pigmentary changes do not indicate act1v1ty 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 de(cid:173)
`scribed 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 l -to-10 scale, because itching is the
`most frequent cutaneous symptom of chronic GVHD.
`The rule of nines as an estimate of BSA involve(cid:173)
`ment 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 (At(cid:173)
`tachment 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 sepa(cid:173)
`rately, as recommended by the Sjogren'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 destruc(cid:173)
`tion. Instructions for administration of the Schirmer's
`test are provided with the instructional manual at:
`http:/ /www.asbmt.org/GvHD Farms.
`The patient symptom intensity self-report profile
`includes the chief eye complaint rated according to a
`l-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, oc(cid:173)
`ular symptoms in patients with chronic GVHD can
`have causes other than chronic GHVD.
`Schirmer's test without anesthesia is not recom(cid:173)
`mended for children younger than 9 years, and eval(cid:173)
`uation by an ophthalmologist may be needed for ob(cid:173)
`jective 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 in(cid:173)
`volvement. The 4 chronic GVHD manifestations as(cid:173)
`sessed in this scale include: (1) mucosa] erythema (0-3)
`grading based on the color intensity; (2) lichen-type
`hyperkeratosis (percent of oral surface area); (3) ulcer(cid:173)
`ations (percent of oral surface area); and (4) presence
`of mucoceles (total number) (Figure 2). Instructions
`
`Response Criteria in Chronic GVDH
`
`for these assessments and a photo dictionary are pro(cid:173)
`vided in the instructional manual on the ~ lorld Wide
`Web: http:/ /www.asbmt.org/GvHDF arms.
`The patient self-report symptom intensity profile
`includes dry mouth (subjective decrease in oral wet(cid:173)
`ness), 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 l-to-10 scale for peak severity during
`the past week.
`Hematopoietic. Parameters to be evaluated for re(cid:173)
`sponse 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) symp(cid:173)
`toms 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 ac(cid:173)
`cording to 0-to-3 severity scales. For upper GI symp(cid:173)
`toms of early satiety, anorexia, nausea , and vomiting, a
`score of I indicates mild, occasional symptoms, with
`little reduction in oral intake. A score of 2 indicates
`moderate, intermittent symptoms, with some reduc(cid:173)
`tion in oral intake, and a score of 3 indicates more
`severe or persistent symptoms tlrroughout the day,
`with marked reduction in oral intake on most days.
`For esophageal symptoms of dysphagia or odynopha(cid:173)
`gia, 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 I indicates occasional
`loose or liquid stools, on some days. A score of 2
`indicates intermittent loose or liquid stools through(cid:173)
`out the day without requiring inten,ention to prevent
`or correct volume depletion, and a score of 3 indicates
`voluminous diarrhea requiring intervention to prevent
`or correct volume depletion.
`Patients witl1 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 evalua(cid:173)
`tion, given tl1e simplicity of this measure and its po(cid:173)
`tential importance for monitoring the success of ther(cid:173)
`apy.
`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)
`
`BB&MT
`
`257
`
`

`

`S. Pavletic et al.
`
`Fi gure 2. Oral manifestations assessed for response in chronic GVHD. A, Moderate erythema of vermi lion lip. Labial mucosa shows severe
`erythema. B, Area of sheetlike lichenoid hyperkeratosis is present inside commissure. C, U lcer with pseudomembranous fibrin exudates
`surr01mded by severe erythema . D , Numerous vesicle-like mucoceles are seen at center of the palate, with patches of lichenoid hyperkeratosis
`and moderate erythematous changes.
`
`after therapy are forced expiratory volume in the first
`second (FEV1) and single breath diffusion lung capac(cid:173)
`ity for carbon monoxide (DLCO) adjusted for hemo(cid:173)
`globin, both of which are included in standard pulmo(cid:173)
`nary 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 mod(cid:173)
`ified LFS is proposed as a simple measure of changes
`in the lung function in patients ,-,jth BOS (see Table
`3). Pulmonary function tests should be performed in
`children who are older than 5 years.
`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 assess(cid:173)
`ments, and its exact role in this setting needs to be
`
`258
`
`determined. To allow validation in trials, absolute
`values of both FEV1 and DLCO should be recorded
`on t!1e 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 inter(cid:173)
`ested in chronic GVHD are developing precise vul(cid:173)
`vovaginal assessment scales. These scales will be useful
`
`Table 3. Categories of the Lung Fimctio11 Score
`
`Category
`
`Lung Function
`
`I
`II
`Ill
`IV
`
`Normal
`Mild decrease
`Moderate decrease
`Severe decrease
`
`LFS
`
`2
`3-5
`6-9
`I 0-1 2
`
`

`

`in selected trials where vulvar and vaginal changes are
`the primary end points of interest [39,40].
`tissue. Active-assisted
`Musculoskeletal connective
`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 stan(cid:173)
`dardized 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].
`
`Chronic GVHD Symptoms
`Lee et al [12] developed a symptom scale designed
`for individuals with chronic GVHD. The question(cid:173)
`naire asks respondents to indicate the degree of bother
`that they experienced during the past 4 weeks as a
`result of symptoms in 7 domains potentially affected
`by chronic GVHD (skin, eyes and mouth, breathing,
`eating and digestion, muscles and joints, energy, emo(cid:173)
`tional distress). Published evidence supports its valid(cid:173)
`ity, reliability, and sensitivity to chronic GVHD se(cid:173)
`verity. Items in this symptom scale can be reported in
`approximately 5 minutes.
`The Lee chronic GVHD symptom scale has been
`tested only in individuals older than 18 years. Given
`its face validity and other desirable properties, how(cid:173)
`ever, this scale could be used for assessment of chronic
`GVHD in pediatric patients using either child or
`parent report, after appropriate modification and psy(cid:173)
`chometric evaluation [52]. Information for the chronic
`GVHD symptom scale could be obtained by self(cid:173)
`report from adolescents older than 12 years. For chil(cid:173)
`dren who are 8 to 12 years of