Graft-versus-host disease (GVHD) is an immunological phenomenon resulting from the reaction of donor immune cells against major or minor histocompatibility antigens of the recipient. GVHD is primarily caused by donor-derived T-cells. Factors influencing the severity of GVHD are related to three main categories: 1) donor or graft, 2) recipient, and 3) treatment. The most influential donor/graft factor is the degree of genetic disparity between the donor and the recipient (HLA match), but other risk factors include female donor to male recipient, donor parity, older donors, and T-cell dose. The occurrence of acute GVHD becomes a risk factor for the development of chronic GVHD. Recipient age and prior infections are also factors. Treatment-related factors include a myeloablative preparative regimen and inadequate post-HCT immune suppression (GVHD prophylaxis).
In the past, GVHD was classified as acute or chronic based on its time to diagnosis following transplant, and other clinical and histological (biopsy or post-mortem) features. Today, there has been increased recognition that acute and chronic GVHD are not dependent upon time since HCT, so determination of acute or chronic should rest on clinical and histologic features.
However, organ staging, and overall grade should only be calculated from the clinical picture, not histology. Acute GVHD usually begins between 10 and 40 days after HCT but can appear earlier or later. The organs most commonly affected by acute GVHD are the skin, gut, or liver. Other sites, such as the lung, may be involved.
Diagnosis
Date of acute GVHD diagnosis _______
Report the date of clinical diagnosis of acute GVHD in DD/MMM/YYYY format. The clinical diagnosis date may not necessarily be the date they symptoms began (Example: the subject developed a rash one week prior to the physician clinically diagnosing acute skin GVHD). If the clinical diagnosis date is not documented, then report the date of histological confirmation.
If the subject developed more than one episode of acute GVHD in the same follow up period, report the date of onset of the first episode of acute GVHD.
Check if previously reported ☐
If the date of clinical diagnosis of acute GVHD is reported in a prior follow up, select “check if previously reported” box.
Maximum grade
Maximum overall grade since last reported for the study
The acute GVHD grading scale is based on clinical evidence (physician observation), not histology. If there is a difference in the clinical grade recorded by the physician and a histological report, use the data from the clinical documentation. Biopsy of affected organs allows for more precise diagnosis as to the presence or absence of GVHD. However, overall grading remains clinical and is based on the criteria published by Przepiorka et al., Bone Marrow Transplant 1995; 15(6):825-8, see table 1 below.
Table 1. GVHD Grading and Staging
| Extent of Organ Involvement | ||||
|---|---|---|---|---|
| Stage | Skin | Liver | Gut | |
| 1 | Rash on <25% of skin | Bilirubin 2-3 mg/dl | Diarrhea > 500 ml/day 3 or persistent nausea | |
| 2 | Rash on 25-50% of skin | Bilirubin 3-6 mg/dl | Diarrhea >1000 ml/day | |
| 3 | Rash on >50% of skin | Bilirubin 6-15 mg/dl | Diarrhea >1500 ml/day | |
| 4 | Generalized erythroderma with bullae | Bilirubin >15 mg/dl | Large volume diarrhea and severe abdominal pain with or without ileus | |
| Grade 4 | ||||
|---|---|---|---|---|
| I | Stage 1-2 | None | None | |
| II | Stage 3 | Stage 1 or | Stage 1 | |
| III | — | Stage 2-3 or | Stages 2-4 | |
| IV5 | Stage 4 | Stage 4 | — | |
|
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Table 2: Percent Body Surfaces
| Body Area | Percent | Total Percentage |
|---|---|---|
| Each Arm | 9% | 18% |
| Each Leg | 18% | 36% |
| Chest & Abdomen | 18% | 18% |
| Back | 18% | 18% |
| Head | 9% | 9% |
| Pubis | 1% | 1% |
Indicate the overall maximum grade of acute GHVD since last reported for the study. If acute GVHD was present, but the maximum grade cannot be determined from the grading and staging table, the overall maximum grade should be left blank.
Example 1: A subject developed stage 2 skin involvement and elevated liver function tests (LFTs) attributed to acute GVHD; however, there was no total bilirubin manifestation. In this case, overall maximum grade I acute GVHD should be reported since the staging/grading can be determined using Table 1.
Example 2: A subject developed acute liver GVHD with elevated LFTs with no total bilirubin manifestation. The progress notes indicate stage 1 (grade II overall) acute GVHD of the liver. In this case, the clinical manifestations do not fit the criteria used in Table 1 and the overall maximum grade should be left blank.
Date maximum grade reached _______
Organ Involvement
Skin
Select the stage that reflects the body surface area involved with a maculopapular rash since last reported for the study. See Table 3 above to determine the percent of body surface area involved with a rash. If the subject has acute GVHD but does not have skin rash or has a rash that is not attributed to acute GVHD (i.e., due to a drug reaction, infection, or some other reason), report “stage 0 – no rash, or no rash attributable to acute GVHD.”
Table 3. Percent Body Surfaces
| Body Area | Percent | Total Percentage |
|---|---|---|
| Each Arm | 9% | 18% |
| Each Leg | 18% | 36% |
| Chest & Abdomen | 18% | 18% |
| Back | 18% | 18% |
| Head | 9% | 9% |
| Pubis | 1% | 1% |
- Stage 0 – no rash, or no rash attributable to acute GVHD
- Stage 1 – < 25% of body surface area
- Stage 2 – < 25-50% of body surface area
- Stage 3 – > 50% of body surface area
- Stage 4 – generalized erythroderma with bullae formation
Lower intestinal tract
Select the stage that reflects the volume of diarrhea since last reported for the study. Input and output records may be useful in determining the volume of diarrhea. If the subject has acute GVHD but does not have diarrhea or the subject has diarrhea, but it is not attributed to acute GVHD (i.e., due to a drug reaction, infection, or some other reason) report “stage 0 – no diarrhea, or diarrhea ≥ 500 mL/day, or no diarrhea attributable to acute GVHD.”
Upper intestinal tract
Select the stage that reflects the presence of persistent nausea or vomiting attributed to acute GVHD since last reported for the study. Do not report nausea or vomiting ongoing but not attributed to acute GVHD.
Liver
Select the stage that reflects the bilirubin level attributed to acute GVHD since last reported for the study. If a subject has evidence of acute GVHD but has a bilirubin level less than 2.0 mg/dL or hyperbilirubinemia, but it is not attributed to acute GVHD (i.e., due to liver dysfunction not related to acute GVHD), select “stage 0 – bilirubin < 2.0 mg/dL, or no liver acute GVHD.”
Therapy
Indicate each therapy given to treat acute GVHD since last reported for this study:
Indicate each therapy given to treat acute GVHD since last reported for this study. Report prophylactic drugs if they were continued after the onset of acute GVHD. If more than one therapy was administered to treat acute GVHD, add a new log line in the Rave application to capture each line of therapy.
Select the therapy administered and report the date when therapy was started in DD/MMM/YYYY format.
If therapy was started in a previous follow up, re-report the initial start date of therapy.
If therapy is ongoing, mark the check box.
Indicate the dose in the “NNNNNNNNNN” format. This allows for ten digits before the decimal and ten digits after the decimal.
Therapy options given to treat acute GVHD include:
ALG (Anti-Lymphocyte Globulin), ALS (Anti-Lymphocyte Serum), ATG (Anti-Thymocyte Globulin ATS (Anti-Thymocyte Serum): Serum or gamma globulin preparations containing polyclonal immunoglobulins directed against lymphocytes. These drugs are usually prepared from animals immunized against human lymphocytes. In addition to reporting the start date of therapy, report the dose in milligrams (mg) and select the animal source. If an “other” animal source was used, specify the source in the text box.
Corticosteroids (systemic): Examples include: dexamethasone, hydrocortisone, methylprednisolone, and prednisone/prednisolone. Only report systemic steroids in this section.
Corticosteroids (topical):“Topical” refers to drugs applied to the skin, eye drops, or inhalation therapy. An exception to this guidance would be the drug budesonide. It is a drug given by mouth for treatment of gut GVHD, but it is considered a “topical” drug since it is not absorbed. In addition to reporting the start date of therapy, report the dose and select the type of topical steroid
Cyclosporine (CSA) (Sandimmune, Neoral): Examples include: sandimmune and Neoral.
ECP (extra-corporeal photopheresis): The subject’s blood is exposed to ultraviolet light outside of their body, and re-infused.
FK 506 (Tacrolimus, Prograf): Alternate names include: Tacrolimus, Prograf. FK 506 inhibits the production of interleukin-2 by T-cells.
Anti CD25 – Zenapax: A type of in vivo monoclonal antibody infused in the subject following HCT.
Anti CD25 – Daclizumab: A type of in vivo monoclonal antibody infused in the subject following HCT.
Anti CD25 – AntiTAC: A type of in vivo monoclonal antibody infused in the subject following HCT.
Campath: A type of in vivo monoclonal antibody infused in the subject following HCT.
Etanercept (Enbrel): A type of in vivo monoclonal antibody infused in the subject following HCT.
Infliximab (Remicade): A type of in vivo monoclonal antibody infused in the subject following HCT.
Other in vivo monoclonal antibody: Monoclonal antibody other than Anti CD25 (Zenapax, Daclizumab, AntiTAC), Campath, Entanercept (Enbrel), and/or Infliximab (Remicade). Specify the other in vivo monoclonal antibody given to treat acute GVHD in the text box.
In vivo immunotoxin: Antibody preparations linked to a toxin that is infused in the subject following HCT. Specify the immunotoxin.
Methotrexate (MTX) (Amethopterin): Example: Amethopterin. MTX inhibits the metabolism of folic acid. It is most often used with cyclosporine and is usually for a short duration of time.
Mycophenolate mofetil (MMF) (CellCept): Alternate name: CellCept. MMF inhibits the de novo pathway used for lymphocyte proliferation and activation.
Sirolimus (Rapamycin, Rapamune): Alternate names: Rapamycin, Rapamune. Sirolimus inhibits the response to interleukin-2, blocking the activation of T-cells.
Tocilizumab: Prevents the protein interleukin-6 (IL-6) from connecting with cells which prevents the activation of cells.
Ursodiol: Suppresses synthesis and secretion of cholesterol from the liver and absorption in the intestines.
Blinded randomized trial: If the subject is on a blinded randomized trial, specify agent being studied in the trial in the text box.
Other agent: Other agents or alternate methods of treatment may be used in combination with drug therapy. Specify the other agent/method given to treat acute GVHD in the text box.
CCG v.1 | CRF v.1
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