Pediatr Transplantation 2015
© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12433
Grading acute graft-versus-host disease: Time to reconsider Goyal RK, Goyal M, Sankaranarayan K. (2015) Grading acute graftversus-host disease: Time to reconsider. Pediatr Transplant, 00: 1–3. DOI: 10.1111/petr.12433. Abstract: Acute graft-versus-host disease (GVHD) is a common and serious complication of allogeneic blood and marrow transplantation. Acute GVHD is commonly graded according to modified Glucksberg criteria. There is considerable within-grade heterogeneity with different patterns of skin, liver, or gut involvement. In this commentary, we provide an analytical review of ambiguities in acute GVHD severity scoring and offer specific proposals meant to generate discussion in the BMT community for adoption, refinement, and where appropriate, validation studies.
Rakesh K. Goyal1,2, Manu Goyal3 and Kumar Sankaranarayan4 1
Division of Blood and Marrow Transplantation and Cellular Therapies at Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA, 2University of Pittsburgh, Pittsburgh, PA, USA, 3Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA, 4Independent Technology Consultant, Pittsburgh, PA, USA
Rakesh K. Goyal, MD, Division of Blood and Marrow Transplantation and Cellular Therapies, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224 1334, USA Tel.: +1 412 692 7610 Fax: +1 412 692 6752 E-mail: [email protected] Accepted for publication 19 December 2014
The most widely used acute GVHD grading scheme was originally proposed over 40 yr ago by Glucksberg et al. and revised by Thomas et al. (1, 2). In 1990, Weisdorf et al. described a syndrome of upper gastrointestinal acute GVHD characterized by persistent nausea with histologic evidence of GVHD in gastric or duodenal mucosa (3). Subsequently, a consensus panel held in Keystone, Colorado, in 1994 recommended inclusion of upper GI GVHD in the grading scheme, downstaging by one if an additional cause for diarrhea or elevated bilirubin was documented, using body surface area for calculating volume of diarrhea in pediatric age patients, and limiting performance status criterion to overall grade IV (4). In 1997, International Blood and Marrow Transplant Research (IBMTR) proposed a severity index in which patients were grouped from A to D based on correlation of organ stages with risks of transplant-
Abbreviations: BMT, bone marrow transplantation; CIBMTR, Center for International Blood and Marrow Transplant Research; EBMT, European Society for Blood and Marrow Transplantation; GI, gastrointestinal; GVHD, graft-versus-host disease.
related mortality and failure of initial GVHD therapy (5). The Keystone Consensus (“Consensus”) staging and grading recommendations, while widely used and referenced, are not always followed as published (6, 7). The acute GVHD grading criteria have also been variously modified in different clinical trials and changes advocated in practice guidelines (8–10). Based on our review, we recommend the following revisions be made to the Consensus acute GVHD staging and Grading scheme (Table 1). These specific proposals are meant to generate discussion in the BMT community for adoption, refinement and where appropriate, validation studies. Issue 1: Assignment of stage 4 gut as overall grade III. Narrative: Consensus scheme assigns stage 2 through 4 of gut as overall grade III while stage 4 skin or liver is assigned grade IV. Large single institution studies have shown that severe gut GVHD is often treatment refractory, and gastrointestinal tract is involved in virtually all fatal cases of acute GVHD (6, 11). In a recent report by Castilla–Llorente, there were no survivors in adults with steroid refractory stage 3–4 gut GVHD with GI bleeding and bilirubin >3 mg/dL (12). The Seattle group in a study of over 2500 1
Goyal et al. Table 1. Consensus acute graft-versus-host disease (GVHD) staging and grading with proposed revisions Stage
Skin*,†
Upper gut
Lower gut†,‡
Liver†
0
No skin rash Maculopapular rash, 50% of body surface area Generalized erythroderma with bullae formation
No diarrhea or diarrhea ≤500 mL/day or 500 but ≤1000 mL/day or 280–555 mL/m2/day Diarrhea >1000 but ≤1500 mL/day or 556–833 mL/m2/day Diarrhea >1500 mL/day or >833 mL/m2/day
Total bilirubin 15.0 mg/dL
None Stage 1 Stage 2–3 Stage 4
None Stage 1 Stage 2–3 Stage 4
Grade¶ I II III IV
Stage 1–2 Stage 3 – Stage 4
None Stage 1 – –
*Use “Rule of Nines” or burn chart to determine extent of rash. † Downstage skin, lower gut, or liver by one if additional cause is documented for rash, diarrhea, or elevated bilirubin, respectively. ‡ Use the actual volume of diarrhea for adults. For patients 50% of skin is scored stage 3. Stage 3 was defined as generalized
Acute GVHD grading
erythroderma in the original description by Glucksberg and continues to be included in the data forms (1, 7, 14). Proposal: Skin stage 3 should be defined as rash >50% of skin or generalized erythroderma. Issue 5: Definition of stage 4 gut. Narrative: Consensus scheme assigned severe abdominal pain with or without ileus as gut stage 4. Stool with frank blood or melena has been added to stage 4 scoring (14). Severe abdominal pain or ileus or bleeding in the absence of prior diarrhea is unlikely to represent acute GVHD. Proposal: Stage 4 gut should be defined as severe abdominal pain, or stool with frank blood or melena with preceding or ongoing diarrhea. Issue 6: Performance status criterion for overall grade IV. Narrative: According to the Consensus scheme, grade IV may also include lesser organ involvement but with extreme decrease in performance status. However, performance score is not formally integrated into practice of grading (14, P. J. Martin, personal communication). Proposal: Grade IV should not be based on performance status, but on organ stage severity. The revisions proposed here are meant to reflect contemporaneous practice and to address some of the ambiguities in acute GVHD severity scoring. These should be tested in a large group of patients and compared to the Consensus and the IBMTR scoring systems for GVHD treatment response, survival, and non-relapse mortality. The CIBMTR and the EBMT clinical outcomes databases can serve as resources to undertake these retrospective analyses. Finally, there can be variability in staging and grading from how the clinical data are interpreted and recorded. Examples include when bodyweight is used instead of body surface area in pediatric patients, and when adult stool volume staging categorical thresholds are applied in adult-sized pediatric patients. A free software aGVHD Grader (www.agvhd.com) based on the tables from the Przepiorka and the Rowlings papers automates severity scoring. Its standardized format and easy access across multiple digital platforms should facilitate consistent and accurate staging and grading. Such a tool can be kept updated to reflect any changes to the grading scheme. A database version enables tracking change over time and can serve as a useful record for outcomes reporting and clinical research (15). Acknowledgments We would like to express our gratitude to Dr. Daniel Weisdorf for his critical review of the manuscript; Dr. Paul
Martin for discussions on the art and the practice of acute GVHD scoring; Ankur Goyal for his contributions to the software design; and Dr. Anubha Mittal for critical proofreading of the manuscript.
References 1. GLUCKSBERG H, STORB R, FEFER A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974: 18: 295–304. 2. THOMAS ED, STORB R, CLIFT RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med 1975: 292: 895–902. 3. WEISDORF DJ, SNOVER DC, HAAKE R, et al. Acute upper gastrointestinal graft-versus-host disease: Clinical significance and response to immunosuppressive therapy. Blood 1990: 76: 624–629. 4. PRZEPIORKA D, WEISDORF D, MARTIN P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995: 15: 825–828. 5. ROWLINGS PA, PRZEPIORKA D, KLEIN JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: Retrospective comparison with Glucksberg grade. Br J Haematol 1997: 97: 855–864. 6. GOOLEY TA, CHIEN JW, PERGAM SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010: 363: 2091–2101. 7. Center for International Blood and Marrow Transplant Research. Form 2100 R3.0: 100 Days Post-HSCT Data. Available at: http://www.cibmtr.org/DataManagement/DataCollectionForms/Documents/2100/Rev3.0/2100R3.0.pdf (accessed October 24, 2014). 8. COG Stem Cell Committee Consensus Guidelines for Establishing Organ Stage and Overall Grade of Acute Graft Versus Host Disease (GVHD), Cited in Children’s Oncology Group protocol ASCT0431. Study Chair: Michael A. Pulsipher, MD2011. 9. CARPENTER PA, MACMILLAN ML. Management of acute graftversus-host disease in children. Pediatr Clin North Am 2010: 57: 273–295. 10. MARTIN PJ, RIZZO JD, WINGARD JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: Recommendations of the American Society of Blood and Marrow Transplantation. Biology of blood and marrow transplantation. Biol Blood Marrow Transplant 2012: 18: 1150–1163. 11. MAC MILLAN ML, D E FOR TE, WEISDORF DJ. What predicts high risk acute graft-versus-host disease (GVHD) at onset?: Identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol 2012: 157: 732–741. 12. CASTILLA-LLORENTE C, MARTIN PJ, MCDONALD GB, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2014: 49: 966–971. 13. MACMILLAN ML, WEISDORF DJ, WAGNER JE, et al. Response of 443 patients to steroids as primary therapy for acute graftversus-host disease: Comparison of grading systems. Biol Blood Marrow Transplant 2002: 8: 387–394. 14. Blood and Marrow Transplant Clinical Trials Network. Technical Manual of Procedures. Available at: https://web.emmes.com/study/bmt2/public/MOP/BMT%20CTN%20Technical%20MOP%20v3.pdf (accessed October 24, 2014). 15. GOYAL RK, VOLLER D, GOYAL M, SANKARANARAYAN K. Grading Acute GVHD: Getting it Right Every Time! Accepted for oral presentation. 2015 Tandem BMT Meetings, February 11– 15, San Diego, CA.
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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12433
Grading acute graft-versus-host disease: Time to reconsider Goyal RK, Goyal M, Sankaranarayan K. (2015) Grading acute graftversus-host disease: Time to reconsider. Pediatr Transplant, 00: 1–3. DOI: 10.1111/petr.12433. Abstract: Acute graft-versus-host disease (GVHD) is a common and serious complication of allogeneic blood and marrow transplantation. Acute GVHD is commonly graded according to modified Glucksberg criteria. There is considerable within-grade heterogeneity with different patterns of skin, liver, or gut involvement. In this commentary, we provide an analytical review of ambiguities in acute GVHD severity scoring and offer specific proposals meant to generate discussion in the BMT community for adoption, refinement, and where appropriate, validation studies.
Rakesh K. Goyal1,2, Manu Goyal3 and Kumar Sankaranarayan4 1
Division of Blood and Marrow Transplantation and Cellular Therapies at Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA, 2University of Pittsburgh, Pittsburgh, PA, USA, 3Electrical Engineering and Computer Sciences, University of California, Berkeley, CA, USA, 4Independent Technology Consultant, Pittsburgh, PA, USA
Rakesh K. Goyal, MD, Division of Blood and Marrow Transplantation and Cellular Therapies, Children’s Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, PA 15224 1334, USA Tel.: +1 412 692 7610 Fax: +1 412 692 6752 E-mail: [email protected] Accepted for publication 19 December 2014
The most widely used acute GVHD grading scheme was originally proposed over 40 yr ago by Glucksberg et al. and revised by Thomas et al. (1, 2). In 1990, Weisdorf et al. described a syndrome of upper gastrointestinal acute GVHD characterized by persistent nausea with histologic evidence of GVHD in gastric or duodenal mucosa (3). Subsequently, a consensus panel held in Keystone, Colorado, in 1994 recommended inclusion of upper GI GVHD in the grading scheme, downstaging by one if an additional cause for diarrhea or elevated bilirubin was documented, using body surface area for calculating volume of diarrhea in pediatric age patients, and limiting performance status criterion to overall grade IV (4). In 1997, International Blood and Marrow Transplant Research (IBMTR) proposed a severity index in which patients were grouped from A to D based on correlation of organ stages with risks of transplant-
Abbreviations: BMT, bone marrow transplantation; CIBMTR, Center for International Blood and Marrow Transplant Research; EBMT, European Society for Blood and Marrow Transplantation; GI, gastrointestinal; GVHD, graft-versus-host disease.
related mortality and failure of initial GVHD therapy (5). The Keystone Consensus (“Consensus”) staging and grading recommendations, while widely used and referenced, are not always followed as published (6, 7). The acute GVHD grading criteria have also been variously modified in different clinical trials and changes advocated in practice guidelines (8–10). Based on our review, we recommend the following revisions be made to the Consensus acute GVHD staging and Grading scheme (Table 1). These specific proposals are meant to generate discussion in the BMT community for adoption, refinement and where appropriate, validation studies. Issue 1: Assignment of stage 4 gut as overall grade III. Narrative: Consensus scheme assigns stage 2 through 4 of gut as overall grade III while stage 4 skin or liver is assigned grade IV. Large single institution studies have shown that severe gut GVHD is often treatment refractory, and gastrointestinal tract is involved in virtually all fatal cases of acute GVHD (6, 11). In a recent report by Castilla–Llorente, there were no survivors in adults with steroid refractory stage 3–4 gut GVHD with GI bleeding and bilirubin >3 mg/dL (12). The Seattle group in a study of over 2500 1
Goyal et al. Table 1. Consensus acute graft-versus-host disease (GVHD) staging and grading with proposed revisions Stage
Skin*,†
Upper gut
Lower gut†,‡
Liver†
0
No skin rash Maculopapular rash, 50% of body surface area Generalized erythroderma with bullae formation
No diarrhea or diarrhea ≤500 mL/day or 500 but ≤1000 mL/day or 280–555 mL/m2/day Diarrhea >1000 but ≤1500 mL/day or 556–833 mL/m2/day Diarrhea >1500 mL/day or >833 mL/m2/day
Total bilirubin 15.0 mg/dL
None Stage 1 Stage 2–3 Stage 4
None Stage 1 Stage 2–3 Stage 4
Grade¶ I II III IV
Stage 1–2 Stage 3 – Stage 4
None Stage 1 – –
*Use “Rule of Nines” or burn chart to determine extent of rash. † Downstage skin, lower gut, or liver by one if additional cause is documented for rash, diarrhea, or elevated bilirubin, respectively. ‡ Use the actual volume of diarrhea for adults. For patients 50% of skin is scored stage 3. Stage 3 was defined as generalized
Acute GVHD grading
erythroderma in the original description by Glucksberg and continues to be included in the data forms (1, 7, 14). Proposal: Skin stage 3 should be defined as rash >50% of skin or generalized erythroderma. Issue 5: Definition of stage 4 gut. Narrative: Consensus scheme assigned severe abdominal pain with or without ileus as gut stage 4. Stool with frank blood or melena has been added to stage 4 scoring (14). Severe abdominal pain or ileus or bleeding in the absence of prior diarrhea is unlikely to represent acute GVHD. Proposal: Stage 4 gut should be defined as severe abdominal pain, or stool with frank blood or melena with preceding or ongoing diarrhea. Issue 6: Performance status criterion for overall grade IV. Narrative: According to the Consensus scheme, grade IV may also include lesser organ involvement but with extreme decrease in performance status. However, performance score is not formally integrated into practice of grading (14, P. J. Martin, personal communication). Proposal: Grade IV should not be based on performance status, but on organ stage severity. The revisions proposed here are meant to reflect contemporaneous practice and to address some of the ambiguities in acute GVHD severity scoring. These should be tested in a large group of patients and compared to the Consensus and the IBMTR scoring systems for GVHD treatment response, survival, and non-relapse mortality. The CIBMTR and the EBMT clinical outcomes databases can serve as resources to undertake these retrospective analyses. Finally, there can be variability in staging and grading from how the clinical data are interpreted and recorded. Examples include when bodyweight is used instead of body surface area in pediatric patients, and when adult stool volume staging categorical thresholds are applied in adult-sized pediatric patients. A free software aGVHD Grader (www.agvhd.com) based on the tables from the Przepiorka and the Rowlings papers automates severity scoring. Its standardized format and easy access across multiple digital platforms should facilitate consistent and accurate staging and grading. Such a tool can be kept updated to reflect any changes to the grading scheme. A database version enables tracking change over time and can serve as a useful record for outcomes reporting and clinical research (15). Acknowledgments We would like to express our gratitude to Dr. Daniel Weisdorf for his critical review of the manuscript; Dr. Paul
Martin for discussions on the art and the practice of acute GVHD scoring; Ankur Goyal for his contributions to the software design; and Dr. Anubha Mittal for critical proofreading of the manuscript.
References 1. GLUCKSBERG H, STORB R, FEFER A, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974: 18: 295–304. 2. THOMAS ED, STORB R, CLIFT RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med 1975: 292: 895–902. 3. WEISDORF DJ, SNOVER DC, HAAKE R, et al. Acute upper gastrointestinal graft-versus-host disease: Clinical significance and response to immunosuppressive therapy. Blood 1990: 76: 624–629. 4. PRZEPIORKA D, WEISDORF D, MARTIN P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995: 15: 825–828. 5. ROWLINGS PA, PRZEPIORKA D, KLEIN JP, et al. IBMTR Severity Index for grading acute graft-versus-host disease: Retrospective comparison with Glucksberg grade. Br J Haematol 1997: 97: 855–864. 6. GOOLEY TA, CHIEN JW, PERGAM SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010: 363: 2091–2101. 7. Center for International Blood and Marrow Transplant Research. Form 2100 R3.0: 100 Days Post-HSCT Data. Available at: http://www.cibmtr.org/DataManagement/DataCollectionForms/Documents/2100/Rev3.0/2100R3.0.pdf (accessed October 24, 2014). 8. COG Stem Cell Committee Consensus Guidelines for Establishing Organ Stage and Overall Grade of Acute Graft Versus Host Disease (GVHD), Cited in Children’s Oncology Group protocol ASCT0431. Study Chair: Michael A. Pulsipher, MD2011. 9. CARPENTER PA, MACMILLAN ML. Management of acute graftversus-host disease in children. Pediatr Clin North Am 2010: 57: 273–295. 10. MARTIN PJ, RIZZO JD, WINGARD JR, et al. First- and second-line systemic treatment of acute graft-versus-host disease: Recommendations of the American Society of Blood and Marrow Transplantation. Biology of blood and marrow transplantation. Biol Blood Marrow Transplant 2012: 18: 1150–1163. 11. MAC MILLAN ML, D E FOR TE, WEISDORF DJ. What predicts high risk acute graft-versus-host disease (GVHD) at onset?: Identification of those at highest risk by a novel acute GVHD risk score. Br J Haematol 2012: 157: 732–741. 12. CASTILLA-LLORENTE C, MARTIN PJ, MCDONALD GB, et al. Prognostic factors and outcomes of severe gastrointestinal GVHD after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2014: 49: 966–971. 13. MACMILLAN ML, WEISDORF DJ, WAGNER JE, et al. Response of 443 patients to steroids as primary therapy for acute graftversus-host disease: Comparison of grading systems. Biol Blood Marrow Transplant 2002: 8: 387–394. 14. Blood and Marrow Transplant Clinical Trials Network. Technical Manual of Procedures. Available at: https://web.emmes.com/study/bmt2/public/MOP/BMT%20CTN%20Technical%20MOP%20v3.pdf (accessed October 24, 2014). 15. GOYAL RK, VOLLER D, GOYAL M, SANKARANARAYAN K. Grading Acute GVHD: Getting it Right Every Time! Accepted for oral presentation. 2015 Tandem BMT Meetings, February 11– 15, San Diego, CA.
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