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The Leukemia/Bone Marrow Transplant Program of BC

Healthcare Professionals
Cancer Management Guidelines

Graft versus Host Disease (GVHD)

Updated: March 2010 - currently under review

Diagnosis

Acute graft versus host disease (GVHD) is the most frequent complication after allogeneic haematopoietic stem cell transplantation (SCT). The incidence of acute GVHD is related to the degree of mismatch between HLA proteins and ranges from 35-45% in recipients of fully matched sibling donors to 80% in recipients of unrelated donor grafts. Other major risk factors for the development of GVHD are older patient (and possibly older donor) age, greater intensity of the conditioning regimen, and donor/recipient sex mismatch, especially with allosensitised female donors. In non-myeloablative transplants, acute GVHD is more likely to occur if donor T-cell chimerism is established rapidly after transplantation. With conventional conditioning regimens, the time of onset of GVHD is typically 2-3 weeks after SCT. With reduced intensity conditioning regimens, acute GVHD may occur later (see below).

Classification

Historically, acute GVHD was distinguished from chronic GVHD by the time of onset (before or more than 100 days after HSCT). In the era of reduced-intensity conditioning regimens and donor lymphocyte infusions, this distinction is no longer clear-cut. Patients may present with a clinical picture of acute GVHD several months after SCT, while GVHD with characteristics of the ‘chronic’ form may occur within 60 days after transplantation. The NIH Consensus Conference recognises 2 categories of GVHD as follows:

1. Acute GVHD (absence of features of chronic), comprising

  • classic acute GVHD (before day 100)
  • persistent, recurrent, or late acute GVHD (after day 100, often upon withdrawal of immunosuppression).

2. Chronic GVHD, comprising

  • classic chronic GVHD (no signs of acute GVHD), and
  • an overlap syndrome, in which features of acute and chronic are present

Clinical Features

Skin is most commonly affected and is usually the first organ involved, often coinciding with engraftment of donor cells. The characteristic maculopapular rash is pruritic and can spread throughout the body, sparing the scalp. In severe cases the skin maybe painful, blister and ulcerate.

Gastrointestinal tract involvement of acute GVHD usually presents as diarrhoea but may also include vomiting, anorexia and/or abdominal pain. The diarrhoea is secretory and often voluminous. Bleeding occurs as a result of mucosal ulceration and carries a poor prognosis. Involvement may be patchy leading to a normal appearance on endoscopy.

Liver disease may be difficult to distinguish from other causes of liver dysfunction following SCT such as veno-occlusive disease, drug toxicity, viral infection or sepsis. The liver is rarely biopsied because of thrombocytopenia, therefore the diagnosis is made clinically.

Stage

Skin

Liver*

Intestinal Tract*

+1

Maculopapular rash <25% of body surface

Bilirubin 35-50 μmol/l

Diarrhoea 500-1000 ml/day or nausea (± vomiting)**

+2

Maculopapular rash 25% -50% of body surface

Bilirubin 51-100 μmol/l

Diarrhoea 1000-1500 ml/day

+3

 Generalised erythroderma

Bilirubin 101-255 μmol/l

Diarrhoea >1500 ml/day or cramps or blood or ileus

+4

Generalised erythroderma with bullous formation and desquamation

Bilirubin >255 μmol/l

Simultaneous presence of any two of the four criteria for stage 3 severity

* If patient has documented GVHD of the liver or gut, and documented alternative cause of hyperbilirubinaemia/diarrhoea (i.e. veno-occlusive disease or mucositis, CMV enteritis or C difficile infection) then downstage GVHD by 1 stage.

** With histological evidence

Functional Grading of Acute GVHD (Glucksberg)

 Grade

Skin 

 Liver

 Gut

 0 (none)

 0

 0

 0

 I (mild)

 +1 to +2

 0

 0

 II (moderate)

  0 to +3#, or 

 +1, and/or

 +1

 III (severe)*

 ---

  +2 to +3 and/or 

  +2 to +4 

 IV (life-threatening)**

 +4

 +4

 ---

# Stage 3 alone is considered overall grade II
* 25% long-term survival; ** 5% survival
** 5% long-term survival

Treatment

The response to primary therapy is of central importance as responses correlate with survival.

Glucocorticoids are the mainstay of acute GVHD therapy. Complete responses are seen in 25% to 40% of patients, and clinically relevant improvement, defined as regression of skin rash or decrease in the volume of diarrhoea and the extent of liver function abnormalities in 40%-50% of patients with grades II or IV acute GVHD.

Treatment

At the onset of acute GVHD

  • Start methylprednisone (MP) 2mg/kg/d IV x 3-5 days (1mg/kg q12 hourly)
  • Continue cyclosporine at therapeutic levels

A biopsy is not mandatory prior to commencing treatment.

Monitoring of Response

If no progression (increase in the stage in any system) after the 6th dose, then continue same therapy. If complete remission, or less than Grade II after the 10th dose of MP start a steroid taper:

Suggested Steroid Taper:
Days 6-10:  1.5mg/kg/day
Days 11-15:  1 mg/kg/day
Days 16-20:  0.5 mg/kg/day
Days 21-28:  0.25mg/kg/day
Days 29+: taper as tolerated; suggest 10% per week

Management of Steroid Refractory Acute GVHD

If manifestations of GVHD in any organ worsen over 3 days of treatment of if the skin does not improve by 5 days, it is unlikely that a response will be achieved in a timely fashion, and secondary therapy should be considered.

Organs with Predominant GVHD Manifestation

 Potential Secondary/Tertiary Therapies

 Skin

 Anti-CD25 monoclonal antibody (basiliximab); ATG**;

 Liver

 ATG**; Anti-CD25

 GI Tract

"Non-absorbable" steroids (beclomethasone, budesonide)*; ATG**; TNF-α blockade (entanercept);

* In patients with prominent intestinal manifestation, the addition of beclomethasone or budesonide may allow a reduction in the dose of sytemically administered steroids.

** Substitute Anti-CD52 in patients whose conditioning regimen included ATG

Other Considerations

Infections are the major non-relapse cause of death in patients receiving therapy for GVHD and all patients should receive infection prophylaxis. This should include PCP prophylaxis with Septra and prevention of herpes virus with acyclovir. While on GVHD therapy, patients need to be monitored for viral reactivation, in particular CMV (and EBV in patients receiving ATG). If there is evidence of reactivation treatment with ganciclovir (and rituximab for EBV), should be given. All patients should receive azole prophylaxis against fungal infections. Invasive molds, especially aspergillus are common in patients with prolonged steroid use.

Chronic immunosuppressive therapy has multiple toxicities. Prolonged therapy with steroids results in muscle weakness and wasting. It is important to make every effort to keep patients mobile and to involve a physiotherapist to develop an individual exercise program. Diabetes, hypertension, osteoporosis, avascular necrosis and other Cushingoid features are common with chronic steroid use and should be monitored for Calcineurin inhibitors frequently cause renal impairment and levels need to be monitored.

Algorithms

Click images to enlarge.

GVHD Treatment Algorithm

Protocols

BCCA Chemotherapy Protocols and PPOs

Publications

  1. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, Martin P, Chien J, Przepiorka D, Couriel D, Cowen EW, Dinndorf P, Farrell A, Hartzman R, Henslee-Downey J, Jacobsohn D, McDonald G, Mittleman B, Rizzo JD, Robinson M, Schubert M, Schultz K, Shulman H, Turner M, Vogelsang G, Flowers MDE. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant 11:945-955, 2005.
  2. Vogelsang GB. How I treat chronic graft-versus-host disease. Blood 95:1196-201, 2001.
  3. Przepiorka D, Kernan NA, Ippoliti C, Papadopoulos EB, Giralt S, Khouri I, Lu J-G, Gajewski J, Durett A, Cleary K, Champlin R, Andersson BS, and Light S. Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease. Blood 95:83-89, 2000.
  4. Sullivan KM, Witherspoon RP, Storb R, Deeg HJ, Dahlberg S, Sanders JE, Appelbaum, FR, Doney KC, Weiden  P, Anasetti C, Loughran TP, Hill R, Shields A, Yee G, Shulman H, Nims J, Strom S, and Thomas ED. Alternating-Day Cyclosporine and Prednisone for Treatment of High-Risk Chronic Graft-v-Host Disease. Blood 72:555-561, 1998.
  5. Abraham R, Szer J, Bardy P and Grigg A. Early cyclosporine taper in high-risk sibling allogeneic bone marrow transplants. Bone Marrow Transplantation 20:773-777, 1997.
  6. Przepiorka D, Weisdorf D, Martin P, Lingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplantation 15(6):825-8, 1995.

 

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patientís care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BCís terms of use available at Terms of Use.

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