Secondary Treatment of Acute Graft-Versus-Host Disease: a Critical Review

REVIEW

Secondary Treatment of Acute Graft-versus-Host Disease: A Critical Review

Paul J. Martin,1,2 Yoshihiro Inamoto,1,2 Mary E. D. Flowers,1,2 Paul A. Carpenter1,3

Management of steroid-resistant or steroid-refractory acute graft-versus-host disease (aGVHD) poses one of the most vexing and difﬁcult problems faced by transplantation physicians. In the current study, we used 10 criteria to evaluate 67 reports describing secondary treatment of patients with aGVHD. The goal of this ex- ercise was not only to provide a critical summary of the literature but also to offer suggestions that could improve future studies. Areas especially in need of improvement include the use of a consistent treatment regimen, the assessment of response at a consistent prespeciﬁed time point, consideration of concomitant treatment in assessing response, documentation that selection bias was minimized, and the use of methods that test a formal statistical hypothesis based on a contemporaneous or historical benchmark. Our results suggest that previous published reports collectively offer little guidance in discerning the most effective treatments for patients with steroid-resistant or steroid-refractory aGVHD. Adherence to the proposed criteria in future reports would enable meaningful comparisons across studies and thereby accelerate progress in evaluating new treatments for patients with aGVHD. Biol Blood Marrow Transplant 18: 982-988 (2012) Ó 2012 American Society for Blood and Marrow Transplantation KEY WORDS: Acute graft-versus-host disease, Treatment, Phase II clinical trials, Review

INTRODUCTION cGVHD [4]. Less than 10% of the reports documented an effort to minimize patient selection bias, used a con- Allogeneic hematopoietic cell transplantation is sistent treatment regimen, or tested a formal statistical frequently complicated by acute and chronic graft- hypothesis that was based on a contemporaneous or versus-host disease (aGVHD and cGVHD) [1,2]. historical benchmark. Only 22% of the reports had Management of steroid-resistant or steroid-refractory a prespecified time for assessment of response, and aGVHD poses one of the most vexing and difficult only 35% to 45% of the reports provided adequate in- problems faced by transplantation physicians. Many formation regarding eligibility criteria, concomitant retrospective reviews and prospective studies have treatment, and overall survival. Based on these obser- been carried out to evaluate approaches for secondary vations, we concluded that previous studies offer little treatment of patients with aGVHD. To date, no con- guidance in discerning the most effective treatments sensus has been reached regarding the optimal choice for patients with steroid-resistant or steroid-refractory of agents for secondary treatment, and clinical manage- cGVHD. In the current study, we used the same list ment is generally approached through empirical trial of 10 criteria to evaluate reports describing secondary and error. Treatment choices are based on physician systemic treatment of patients with aGVHD. experience, ease of use, need for monitoring, risk of toxicity, and potential exacerbation of pre-existing comorbidity [3]. METHODS In a previous review, we used a list of 10 criteria to Literature Search evaluate reports describing secondary treatment of We searched the Medline (PubMed) database using a broad search strategy to identify studies evaluat- 1 2 From the Division of Clinical Research; Department of Medicine; ing secondary treatment of aGVHD with reports and 3Pediatrics, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington. published between 1990 and 2011. The search was Financial disclosure: See Acknowledgments on page 986. conducted using the terms ‘‘Graft versus host disease’’ Correspondence and reprint requests: Paul J. Martin, MD, Fred and ‘‘Treatment’’ excluding ‘‘Review.’’ Relevant refer- Hutchinson Cancer Research Center, PO Box 19024, Seattle, ences in the publications identified were also reviewed. WA 98109-1024 (e-mail: [email protected]). Both retrospective and prospective studies were in- Received February 8, 2012; accepted April 10, 2012 Ó 2012 American Society for Blood and Marrow Transplantation cluded, but studies with cohorts containing fewer 1083-8791/$36.00 than 10 patients, case reports, and studies of agents doi:10.1016/j.bbmt.2012.04.006 that are not commercially available were excluded.

982 Biol Blood Marrow Transplant 18:982-988, 2012 Secondary Treatment of aGVHD 983

Review Criteria therapy for standard or high-risk disease and for Each report was evaluated according to the follow- secondary therapy than for subsequent therapies. ing 10 criteria. For third-line or subsequent therapy, such consistency is feasible only if prior treatment with agents 1. Adequately defined eligibility criteria. Inclusion other than glucocorticoids is discontinued. and exclusion criteria should specify affected sites, 4. Objective criteria for organ response. Categor- severity of manifestations, and prior treatment ical criteria should be defined for complete used to define the cohort. Exclusion criteria should response, partial response, stable disease, and indicate whether factors such as the presence of worsening for each organ or site affected by infection, inability to tolerate the study treatment, GVHD, because conclusions of the study are presence of persistent malignancy, or low perfor- based on response rates. Definitions require for- mance score were used to define the cohort. Studies mal assessment at baseline and at the comparison intended to evaluate treatment of ‘‘steroid-refrac- time point. Scales for staging organ severity and tory’’ GVHD should indicate the glucocorticoid overall GVHD grade can be used for this purpose. dose and duration of treatment used to define the 5. Unambiguous criteria for overall response. cohort. Eligibility criteria are typically more pre- The definition of overall response is distinct cisely defined for prospective studies than for retro- from the criteria for organ response. Overall re- spective studies. Data from retrospective studies sponses are often defined according to the overall describing all patients who received the study treat- pattern of organ responses. At a minimum, overall ment of interest are difficult to interpret unless partial response indicates improvement in at least additional selection criteria are applied to improve one organ. The category assigned for patients with homogeneity within the study cohort. improvement in one organ but deterioration in an- 2. Documented minimization of bias in the selec- other organ should be clearly stated. tion of patients. Readers should be given enough 6. Prespecified time for assessment of response. information to determine whether the characteris- To facilitate comparisons between studies, at least tics of the patients included in a study are represen- one specified time point should be used for assess- tative of the more general population of patients ment of response, and the data for this assessment with steroid-resistant or steroid-refractory should be shown. Additional information can be aGVHD. Risk factors that could affect outcomes shown as a time-to-initial partial or complete re- should be delineated. Ideally, either a historical sponse or as time-to-initial complete response, or contemporaneous cohort should be identified but this approach cannot account for subsequent for comparison, and any differences in the preva- loss of response. The number of patients who lence of risk factors between the study cohort and died, had recurrent malignancy, or had a treatment the comparison cohort should be noted. The use change before the assessment time point should of randomization to define cohorts helps to ensure be specified, and the results should clearly indicate the absence of bias, but this procedure does not en- whether these patients were excluded from consid- sure that the study cohort is representative of the eration in the assessment of response or whether more general population of patients with the indi- they were included as nonresponders. Tabulation cation of interest. Enrollment of all consecutive of results according to ‘‘best response’’ or ‘‘last patients who meet eligibility criteria could provide value carried forward’’ is not appropriate because a representative cohort but would raise ethical these categories do not reflect clinical benefit at questions about informed consent. a specific time point. 3. Consistent treatment regimen. The study treat- 7. Concomitant treatment taken into account. ment of interest should be administered in a consis- New systemic treatment for patients with GVHD tent manner in dose, schedule, and duration of added after enrollment but before the assessment administration. Differences in dose, schedule, or time point because of inadequately controlled dis- duration of administration can be addressed by ease manifestations should be categorized as non- stratified analysis of each specific subgroup. As response. Even in studies that use ‘‘best response’’ much as possible, concomitant treatment with as the endpoint, the text should state whether re- immunosuppressive agents other than glucocorti- sponse was evaluated before any new systemic coids should also be administered in a consistent treatment was added. Changes in glucocorticoid manner in order to facilitate the interpretation of dose should be described, but a temporary small in- results. Such consistency greatly improves the abil- crease in glucocorticoid dose during a taper should ity to interpret results and to confirm the results in not be categorized as nonresponse, because tempo- subsequent studies. Concomitant treatment can rary flares of GVHD activity cannot be avoided be standardized more easily in studies of initial when conscientious efforts are made to determine 984 P. J. Martin et al. Biol Blood Marrow Transplant 18:982-988, 2012

Table 1. Initial Agreement between Evaluatorsa

Criterion Percent Agreement

Eligibility criteria 60 Minimization of selection bias 81 Consistent treatment regimen 61 Organ response criteria 82 Overall response criteria 75 Prespecified time of assessment 84 Concomitant treatment 60 Historical benchmark 93 Statistical hypothesis 97 Survival curve 76 aEach of the 67 selected reports was independently evaluated by 2 reviewers. Results in the table indicate the percent initial agreement between the 2 reviewers for each criterion. Figure 1. Treatments evaluated in prior reports. Treatments are listed the minimum glucocorticoid dose needed to in order of frequency among the 67 reports included in the literature control GVHD. review. 8. Well-established control benchmark. A specific historical or concurrent control benchmark (Table 1). Agreement was less than 80% for 5 of the should be used to establish a null hypothesis for 10 criteria, including adequately defined eligibility cri- the primary endpoint. Response criteria for the teria, use of a consistent treatment regimen, unambig- benchmark and study cohorts should be identical uous criteria for overall response, accounting for or closely similar. concomitant treatment in the assessment of response, 9. Statistical hypothesis and power estimate. The and survival data. Judgments sometimes differed with methods should provide values for the null and al- respect to the level of detail needed for adequate char- ternative hypotheses and for the 1-sided or 2-sided acterization of the inclusion and exclusion criteria, the type 1 error, together with estimates of statistical importance of using the agent of interest at exactly the power and the necessary sample size. Although same dose in all patients, and the feasibility of harmo- these considerations might be difficult to apply nizing concomitant immunosuppressive treatment in in retrospective studies, they should always be ap- all patients. The reviewers agreed that allowances can plied in prospective studies. be made for minor differences in dose of the agent un- 10. Survival. The results should show survival of the der investigation and that concomitant treatment can cohort from the onset of study treatment. be harmonized with respect to agents previously used Kaplan-Meier curves should show tic marks defor treatment but not for agents previously used for picting end of follow-up, especially if the mini- prophylaxis. Some differences of opinion were caused mum follow-up time for surviving patients is less by ambiguities in the definitions of response in patients than 6 months. Alternatively, results can be shown who had improvement in one organ with progression in in tables indicating time to death or last follow-up another organ and by an absence of explicit information for each patient. When response definitions differ, explaining how response was evaluated in patients who these data provide the only gauge that can be used had additional agents added before the response was as a simple and universally applicable method for evaluated. Differences regarding survival information comparisons with other studies. were mostly related to confusion about follow-up time for surviving patients. The criterion requires in- Review Procedures formation about follow-up time only when the minimum follow-up time is less than 6 months. Two individuals (PAC and PJM) independently Across the 67 studies, 19 different agents were reviewed reports of studies testing the use of agents evaluated (Figure 1). Horse antithymocyte globulin for secondary treatment of patients with aGVHD. and extracorporeal photopheresis were the most fre- Reports were evaluated according to whether each quently studied agents (n 5 8 and 7, respectively) fol- criterion was met or not, based on careful reading of lowed by mycophenolate mofetil, inolimomab, the text. Differences in assessments were reconciled daclizumab (n 5 6 each), combinations of agents by joint review to arrive at a consensus. (n 5 5), sirolimus, infliximab, and alemtuzumab (n 5 4 each), and methotrexate and basiliximab 5 RESULTS (n 3 each). The distribution of scores representing the total number of criteria met by each report ranged A total of 67 studies were selected for review [5-71]. from a low of 0 (n 5 1) up to a maximum of 8 (n 5 1; Initial agreement between the 2 reviewers in assessing Figure 2). The mean score for all 67 reports was 4.2 the 10 criteria ranged between 60% and 97% and did not differ between retrospective studies Biol Blood Marrow Transplant 18:982-988, 2012 Secondary Treatment of aGVHD 985

external experience [19], or randomized controls [48] for the evaluation of results, but without testing formal null and alternative statistical hypotheses. One report described a formal statistical hypothesis with randomized controls [52].

DISCUSSION

The number of deficiencies in reports was some- what lower for studies of secondary treatment of aGVHD compared with studies of secondary treat- Figure 2. Distribution of scores representing the total numberof criteria ment of cGVHD [4]. The average score for all 67 re- met by each report for the 67 studies included in the literature review. ports was 4.3 for aGVHD studies, compared with 2.5 for all 60 reports of cGVHD studies during the same time period [4]. Compared to cGVHD studies, (n 5 44) compared with prospective studies (n 5 23) or aGVHD studies seemed to have fewer deficiencies in between single-center studies (n 5 46) compared with the use of well-defined eligibility criteria, a consistent multicenter studies (n 5 21; Table 2). Reports pub- treatment regimen, objective response criteria and un- lished before 2000 (n 5 7) had a mean score of 3.4, ambiguous overall response criteria, and in reporting compared with 4.3 for those reported since then survival data. Reports of aGVHD treatment seemed (n 5 60; Table 3). The proportion of reports with to focus more frequently on second-line treatment, adequately defined eligibility criteria and survival with less frequent aggregation of results for second- information improved across time. line treatment with those for third, fourth, and subse- In 57% to 88% of all reports, adequate informa- quent lines of treatment. These eligibility criteria tion regarding eligibility criteria, organ response crite- could have made it more feasible to apply a consistent ria, overall response criteria, and overall survival was treatment regimen in aGVHD studies as compared provided (Table 2). Only one-third of all reports de- with cGVHD studies. The availability of long- scribed a consistent treatment regimen, assessed re- established and widely accepted scales for assessment sponse at a prespecified time point, and accounted of organ stages and overall grade has facilitated the for effects of concomitant treatment. As might have use of objective response criteria in studies of aGVHD been expected, treatment regimens were more fre- [72-74]. The development of similar scales for quently administered consistently in prospective stud- cGVHD has been hampered by the multiple protean ies (61%) than in retrospective studies (27%). Only manifestations of this disease and its greater 18% of the reports demonstrated an effort to minimize complexity as compared to aGVHD [75]. or account for bias in the selection of patients. Reports Many deficiencies remain in reports of aGVHD of two phase 2 studies described a formal statistical hy- studies. Areas especially in need of improvement in- pothesis. In these 2 reports, the benchmark overall clude the use of a consistent treatment regimen, the as- response rates for the null hypothesis were set at sessment of response at a consistent prespecified time 20% [13] and 50% [38], respectively, without refer- point, consideration of concomitant treatment in as- ence to prior experience or results of other studies. sessing response, documentation that selection bias Six reports described prior local [18,30,44,58] or was minimized, and the use of methods that test

Table 2. Assessment of Prior Reports, According to Study Typea

Percent of Reports Fulﬁlling Criterion

Criterion Total (n 5 67) Retrospectiveb (n 5 44) Prospective (n 5 23) Single Center (n 5 46) Multicenter (n 5 21)

Eligibility criteria 57 55 61 54 62 Minimization of selection bias 18 20 13 17 19 Consistent treatment regimen 39 27 61 39 38 Organ response criteria 88 89 87 87 90 Overall response criteria 73 77 65 67 86 Prespeciﬁed time of assessment 34 32 39 35 33 Concomitant treatment 37 43 26 39 33 Historical benchmark 10 9 13 7 19 Statistical hypothesis 4 0 13 2 10 Survival curve 61 64 57 67 48 Average total score 4.2 4.2 4.4 4.2 4.4 aData in the table indicate the percentage of reports in each category that were judged to meet each of the indicated criteria. bIn 3 reports, the retrospective or prospective design of the study was not clearly stated. 986 P. J. Martin et al. Biol Blood Marrow Transplant 18:982-988, 2012

Table 3. Assessment of Prior Reports According to Year of publication is to persuade others, application of the a Publication criteria was very strict, and no credit was given if the Percent of Reports text did not address the criterion or if the text was Fulﬁlling Criterion not clear. Therefore, in many cases, deﬁciencies in

1990-1999 2000-2004 2005-2011 the report might not have been representative of Criterion (n 5 7) (n 5 19) (n 5 41) a study as it was actually conducted. Important details could have been omitted from some reports because of Eligibility criteria 29 53 63 Minimization of selection bias 0 16 22 word limits. When necessary, future reports could Consistent treatment regimen 57 32 39 provide this information in online supplements. The Organ response criteria 100 74 93 proposed criteria do not directly measure the diligence Overall response criteria 71 84 68 Prespecified time of assessment 29 53 27 of the investigator in ensuring that the data are accu- Concomitant treatment 29 42 37 rate and unbiased. Such an assessment would require Historical benchmark 0 11 12 onsite monitoring to compare the data against source Statistical hypothesis 0 5 5 Survival curve 29 58 68 documents. Average total score 3.4 4.3 4.3 Although the 2 reviewers did not have perfect aData in the table indicate the percentage of reports in each category agreement regarding each criterion in each study, it that were judged to meet each of the indicated criteria. was clear that the reports had many deficiencies. Our results suggest that previously published reports col- a formal statistical hypothesis based on a contempora- lectively offer little guidance in discerning the most ef- neous or historical benchmark. To facilitate the devel- fective treatments for patients with steroid-resistant opment of new treatment for aGVHD, the American or steroid-refractory aGVHD. Adherence to the pro- Society of Blood and Marrow Transplantation has en- posed criteria in future reports would enable meaning- dorsed recommendations that could improve the con- ful comparisons across studies and thereby accelerate duct and reporting of future studies [76]. progress in evaluating new treatments for patients Prior GVHD therapies should be discontinued in with aGVHD. Promising candidate treatments identi- studies that include patients with third, fourth, and fied in robust phase II studies could be taken forward in subsequent lines of treatment in order to establish phase III studies of secondary treatment, and success- a consistent treatment regimen, so that valid compari- ful results in such a study would establish a new bench- sons can be made with results of other studies. For mark for future phase II studies of secondary therapy. studies of initial treatment for aGVHD, a consensus Promising candidate treatments could also be tested in may be emerging that response should be evaluated phase II studies of primary treatment. Most impor- at day 28, and strong agreement has emerged that pa- tantly, successful results in phase III studies of either tients who are given additional therapy before the as- secondary or primary treatment would improve pa- sessment day should be classified as not having tient outcomes and establish new standards of care. a response. Although the day-28 response assessment might not necessarily serve as the best measure of success in studies of secondary therapy, comparisons be- ACKNOWLEDGMENTS tween studies would be facilitated if these results The authors thank Stuart Tenney for assistance in were routinely reported. In addition, a survival plot preparing the manuscript. should be included routinely in order to facilitate com- This study was supported by research grant parisons between studies. CA98906 from the National Institutes of Health, The involvement of only 2 reviewers and the in- Department of Health and Human Services. Y.I. is complete agreement between reviewers in judging a recipient of the JSPS Postdoctoral Fellowships for whether reports met criteria are limitations of the cur- Research Abroad. rent study. We considered the merits of recruiting Financial disclosure: The authors declare no finan- a larger number of reviewers to assess and grade the cial conflicts of interest. published reports, but we decided that this extra effort would be unlikely to change the conclusion that the published reports have many deficiencies. To some ex- REFERENCES tent, ambiguity in the initial description of the criteria contributed to lack of agreement between the re- 1. Cutler C, Antin JH. Manifestations and treatment of acute graft- versus-host disease. In: Appelbaum FR, Forman SJ, Negrin RS, viewers. The reviews were done in 3 stages, and at Blume KG, editors. Thomas’ Hematopoietic Cell Transplantation. the end of each stage, the definitions were refined in Oxford, UK: Wiley-Blackwell; 2009. p. 1287-1303. an effort to eliminate ambiguities and to clarify the cri- 2. Pavletic SZ, Vogelsang GB. Chronic graft-versus-host disease: teria. In many cases, discrepant assessments between clinical manifestations and therapy. In: Appelbaum FR, Forman SJ, Negrin R, Blume KG, editors. Thomas’ Hematopoietic the reviewers were related to the interpretation of am- Cell Transplantation. Oxford, UK: Wiley-Blackwell; 2009. p. biguous language in the report. Because the purpose of 1304-1324. Biol Blood Marrow Transplant 18:982-988, 2012 Secondary Treatment of aGVHD 987

3. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109: 22. MacMillan ML, Weisdorf DJ, Wagner JE, et al. Response of 4119-4126. 443 patients to steroids as primary therapy for acute graft- 4. Martin PJ, Inamoto Y, Carpenter PA, Lee SJ, Flowers ME. versus-host disease: comparison of grading systems. Biol Blood Treatment of chronic graft-versus-host disease: past, present Marrow Transplant. 2002;8:387-394. and future. Korean J Hematol. 2011;46:153-163. 23. Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dorken€ B, 5. Herve P, Wijdenes J, Bergerat JP, et al. Treatment of Arnold R. Basiliximab is well tolerated and effective in the treat- corticosteroid resistant acute graft-versus-host disease by ment of steroid-refractory acute graft-versus-host disease after in vivo administration of anti-interleukin-2 receptor monoclonal allogeneic stem cell transplantation. Bone Marrow Transplant. antibody (B-B10). Blood. 1990;75:1017-1023. 2002;30:899-903. 6. Cuthbert RJ, Phillips GL, Barnett MJ, et al. Anti-interleukin-2 24. Jacobsohn DA, Hallick J, Anders V, McMillan S, Morris L, receptor monoclonal antibody (BT 563) in the treatment of se- Vogelsang GB. Infliximab for steroid-refractory acute GVHD: vere acute GVHD refractory to systemic corticosteroid therapy. a case series. Am J Hematol. 2003;74:119-124. Bone Marrow Transplant. 1992;10:451-455. 25. Messina C, Locatelli F, Lanino E, et al. Extracorporeal photo- 7. Roy J, McGlave PB, Filipovich AH, et al. Acute graft-versus- chemotherapy for paediatric patients with graft-versus-host dis- host disease following unrelated donor marrow transplantation: ease after haematopoietic stem cell transplantation. Br J failure of conventional therapy. Bone Marrow Transplant. 1992; Haematol. 2003;122:118-127. 10:77-82. 26. Couriel D, Saliba R, Hicks K, et al. Tumor necrosis factor-alpha 8. Herbelin C, Stephan JL, Donadieu J, et al. Treatment of steroid- blockade for the treatment of acute GVHD. Blood. 2004;104: resistant acute graft-versus-host disease with an anti-IL-2- 649-654. receptor monoclonal antibody (BT 563) in children who 27. Ho VT, Zahrieh D, Hochberg E, et al. Safety and efficacy of de- received T cell-depleted, partially matched, related bone mar- nileukin diftitox in patients with steroid-refractory acute graft- row transplants. Bone Marrow Transplant. 1994;13:563-569. versus-host disease after allogeneic hematopoietic stem cell 9. Hertenstein B, Stefanic M, Sandherr M, Bunjes D, Mertens T, transplantation. Blood. 2004;104:1224-1226. Arnold R. Treatment of steroid-resistant acute graft-vs-host 28. Kim JG, Sohn SK, Kim DH, et al. Different efficacy of myco- disease after allogeneic marrow transplantation with anti- phenolate mofetil as salvage treatment for acute and chronic interleukin-2 receptor antibody (BT563). Transplant Proc. GVHD after allogeneic stem cell transplant. Eur J Haematol. 1994;26:3114-3116. 2004;73:56-61. 10. Kanamaru A, Takemoto Y, Kakishita E, et al. FK506 treatment 29. Patriarca F, Sperotto A, Damiani D, et al. Infliximab treatment of graft-versus-host disease developing or exacerbating during for steroid-refractory acute graft-versus-host disease. Haemato- prophylaxis and therapy with cyclosporin and/or other immuno- logica. 2004;89:1352-1359. suppressants. Japanese FK506 BMT Study Group. Bone Marrow 30. Srinivasan R, Chakrabarti S, Walsh T, et al. Improved survival in Transplant. 1995;15:885-889. steroid-refractory acute graft versus host disease after non- 11. Dugan MJ, DeFor TE, Steinbuch M, Filipovich AH, myeloablative allogeneic transplantation using a daclizumab- Weisdorf DJ. ATG plus corticosteroid therapy for acute graft- based strategy with comprehensive infection prophylaxis. Br J versus-host disease: predictors of response and survival. Ann Haematol. 2004;124:777-786. Hematol. 1997;75:41-46. 31. Bay JO, Dhedin N, Goerner M, et al. Inolimomab in steroid- 12. McCaul KG, Nevill TJ, Barnett MJ, et al. Treatment of steroid- refractory acute graft-versus-host disease following allogeneic resistant acute graft-versus-host disease with rabbit antithymo- hematopoietic stem cell transplantation: retrospective analysis cyte globulin. J Hematother Stem Cell Res. 2000;9:367-374. and comparison with other interleukin-2 receptor antibodies. 13. PrzepiorkaD,Kernan NA, IppolitiC,etal.Daclizumab,ahuman- Transplantation. 2005;80:782-788. ized anti-interleukin-2 receptor alpha chain antibody, for treat- 32. Bolanos-Meade~ J, Jacobsohn DA, Margolis J, et al. Pentostatin ment of acute graft-versus-host disease. Blood. 2000;95:83-89. in steroid-refractory acute graft-versus-host disease. J Clin On- 14. Basara N, Kiehl MG, Blau W, et al. Mycophenolate mofetil in col. 2005;23:2661-2668. the treatment of acute and chronic GVHD in hematopoietic 33. Couriel DR, Saliba R, Escalon MP, et al. Sirolimus in combina- stem cell transplant patients: four years of experience. Transplant tion with tacrolimus and corticosteroids for the treatment of re- Proc. 2001;33:2121-2123. sistant chronic graft-versus-host disease. Br J Haematol. 2005; 15. Benito AI, Furlong T, Martin PJ, et al. Sirolimus (rapamycin) for 130:409-417. the treatment of steroid-refractory acute graft-versus-host dis- 34. Huang XJ, Jiang Q, Chen H, et al. Low-dose methotrexate for ease. Transplantation. 2001;72:1924-1929. the treatment of graft-versus-host disease after allogeneic hema- 16. Mollee P, Morton AJ, Irving I, Durrant S. Combination therapy topoietic stem cell transplantation. Bone Marrow Transplant. with tacrolimus and anti-thymocyte globulin for the treatment 2005;36:343-348. of steroid-resistant acute graft-versus-host disease developing 35. Knop S, Hebart H, Gscheidle H, et al. OKT3 muromonab as during cyclosporine prophylaxis. Br J Haematol. 2001;113: second-line and subsequent treatment in recipients of stem cell 217-223. allografts with steroid-resistant acute graft-versus-host disease. 17. Khoury H, Kashyap A, Adkins DR, et al. Treatment of steroid- Bone Marrow Transplant. 2005;36:831-837. resistant acute graft-versus-host disease with anti-thymocyte 36. Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, globulin. Bone Marrow Transplant. 2001;27:1059-1064. Mayer J. Mycophenolate mofetil for the treatment of acute 18. Remberger M, Aschan J, Barkholt L, Tollemar J, Ringden O. and chronic steroid-refractory graft-versus-host disease. Ann Treatment of severe acute graft-versus-host disease with anti- Hematol. 2005;84:681-685. thymocyte globulin. Clin Transplant. 2001;15:147-153. 37. Mayer J, Krejcı M, Doubek M, et al. Pulse cyclophosphamide for 19. Willenbacher W, Basara N, Blau IW, Fauser AA, Kiehl MG. corticosteroid-refractory graft-versus-host disease. Bone Marrow Treatment of steroid refractory acute and chronic graft- Transplant. 2005;35:699-705. versus-host disease with daclizumab. Br J Haematol. 2001;112: 38. Schmidt-Hieber M, Fietz T, Knauf W, et al. Efficacy of the 820-823. interleukin-2 receptor antagonist basiliximab in steroid-refractory 20. Arai S, Margolis J, Zahurak M, Anders V, Vogelsang GB. Poor acute graft-versus-host disease. Br J Haematol. 2005;130:568-574. outcome in steroid-refractory graft-versus-host disease with an- 39. Shaughnessy PJ, Bachier C, Grimley M, et al. Denileukin difti- tithymocyte globulin treatment. Biol Blood Marrow Transplant. tox for the treatment of steroid-resistant acute graft-versus-host 2002;8:155-160. disease. Biol Blood Marrow Transplant. 2005;11:188-193. 21. Graziani F, Van Lint MT, Dominietto A, et al. Treatment of 40. Wolff D, Roessler V, Steiner B, et al. Treatment of steroid- acute graft versus host disease with low dose-alternate day resistant acute graft-versus-host disease with daclizumab and anti-thymocyte globulin. Haematologica. 2002;87:973-978. etanercept. Bone Marrow Transplant. 2005;35:1003-1010. 988 P. J. Martin et al. Biol Blood Marrow Transplant 18:982-988, 2012

41. Bordigoni P, Dimicoli S, Clement L, et al. Daclizumab, an effi- chronic graft-versus-host disease in children. Bone Marrow cient treatment for steroid-refractory acute graft-versus-host Transplant. 2008;41:571-577. disease. Br J Haematol. 2006;135:382-385. 58. Le Blanc K, Frassoni F, Ball L, et al. Mesenchymal stem cells for 42. Funke VA, de Medeiros CR, Setubal DC, et al. Therapy for se- treatment of steroid-resistant, severe, acute graft-versus-host vere refractory acute graft-versus-host disease with basiliximab, disease: a phase II study. Lancet. 2008;371:1579-1586. a selective interleukin-2 receptor antagonist. Bone Marrow 59. Perfetti P, Carlier P, Strada P, et al. Extracorporeal photophere- Transplant. 2006;37:961-965. sis for the treatment of steroid refractory acute GVHD. Bone 43. Greinix HT, Knobler RM, Worel N, et al. The effect of inten- Marrow Transplant. 2008;42:609-617. sified extracorporeal photochemotherapy on long-term survival 60. Furlong T, Martin P, Flowers ME, et al. Therapy with myco- in patients with severe acute graft-versus-host disease. Haemato- phenolate mofetil for refractory acute and chronic GVHD. logica. 2006;91:405-408. Bone Marrow Transplant. 2009;44:739-748. 44. Kennedy GA, Butler J, Western R, Morton J, Durrant S, 61. Ghez D, Rubio MT, Maillard N, et al. Rapamycin for refractory Hill GR. Combination antithymocyte globulin and soluble acute graft-versus-host disease. Transplantation. 2009;88: TNFalpha inhibitor (etanercept) 1/- mycophenolate mofetil 1081-1087. for treatment of steroid refractory acute graft-versus-host dis- 62. Martınez C, Solano C, Ferra C, et al. Alemtuzumab as treat- ease. Bone Marrow Transplant. 2006;37:1143-1147. ment of steroid-refractory acute graft-versus-host disease: re- 45. de Lavallade H, Mohty M, Faucher C, Furst€ S, El-Cheikh J, sults of a phase II study. Biol Blood Marrow Transplant. 2009; Blaise D. Low-dose methotrexate as salvage therapy for refrac- 15:639-642. tory graft-versus-host disease after reduced-intensity condition- 63. Miano M, Cuzzubbo D, Terranova P, et al. Daclizumab as use- ing allogeneic stem cell transplantation. Haematologica. 2006;91: ful treatment in refractory acute GVHD: a paediatric experi- 1438-1440. ence. Bone Marrow Transplant. 2009;43:423-427. 46. Pinana~ JL, Valcarcel D, Martino R, et al. Encouraging results 64. Rao K,RaoA, Karlsson H, Jagani M, Veys P, Amrolia PJ. Improved with inolimomab (anti-IL-2 receptor) as treatment for refractory survival and preserved antiviral responses after combination ther- acute graft-versus-host disease. Biol Blood Marrow Transplant. apy with daclizumab and infliximab in steroid-refractory graft- 2006;12:1135-1141 [Erratum in Biol Blood Marrow Transplant. versus-host disease. J Pediatr Hematol Oncol. 2009;31:456-461. 2007;13:124.]. 65. Schnitzler M, Hasskarl J, Egger M, Bertz H, Finke J. Successful 47. Teachey DT, Bickert B, Bunin N. Daclizumab for children with treatment of severe acute intestinal graft-versus-host resistant to corticosteroid refractory graft-versus-host disease. Bone Marrow systemic and topical steroids with alemtuzumab. Biol Blood Mar- Transplant. 2006;37:95-99. row Transplant. 2009;15:910-918. 48. Van Lint MT, Milone G, Leotta S, et al. Treatment of acute 66. Hoda D, Pidala J, Salgado-Vila N, et al. Sirolimus for treatment graft-versus-host disease with prednisolone: significant survival of steroid-refractory acute graft-versus-host disease. Bone Mar- advantage for day 15 responders and no advantage for nonre- row Transplant. 2010;45:1347-1351. sponders receiving anti-thymocyte globulin. Blood. 2006;107: 67. Onishi C, Ohashi K, Sawada T, et al. A high risk of life- 4177-4181. threatening infectious complications in mycophenolate mofetil 49. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombi- treatment for acute or chronic graft-versus-host disease. Int J nant human soluble tumor necrosis factor receptor fusion pro- Hematol. 2010;91:464-470. tein as treatment for steroid refractory graft-versus-host 68. Perotti C, Del Fante C, Tinelli C, et al. Extracorporeal photo- disease following allogeneic hematopoietic stem cell transplan- chemotherapy in graft-versus-host disease: a longitudinal study tation. Am J Hematol. 2007;82:45-52. on factors influencing the response and survival in pediatric pa- 50. Knop S, Hebart H, Gratwohl A, et al. Treatment of tients. Transfusion. 2010;50:1359-1369. steroid-resistant acute GVHD with OKT3 and high-dose 69. Pidala J, Kim J, Perkins J, et al. Mycophenolate mofetil for the steroids results in better disease control and lower inci- management of steroid-refractory acute graft vs host disease. dence of infectious complications when compared to Bone Marrow Transplant. 2010;45:919-924. high-dose steroids alone: a randomized multicenter trial 70. Gonzalez Vicent M, Ramirez M, Sevilla J, Abad L, Diaz MA. by the EBMT Chronic Leukemia Working Party. Leuke- Analysis of clinical outcome and survival in pediatric patients un- mia. 2007;21:1830-1833. dergoing extracorporeal photopheresis for the treatment of 51. Berger M, Pessolano R, Albiani R, et al. Extracorporeal photo- steroid-refractory GVHD. J Pediatr Hematol Oncol. 2010;32: pheresis for steroid resistant graft versus host disease in pediatric 589-593. patients: a pilot single institution report [Erratum in J Pediatr 71. Schub N, Gunther€ A, Schrauder A, et al. Therapy of steroid- Hematol Oncol. 2008;30:115]. J Pediatr Hematol Oncol. 2007;29: refractory acute GVHD with CD52 antibody alemtuzumab is 678-687. effective. Bone Marrow Transplant. 2011;46:143-147. 52. Macmillan ML, Couriel D, Weisdorf DJ, et al. A phase 2/3 mul- 72. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of ticenter randomized clinical trial of ABX-CBL versus ATG as therapy for acute graft-versus-host disease: initial treatment. secondary therapy for steroid-resistant acute graft-versus-host Blood. 1990;76:1464-1472. disease. Blood. 2007;109:2657-2662. 73. Weisdorf D, Haake R, Blazar B, et al. Treatment of moderate/ 53. Perales MA, Ishill N, Lomazow WA, et al. Long-term severe acute graft-versus-host disease after allogeneic bone mar- follow-up of patients treated with daclizumab for steroid- row transplantation: an analysis of clinical risk features and out- refractory acute graft-vs-host disease. Bone Marrow Trans- come. Blood. 1990;75:1024-1030. plant. 2007;40:481-486. 74. Martin PJ, Bachier CR, Klingemann HG, et al. Endpoints for 54. Sleight BS, Chan KW, Braun TM, Serrano A, Gilman AL. In- clinical trials testing treatment of acute graft-versus-host disease: fliximab for GVHD therapy in children. Bone Marrow Trans- a joint statement. Biol Blood Marrow Transplant. 2009;15:777-784. plant. 2007;40:473-480. 75. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic re- 55. Calore E, Calo A, Tridello G, et al. Extracorporeal photoche- sponse in chronic graft-versus-host disease: National Institutes of motherapy may improve outcome in children with acute Health consensus development project on criteria for clinical trials GVHD. Bone Marrow Transplant. 2008;42:421-425. in chronic graft-versus-host disease: IV. Response Criteria Work- 56. Gomez-Almaguer D, Ruiz-Arguelles€ GJ, del Carmen Tarin- ing Group report. Biol Blood Marrow Transplant. 2006;12:252-266. Arzaga L, et al. Alemtuzumab for the treatment of steroid- 76. Martin PJ, Rizzo JD, Wingard JR, et al. First and second-line refractory acute graft-versus-host disease. Biol Blood Marrow systemic treatment of acute graft-versus-host disease: recom- Transplant. 2008;14:10-15. mendations of the American Society of Blood and Marrow 57. Inagaki J, Nagatoshi Y, Hatano M, Isomura N, Sakiyama M, Transplantation. Biol Blood Marrow Transplant. 2012 [Epub Okamura J. Low-dose MTX for the treatment of acute and ahead of print].