KJH
`THE KOREAN JOURNAL OF HEMATOLOGY
`~
`
`R E V I E W A R T I C L E
`
`V O L U M E 4 6 (cid:564) N U M B E R 3 (cid:564) S e p te m b e r 2 0 1 1
`
`Treatment of chronic graft-versus-host disease: Past, present and
`future
`Paul J. Martin1,2, Yoshihiro Inamoto1,2, Paul A. Carpenter1,3, Stephanie J. Lee1,2, Mary E.D. Flowers1,2
`1Division of Clinical Research, Fred Hutchinson Cancer Research Center, Departments of 2Medicine and 3Pediatrics, University of
`Washington, Seattle, WA, USA
`
`p-ISSN 1738-7949 / e-ISSN 2092-9129
`http://dx.doi.org/10.5045/kjh.2011.46.3.153
`Korean J Hematol 2011;46:153-63.
`
`Received on August 12, 2011
`Accepted on August 19, 2011
`
`*This study was supported by research
`grant CA98906 from the National
`Institutes of Health, Department of Health
`and Human Services. Y.I. is a recipient of
`the JSPS Postdoctoral Fellowships for
`Research Abroad.
`
`Correspondence to
`Paul J. Martin, M.D.
`Fred Hutchinson Cancer Research Center,
`P.O. Box 19024, Seattle, WA 98109-1024,
`USA
`Tel: (cid:1024)1-206-667-4798
`Fax: (cid:1024)1-206-667-5255
`E-mail: pmartin@fhcrc.org
`(cid:59926) 2011 Korean Society of Hematology
`
`Chronic GVHD was recognized as a complication of allogeneic hematopoietic cell
`transplantation more than 30 years ago, but progress has been slowed by the limited
`insight into the pathogenesis of the disease and the mechanisms that lead to development
`of immunological tolerance. Only 6 randomized phase III treatment studies have been
`reported. Results of retrospective studies and prospective phase II clinical trials suggested
`overall benefit from treatment with mycophenolate mofetil or thalidomide, but these
`results were not substantiated by phase III studies of initial systemic treatment for chronic
`GVHD. A comprehensive review of published reports showed numerous deficiencies in
`studies of secondary treatment for chronic GVHD. Fewer than 10% of reports
`documented an effort to minimize patient selection bias, used a consistent treatment
`regimen, or tested a formal statistical hypothesis that was based on a contemporaneous
`or historical benchmark. In order to enable valid comparison of the results from different
`studies, eligibility criteria, definitions of individual organ and overall response, and time
`of assessment should be standardized. Improved treatments are more likely to emerge
`if reviewers and journal editors hold authors to higher standards in evaluating manuscripts
`for publication.
`
`Key Words Chronic graft-versus-host disease, Treatment, Phase II clinical trials, Review
`
`INTRODUCTION - THE PAST
`
`Allogeneic hematopoietic cell transplantation (HCT) is
`frequently complicated by acute and chronic graft-versus-
`host disease (GVHD) [1, 2]. Although considerable progress
`has been made in the development of methods to prevent
`or treat acute GVHD, similar progress in chronic GVHD
`has languished by comparison after the clinical and
`pathologic features of this syndrome were first described
`in 1980 [3]. Interest in this debilitating complication of HCT
`was rejuvenated when recommendations of the National
`Institutes of Health Consensus Conference on Criteria for
`Clinical Trials in Chronic Graft-versus-host disease were
`published in 2005-2006 [4-9].
`The Consensus Conference recognized two major cate-
`gories of GVHD, each with 2 subcategories [4]. Acute GVHD
`with onset before day 100 was defined as “classic GVHD.”
`A separate category was recognized for persistent, recurrent
`
`or late-onset acute GVHD beyond day 100 after HCT.
`Chronic GVHD was separated from acute GVHD not by
`time from HCT but by the presence of diagnostic criteria
`or by distinctive findings supported by biopsy or other
`procedures. Classic chronic GVHD was defined by unam-
`biguous chronic GVHD manifestations in the absence of
`abnormalities such as cutaneous erythema, liver function
`abnormalities, or gastrointestinal manifestations typical of
`acute GVHD. “Overlap syndrome” is a subcategory of chronic
`GVHD characterized by chronic GVHD in the presence of
`one or more manifestations typical of acute GVHD.
`Chronic GVHD is a pleomorphic syndrome with “auto-
`immune” features that sometimes resemble clinical findings
`in scleroderma and Sjögren syndrome. The onset usually
`occurs between 3 and 15 months after HCT [10-13]. Risk
`factors associated with an increased risk of chronic GVHD
`include the use of a mobilized blood cell graft or an
`HLA-mismatched or unrelated donor, older patient age and
`a history of acute GVHD [12]. The risk of chronic GVHD
`
`0 0 0
`This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0)
`which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
`
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`154
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`Paul J. Martin, et al.
`
`can be decreased by exhaustive depletion of T cells from
`the graft or by treatment of the recipient with rabbit
`antibodies specific for human T cells as part of the con-
`ditioning regimen before HCT [12, 14, 15]. Without these
`measures, approximately 30% to 50% of HCT recipients
`develop chronic GVHD [2, 16].
`Chronic GVHD can affect multiple organs and sites, in-
`cluding the skin and subcutaneous connective tissues,
`lacrimal and salivary glands, oral mucosa, lungs, esophagus,
`joints, gastrointestinal tract and liver. The disease is char-
`acterized by immune dysfunction with an increased risk
`of infections and a 30% to 50% risk of mortality during
`the first 5 years after diagnosis [10, 11]. Chronic GVHD
`has been associated with a reduced risk of recurrent
`malignancy after HCT [17-22], but despite this benefit,
`survival is not improved [22]. A prognostic scoring system
`has recently been proposed based on factors present at the
`time of chronic GVHD diagnosis [13].
`
`PRINCIPLES OF TREATMENT - THE PRESENT
`
`To date, only 6 randomized phase III studies have ever
`been reported for initial treatment of chronic GVHD [23-28].
`The study by Koc et al. [26] was the only one that indicated
`benefit. Results of this study suggested that treatment with
`cyclosporine reduced the amount of glucocorticoid treatment
`needed to control the disease, as indicated by a decreased
`frequency of avascular necrosis. The generally recommended
`approach for treatment of chronic GVHD involves continued
`administration of the calcineurin inhibitor used for GVHD
`prophylaxis together with prednisone initially at 1 mg/kg/day
`[2, 29, 30]. Strategies for tapering the dose of prednisone
`vary considerably, but as a general principle, efforts should
`be made to use the minimum dose that is sufficient to control
`GVHD manifestations. At our center, the dose of prednisone
`is tapered to an alternate-day schedule of administration
`after initial clinical improvement, which generally occurs
`within 6 weeks after starting treatment. The dose of prednisone
`is then tapered to 0.5 mg/kg every other day and generally
`continued until reversible manifestations of the disease resolve.
`The dose of prednisone is then gradually tapered with careful
`monitoring for recurrent manifestations of chronic GVHD.
`Doses of the calcineurin inhibitor are gradually decreased
`after treatment with prednisone has been withdrawn.
`The median duration of treatment for chronic GVHD is
`approximately 2 years in patients who had HCT with marrow
`cells and approximately 3.5 years in those who had HCT
`with growth factor-mobilized blood cells [31]. The current
`therapeutic approach functions primarily to prevent immune-
`mediated damage, while awaiting the development of toler-
`ance. Evidence to suggest that current treatments accelerate
`the development of immunological tolerance is lacking. The
`mechanisms that facilitate development of tolerance have
`not been defined.
`Administration of medications to prevent infection with
`Pneumocystis jirovecii and encapsulated bacteria is necessary
`
`Korean J Hematol 2011;46:153-63.
`
`during treatment for chronic GVHD [32]. Some patients
`may need topical or systemic treatment to prevent mucocu-
`taneous candida infection. Patients at risk of Varicella zoster
`activation should be given antiviral prophylaxis, and CMV
`monitoring and preemptive treatment is necessary in patients
`at risk of CMV infection [33]. Activation of CMV during
`the first 3 months after HCT suggests an increased risk of
`subsequent reactivation in patients with chronic GVHD.
`Systemic immunosuppressive treatment should be admin-
`istered at the lowest effective dose in order to minimize
`the risk of infections and other complications. Many steroid-
`related complications can be avoided or at least minimized
`by an alternate-day schedule of administration [34], and
`topical treatment can be used to minimize the need for
`systemic treatment [35]. Bone mineral density should be
`monitored yearly, and losses should be minimized through
`weight bearing exercise, administration of calcium and
`vitamin D supplements and hormone replacement.
`Indications for secondary treatment include worsening
`manifestations in a previously affected organ, development
`of manifestations in a previously unaffected organ, absence
`of improvement after 1 month of treatment, or inability
`to decrease the dose of prednisone below 1.0 mg/kg/day
`within 2 months [30, 36]. Numerous clinical trials have been
`carried out to evaluate approaches for secondary treatment
`of chronic GVHD. To date, no consensus has been reached
`regarding the optimal choice of agents for secondary
`treatment, and clinical management is generally approached
`through empirical trial and error [36]. Treatment choices
`are based on physician experience, ease of use, need for
`monitoring, risk of toxicity and potential exacerbation of
`pre-existing co-morbidity.
`
`MYCOPHENOLATE MOFETIL: A CASE STUDY
`ILLUSTRATING CURRENT PROBLEMS
`
`Progress in the clinical management of chronic GVHD
`has been slowed by limited insight into the pathogenesis
`of the disease and the mechanisms that lead to development
`of immunological tolerance. In the absence of pathophy-
`siologic understanding, physicians must rely on personal or
`published empirical experience in making decisions regard-
`ing treatment. In principle, results of treatment in patients
`with “steroid-refractory” or “steroid-resistant” chronic GVHD
`could be used to identify promising agents for initial treat-
`ment. Effective agents would be expected to decrease reliance
`on glucocorticoids and could conceivably decrease the dura-
`tion of time needed for resolution of the disease.
`A variety of retrospective and phase II studies suggested
`that MMF could be used successfully for secondary treatment
`of chronic GVHD. In results of a survey published in 2002,
`nearly 80% of clinicians reported that they had used myco-
`phenolate mofetil (MMF) with great success or at least some
`success for treatment of chronic GVHD [37]. In another survey
`proposing a hypothetical scenario describing a case of high-risk
`chronic GVHD, 54% of the respondents indicated that they
`
`

`

`Treatment of chronic GVHD
`
`155
`
`would add MMF for initial treatment of chronic GVHD [38].
`These results supported a formal test of the hypothesis that
`the addition of MMF to standard initial treatment could
`improve outcomes for patients with chronic GVHD.
`We therefore conducted a prospective, double-blind, ran-
`domized phase III clinical trial to test this hypothesis [27].
`The primary endpoint was resolution of reversible mani-
`festations of chronic GVHD within 2 years after enrollment,
`before death or the onset of recurrent malignancy and
`without the need for secondary systemic treatment. It was
`expected that the use of MMF would shorten the time to
`response, decrease systemic steroid exposure, and decrease
`the risk of transplant-related mortality without increasing
`the risk of recurrent malignancy, thereby potentially im-
`proving overall survival. Results of the trial, however, did
`not show any benefits of treatment with MMF. Potential
`reasons for the negative results were thoroughly explored.
`The absence of success in this randomized trial could not
`be attributed to an imbalance of risk factors between the
`arms, sub-optimal dosing of MMF or non-adherence with
`administration of the study drug. Hence, this clinical trial
`definitively demonstrated that addition of MMF to standard
`initial treatment did not improve outcomes for patients with
`chronic GVHD.
`These unexpected results conflicted with previously pre-
`vailing clinical impressions and motivated a careful review
`of prior reports evaluating the use of MMF for treatment
`of chronic GVHD. Overall results of 9 such studies suggested
`that secondary treatment with MMF produced a 20%
`complete response rate and a 65% complete or partial
`response rate (Table 1) [39-47]. One of these studies also
`evaluated results in 10 patients who received MMF as part
`of the initial treatment regimen for chronic GVHD [45].
`Seven of the 10 patients had a complete response, and 2
`had a partial response, yielding an overall 90% rate of
`complete or partial response. In addition, a further study
`from our center had shown that the proportion of patients
`who discontinued systemic immunosuppressive treatment
`after resolution of reversible abnormalities increased pro-
`gressively from 9% to 17% and 26% at 1, 2 and 3 years,
`respectively, after starting treatment with MMF [48].
`Similar discrepancies have been observed in studies to
`
`Table 1. Response rates in prior studies of mycophenolate mofetil.
`
`Study
`
`Type
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`
`Retrospective
`Prospective
`Prospective
`Prospective
`Retrospective
`Retrospective
`Retrospective
`Retrospective
`Prospective
`Total
`
`N
`
`26
` 5
`21
`15
`11
`13
`13
`24
`11
`139
`
`CR
`
`2
`2
`5
`2
`3
`1
`4
`5
`4
`28 (20%)
`
`PR
`
`10
` 3
` 8
` 7
` 5
` 9
` 5
`13
` 3
`63
`
`CR+PR (%)
`
`12 (46)
`5 (100)
`13 (62)
`9 (60)
`8 (73)
`10 (77)
`9 (69)
`18 (75)
`7 (64)
`91 (65)
`
`evaluate the efficacy of thalidomide for treatment of chronic
`GVHD. Results of 6 retrospective studies and prospective
`phase II clinical trials suggested favorable outcomes with
`the use of thalidomide for secondary treatment of chronic
`GVHD [49-54]. The two randomized prospective studies
`testing the use of thalidomide for primary treatment of
`chronic GVHD, however, showed no benefit [24, 25].
`Results of the randomized trials defied expectations
`coming from at least 16 studies evaluating the use of MMF
`or thalidomide for treatment of chronic GVHD. At least
`2 explanations could be proposed to explain this discrepancy.
`1) Results of secondary treatment might not predict efficacy
`as an added agent for primary treatment, perhaps because
`most patients do not need additional agents in order to gain
`maximal benefit from initial treatment. Experience at our
`center, however, has indicated that systemic treatment is
`changed in approximately 60% of patients during the first
`3 years because of inadequate response to primary therapy
`for chronic GVHD [55]. 2) Alternatively, previous studies
`might have had unrecognized limitations leading to over-
`stated expectations.
`
`PROPOSED QUALITY INDICATORS FOR
`EVALUATING REPORTS
`
`Previous publications have identified quality indicators
`for evaluation of phase III clinical trials [56, 57], but to
`our knowledge, similar quality criteria have not been pre-
`viously proposed for phase II trials and retrospective studies.
`Therefore, before embarking on a detailed review of the
`10 previous studies evaluating the use of MMF, we developed
`a list of 10 quality indicators that could be used to characterize
`an ideal prospective phase II clinical trial or retrospective
`study of treatment for GVHD. The proposed quality indi-
`cators are summarized below.
`
`1. Adequately defined eligibility criteria
`Inclusion and exclusion criteria should specify affected
`sites, severity of manifestations, and prior treatment used
`to define the cohort. Exclusion criteria should indicate
`whether factors such as the presence of infection, inability
`to tolerate the study treatment, presence of persistent malig-
`nancy or low performance score were used to define the
`cohort. Studies intended to evaluate treatment of “steroid-
`refractory” GVHD should indicate the glucocorticoid dose
`and duration of treatment used to define the cohort. Eligi-
`bility criteria are typically more precisely defined for pro-
`spective studies than for retrospective studies. Data from
`retrospective studies describing all patients who received
`the study treatment of interest are difficult to interpret unless
`additional selection criteria are applied to improve homo-
`geneity within the study cohort.
`
`2. Documented minimization of bias in the selection of pa-
`tients
`Readers should be given enough information to determine
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`Paul J. Martin, et al.
`
`whether the characteristics of the patients included in a
`study are representative of the more general population of
`patients with chronic GVHD. Risk factors that could affect
`outcome should be delineated. Ideally, either an historical
`or contemporaneous cohort should be identified for com-
`parison, and any differences in the prevalence of risk factors
`between the study cohort and the comparison cohort should
`be noted. The use of randomization to define cohorts helps
`to ensure the absence of bias, but this procedure does not
`ensure that the study cohort is representative of the more
`general population of patients with the indication of interest.
`Enrollment of all consecutive patients who meet eligibility
`criteria can ensure that the cohort is representative of the
`more general population, but this approach would raise
`concerns about the adequacy of informed consent. Thus,
`comparisons of demographics and risk factors between
`patients who participated and those who did not are crucial.
`
`ment in at least one organ. The category assigned for patients
`with improvement in one organ but deterioration in another
`organ should be clearly stated.
`
`6. Specified time for assessment of response
`To facilitate comparisons between studies, at least one
`specified time point should be used for assessment of re-
`sponse, and the data for this assessment should be shown.
`Additional information can be shown as a time to event
`analysis. The number of patients who died or had recurrent
`malignancy before the assessment time point should be
`specified, and results should clearly indicate whether these
`patients were excluded from consideration in the assessment
`of response or whether they were included as non-responders.
`Tabulation of results according to “best response” or “last
`value carried forward” is not appropriate, since these categories
`do not reflect clinical benefit at a specific time point.
`
`3. Consistent treatment regimen
`The study treatment of interest should be administered
`in a consistent manner in dose, schedule and duration of
`administration. Differences in dose, schedule or duration
`of administration can be addressed by stratified analysis of
`each specific subgroup. As much as possible, concomitant
`treatment with immunosuppressive agents other than gluco-
`corticoids should also be administered in a consistent manner
`in order to facilitate the interpretation of results. Such con-
`sistency greatly improves the ability to interpret results and
`to confirm the results in subsequent studies. Concomitant
`treatment can be standardized more easily in studies of initial
`therapy for standard or high-risk disease and for secondary
`therapy than in studies of subsequent therapies. For third-line
`or subsequent therapy, such consistency is feasible only if
`prior treatment with agents other than glucocorticoids is
`discontinued.
`
`4. Objective criteria for organ response
`Categorical criteria should be defined for complete
`response, partial response, no change, and worsening for
`each organ or site affected by GVHD, even if organ response
`criteria have not been validated, since conclusions of the
`study are based on response rates. Definitions require formal
`assessment at baseline and at the comparison time point.
`In many studies, partial response was defined as “at least
`50% improvement” in disease manifestations. This terse, and
`likely oversimplified, definition meets the formal criterion
`of objectivity but suggests that the response assessment
`actually reflects a general overall impression, as opposed
`to a detailed comparison of changes in chronic GVHD
`manifestations in each organ between baseline and the
`assessment time.
`
`5. Unambiguous criteria for overall response
`The definition of overall response is distinct from the
`criteria for organ response. Overall responses are often
`defined according to the overall pattern of organ responses.
`At a minimum, overall partial response indicates improve-
`
`Korean J Hematol 2011;46:153-63.
`
`7. Concomitant treatment taken into account
`New systemic treatment for GVHD added after enrollment
`but before the assessment time point because of inadequately
`controlled disease manifestations should be categorized as
`non-response. Even in studies that use “best response” as
`the endpoint, the text should state whether response was
`evaluated before any new systemic treatment was added.
`Changes in glucocorticoid dose should be described, but a
`temporary small increase in glucocorticoid dose during a
`taper should not be categorized as non-response, because
`temporary flares of GVHD activity cannot be avoided when
`conscientious efforts are made to determine the minimum
`glucocorticoid dose needed to control GVHD.
`
`8. Well-established control benchmark
`A specific historical or concurrent control benchmark
`should be used to establish a null hypothesis for the primary
`endpoint. Response criteria for the benchmark and study
`cohorts should be identical or closely similar.
`
`9. Statistical hypothesis and power estimate
`The methods should provide values for the null and alter-
`native hypotheses and for the one-sided or two-sided type
`1 error, together with estimates of statistical power and the
`necessary sample size. Although these considerations might
`be difficult to apply in retrospective studies, they should
`always be applied in prospective studies.
`
`10. Survival
`The results should show survival of the cohort from the
`onset of study treatment. Kaplan-Meier curves should show
`tic marks depicting end of follow-up, especially if the
`minimum follow-up time for surviving patients is less than
`6 months. Alternatively, results can be shown in tables
`indicating time to death or last follow-up for each patient.
`When response definitions differ, survival data provide the
`only gauge that can be used as a simple and universally
`applicable method for comparisons with other studies.
`
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`

`Treatment of chronic GVHD
`
`157
`
`Table 2. Quality of prior reports of studies testing mycophenolate
`mofetil.
`
`Quality criterion
`
`Study number
`
`1 2 3 4 5 6 7 8 9 10
`
`Total
`
`Eligibility criteria
`Minimization of selection bias
`Consistent treatment regimen Y
`Objective response criteria
`Overall response criteria
`Time of assessment
`Concomitant treatment
`Historical benchmark
`Statistical hypothesis
`Survival curve
`Total
`
`Y
`
`Y
`
`Y
`
`Y Y
`
`Y Y
`Y
`
`Y Y Y Y
`
`Y
`
`Y
`Y
`Y Y
`
`Y
`Y
`1 2 2 4 2 2 1 0 2 4
`
`3
`0
`3
`2
`2
`1
`7
`0
`0
`2
`
`EVALUATION OF PRIOR REPORTS FOR
`STUDIES OF MMF
`
`Two individuals (YI and PM) independently reviewed
`the 10 prior reports of studies testing the use of MMF for
`secondary treatment of chronic GVHD [39-48]. Reports were
`evaluated according to whether each quality criterion was
`met or not, based on careful reading of the text. Differences
`in scores were reconciled by joint review to arrive at a
`consensus. Since the purpose of publication is to persuade
`others, application of the criteria was very strict, and no
`credit was given if the text did not address the criterion
`or if the text was not clear. Therefore, in many cases, defi-
`ciencies in the report might not have been representative
`of a study as it was actually conducted.
`Results for the 10 studies of MMF are summarized in
`Table 2. Scores at the bottom of the table represent the
`total number of criteria met by each report. One report
`failed to meet any of the 10 criteria. Two reports met 4
`criteria, and none had higher scores. The mean score for
`the 10 reported studies was 2.0. Scores at the right margin
`of the table represent the number of reports that met each
`criterion. None of the reports attempted to demonstrate that
`bias had been minimized in the selection of patients, used
`an historical or contemporaneous benchmark or tested a
`statistical hypothesis. Only one report had a specified time
`of assessment, and only two had objective response criteria
`and well-defined overall response criteria. Three reports
`employed a consistent treatment regimen, while 7 accounted
`for possible effects of concomitant treatment.
`
`COMPREHENSIVE REVIEW OF PRIOR REPORTS
`
`Results of the review of reports for studies testing MMF
`prompted a more comprehensive review of studies testing
`systemic agents for secondary treatment of chronic GVHD
`
`Table 3. Initial agreement between evaluators.a)
`
`Quality criterion
`
`Agreement
`
`Eligibility criteria
`87%
`Minimization of selection bias
`97%
`Consistent treatment regimen
`92%
`Objective response criteria
`75%
`Overall response criteria
`78%
`Time of assessment
`88%
`Concomitant treatment
`72%
`Historical benchmark
`97%
`Statistical hypothesis
`98%
`Survival curve
`87%
`a)Each of the 60 selected reports was independently evaluated by 2
`reviewers. Results in the table indicate the percent agreement
`between the 2 reviewers for each quality criterion.
`
`published between 1990 and 2011. We searched the Medline
`(PubMed) database using a broad search strategy to identify
`studies evaluating secondary treatment of chronic GVHD.
`The search was conducted using the terms “Chronic graft
`versus host disease” and “Treatment” excluding ‘”Review.”
`Relevant references in the publications identified were also
`reviewed. Both retrospective and prospective studies were
`included, but studies with cohorts containing fewer than
`10 patients (N=26), phase III studies and case reports were
`excluded. A total of 60 studies were selected for review
`[39-54, 58-101]. Initial agreement between the two reviewers
`was high, ranging between 72% and 98% (Table 3).
`Across the 60 studies, 17 different agents were evaluated
`(Fig. 1). Extracorporeal photopheresis was the most fre-
`quently studied agent (N=17) followed by mycophenolate
`mofetil (N=10), thalidomide (N=6), sirolimus or everolimus
`(N=4) and rituximab (N=4). The distribution of scores re-
`presenting the total number of criteria met by each report
`ranged from a low of 0 (N=6) to 8 (N=1) [61] (Fig. 2). The
`mean score for all 60 reports was 2.5. The mean score for
`prospective studies (N=31) was 3.1, compared to 1.8 for
`retrospective studies (N=29). The mean score for multicenter
`studies (N=7) was 3.6, compared to 2.3 for single-center
`studies (N=53).
`Approximately 35% to 45% of all reports provided
`adequate information regarding eligibility criteria, organ
`response criteria, overall response criteria, concomitant
`treatment and overall survival (Table 4). Only 22% of the
`reports had a specified time for assessment of response, and
`less than 10% of the reports documented an absence of bias
`in the selection of patients, used a consistent treatment
`regimen, or tested a formal statistical hypothesis on the basis
`of a benchmark from a contemporaneous or historical cohort.
`The percentage of reports fulfilling quality indicators was
`generally higher for prospective studies than for retrospective
`studies (Table 4).
`
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`158
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`Paul J. Martin, et al.
`
`Extracorporeal photopheresis
`Mycophenolate mofetil
`Thalidomide
`Sirolimus or everolimus
`Rituximab
`Pentostatin
`Methotrexate
`Tacrolimus
`lmatinib
`Thoraco-abdominal irradiation
`Pulse steroid
`Mesenchymal stem cells
`Etretinate
`Etanercept
`Clofazimine
`Chloroquine
`Alefacept ...,.._ ________ ~
`
`0
`
`15
`10
`5
`Number of reports
`
`20
`
`Fig. 1. Treatments evaluated in prior reports. Treatments are listed in
`order of frequency among the 60 reports included in the literature
`review.
`
`16
`
`14
`
`~ 12
`g_ 10
`~
`o 8
`~ E 6
`:,
`z 4
`
`2
`
`0
`
`0
`
`2
`
`3
`
`6
`5
`4
`Total score
`
`7
`
`8
`
`9
`
`10
`
`Fig. 2. Distribution of scores representing the total number of criteria
`met by each report for the 60 studies included in the literature review.
`
`SHORTCOMINGS IN THE CURRENT STATE OF AFFAIRS
`
`Despite their many shortcomings, all 10 reports evaluating
`MMF offered favorable overall assessments, 8 in the abstract,
`and 2 in the discussion. All 10 reports called for additional
`studies, 3 in the abstract, and 7 in the discussion. The contrast
`with results of the prospective phase III trial testing MMF
`for initial treatment of chronic GVHD raises a general
`concern that other previously tested agents also do not
`provide as much benefit as suggested in the reports. The
`approach used in most reports relies on the assumption that
`any improvement after new treatment must have resulted
`from the new treatment, but most of the studies did not
`attempt to assess the durability of response. Taken as a whole,
`the collection of reports does not facilitate comparisons of
`efficacy from one agent to the next, and readers are left
`
`Korean J Hematol 2011;46:153-63.
`
`Table 4. Quality of prior reports.a)
`
`Quality criterion
`
`Percent of reports fulfilling criterion
`
`Total
`(N=60)
`
`Retrospective
`(N=29)
`
`Prospective
`(N=31)
`
`Eligibility criteria
`38%
`17%
`58%
`Minimization of selection bias
`5%
`3%
`6%
`Consistent treatment regimen
`8%
`14%
`3%
`Objective response criteria
`45%
`24%
`65%
`Overall response criteria
`43%
`24%
`52%
`Time of assessment
`22%
`10%
`32%
`Concomitant treatment
`38%
`21%
`55%
`Historical benchmark
`2%
`0%
`3%
`Statistical hypothesis
`3%
`0%
`6%
`Survival curve
`38%
`45%
`32%
`a)Data in the table indicate the percentage of reports in each
`category that were judged to meet each of the indicated quality
`criteria.
`
`to conclude that everything works, more or less.
`Investigators prefer new treatment to be effective, and
`under the “publish or perish” pressures of academic life,
`authors may lose objectivity and attempt to portray results
`as positively as possible. None of the 60 reviewed results
`indicated negative overall results, strongly suggesting a
`powerful bias by authors and journals to publish only the
`results of “positive” studies. Conclusions from retrospective
`studies and phase II clinical trials should be stated more
`cautiously. For example, we suggest that an appropriate
`conclusion from the studies of MMF would be the following:
`“Our results demonstrate the feasibility of using MMF to
`treat chronic GVHD. The true merits of using MMF for
`this indication can be evaluated only in a prospective
`controlled trial”. Small retrospective studies have very
`limited value for assessing results of a new treatment, and
`the distinction between retrospective studies and prospective
`studies is important. Nonetheless, many prospective phase
`II studies still fall far short of the ideal.
`Progress would be enhanced if studies could be conducted
`in a way that allows results to be compared from one study
`to the next in a more informative way. Aggregation of results
`for secondary therapy with those for third, fourth and
`subsequent lines of treatment makes such comparisons im-
`possible, due to large variation in prior treatment and
`concomitant therapy. Comparisons are also impeded by an
`inability to estimate the baseline prognosis of patients
`enrolled in any given study as compared to those enrolled
`in other studies.
`The current state of affairs has many harmful effects. Most
`reviews that summarize previous literature regarding treat-
`ment of chronic GVHD focus on overall complete and partial
`responses, leading readers to uncritical acceptance of con-
`clusions that agents are effective, when in fact, they are
`not. Agents that are accepted as effective could actually
`cause unrecognized harm, as suggested by results of the phase
`III MMF study [27]. Clinicians who believe that they already
`
`

`

`Treatment of chronic GVHD
`
`159
`
`know what is best have little incentive to participate in
`clinical trials. As a consequence, progress has stalled, and
`no one is able to identify new treatments that are truly
`effective. Progress would be enhanced if investigators could
`identify truly promising results from phase II trials and move
`forward more quickly to testing in definitive phase III trials.
`
`THE NEED FOR STANDARDIZATION
`- A PROPOSAL FOR THE FUTURE
`
`Progress would be greatly enhan