aGvHD,   cGvHD,  GvHD Prophylaxis

Updated consensus of the EBMT | Prophylaxis and management of post-transplant GvHD

Methods used to prevent and treat graft-versus-host disease (GvHD) vary worldwide due to a lack of consensus on best practice and availability of different therapies. In 2014, the European Society of Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN) published guidelines on how to manage GvHD in standard-risk sibling (9/10 human leukocyte antigen [HLA]-matched) or matched unrelated donor (MUD; 10/10 HLA-matched) allogeneic hematopoietic stem cell transplant (allo-HSCT).1 The guidelines specifically focus on adult patients receiving allo-HSCT to treat a hematological malignancy with bone marrow (BM) or peripheral blood (PB) as the stem cell source.2

Recently, these guidelines were updated, based on evidence from trials, meta-analyses, systematic reviews published post-2014, and expert opinions on debated topics. This article summarizes the changes to these guidelines. The following transplant settings were not included in the recommendations: pediatric, haploidentical, and mismatched unrelated donor transplant.2

Thirty-eight statements on the topics of GvHD prophylaxis, drug management, and treatment of acute GvHD (aGvHD) and chronic (cGvHD) were created by five experts (termed the ‘task force’). An EBMT GvHD management recommendation panel of 20 experts was subsequently established, and the statements underwent a consensus process by Delphi consensus protocols. Altogether, a 100% (20/20) consensus was reached on 29 recommendations, and 95% (19/20) consensus was reached on the remaining nine recommendations.2

Recommendations are classified within four consensus evidence groups, modified from the National Comprehensive Cancer Network (NCCN) definitions (Table 1).

Table 1. Categories of evidence2

Category

Evidence

Consensus

1

High-level evidence, e.g. randomized trials and meta analyses

100%

2A

Lower-level evidence, e.g. smaller randomized trials

100%

2B

Lower-level evidence, required two rounds of comments

80–100%

2C

Not supported by direct evidence, but published and adopted in clinical protocols

Key updates2

  • Broader use of rabbit anti-T-lymphocyte globulin (rATG)
  • Lower steroid doses for Grade 2 aGvHD with isolated skin or gastrointestinal (GI) manifestations
  • Fluticasone, azithromycin, and montelukast (FAM) for bronchiolitis obliterans syndrome
  • New treatment options for steroid-refractory (SR) aGvHD and cGvHD

Prophylaxis of GvHD2

  • Patients undergoing MUD allo-HSCT and patients undergoing matched-related donor (MRD) allo-HSCT who are at a high risk of GvHD should receive ATG
  • Prophylaxis with the calcineurin inhibitors cyclosporin or tacrolimus was considered equivalent
  • For patients receiving myeloablative conditioning (MAC) prior to allo-HSCT, the panel recommended methotrexate (MTX) + a calcineurin inhibitor
  • In common practice, the panel recommend a mycophenolate mofetil (MMF) regimen for patients receiving non-MAC and reduced intensity conditioning (RIC)

A summary of recommendations made by the panel for GvHD prophylaxis are shown in Table 2.

Table 2. Recommendations for GvHD prophylaxis2

Transplant or conditioning setting

Recommendations

% approval

Evidence & consensus category

MRD or MUD

Calcineurin inhibitor + antimetabolite

100

1

Sibling or MUD

Tacrolimus or cyclosporin, based on center experience 

100

1

MAC

MTX

100

1

MAC with contraindications to MTX or for patients who need rapid engraftment

MMF instead of MTX

100

2A

Non-MAC and RIC

MMF

100

2A

MUD

rATG

100

1

MRD allo-HSCT with PB and high risk of GvHD

rATG

95

2B

GvHD; graft-versus-host disease; MAC, myeloablative conditioning; MMF, mycophenolate mofetil; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; PB, peripheral blood; rATG, rabbit anti-thymocyte globulin; RIC, reduced intensity conditioning

Drug management during prophylaxis2

  • Level of evidence for this section is low
  • Target serum concentration of cyclosporin depends on the dosing schedule and transplant setting (Table 3)
  • Cyclosporin or tacrolimus duration of prophylaxis: 6 months (Table 3)
    • Dose tapering should be adjusted based on individual patient risk of relapse, T-cell chimerism and whether the patient has, or does not have, GvHD
  • Evidence was insufficient to recommend sirolimus as prophylaxis
  • ATG dose and duration shown in Table 3
    • No recommendations on timing of rATG administration are given based on a lack of evidence

Table 3. Recommendations for drug management during GvHD prophylaxis2

Drug/dosing

Recommendations

% approval

Evidence & consensus category

Cyclosporine

Start

Initiate on day before infusion of graft as two daily doses or 24-hour infusion. Initial dose: 3 mg/kg/day, IV

95

2B

Cyclosporine

Duration

Standard: 6 months

Adjust based on risk of relapse, chimerism, and presence/absence of GvHD

No GvHD: taper from 4 months until regimen stopped

High risk of relapse and BM graft (especially with complete chimerism): faster tapering

Signs of aGvHD (except mild cutaneous) or cGvHD: do not taper dose

Persistent disease or relapse but no GvHD: carefully taper

100

2A

Cyclosporine early target concentration

For two daily doses, target concentration for first 4 weeks post-transplant: 200–300 µg/L

For a continuous infusion, a higher target concentration is required

100

2A

Subsequent cyclosporine target concentration

Balance target concentration with risk of GvHD developing and relapse

In most cases of standard-risk HLA-matched transplant, target concentration: 100–200 µg/L until 3 months post-transplant with twice-daily dosing schedule

95

2C

Cyclosporine dose monitoring

Monitor with whole blood sampling for 12 hours after each dose, not using the lines the infusion was given with

100

2A

Cyclosporine doses adaptation

Adapt to avoid toxicity based on institutional guidelines

100

2C

MTX dose

Start

Initial dose: 15mg/m2, given as bolus IV injection on first day post-transplant

Duration

MAC transplants: two additional doses of 10 mg/m2 on Day 3 and Day 6 post-transplant, and a further dose on Day 11 post-transplant can be given

RIC transplants: Lower doses on Day 3 and Day 6 post-transplant

100

2A

MTX toxicity

Leucovorin rescue is recommended — however, there is no evidence supporting its use to reduce MTX toxicity or to enhance MTX efficacy

100

2A

Leucovorin dose

Start

24 hours post-MTX

Duration

One day post-transplant: 3 × 15 mg doses every 6 hours

Dose to increase to 4 × 15 mg doses every 6 hours after MTX doses 3, 6, and 11 days post-transplant

Leucovorin: IV injection

100

2A

MMF dose

IV or orally in 3 × 10–15 mg/kg doses

Adapt dose by toxicity

100

2A

MMF duration

Start

One day post-transplant

Duration

MRD: commonly ~ 30 days

MUD: 2–3 months

Adapt to risk of relapse and GvHD

Persistent disease/relapse and no GvHD: earlier stop of MMF should be considered

95

2B

rATG start and duration

No recommendations for timing have been given

 

 

rATG: Grafalon® dose

MRD: 30 mg/kg

MUD: 60 mg/kg

Lower doses (15–30 mg/kg) effective in some studies

95

2B

rATG: Thymoglobulin®

dose

MRD: 2.5–5 mg/kg

MUD: 4.5–6 mg/kg

Higher doses associated with higher risk of infectious complications

100

2A

aGvHD, acute graft-versus-host disease; BM, bone marrow; cGvHD, chronic graft-versus-host disease; GvHD, graft-versus-host disease; IV, intravenous; MAC, myeloablative conditioning; MRD, matched related donor; MTX, methotrexate; MUD, matched unrelated donor; rATG, rabbit anti-thymocyte globulin; RIC, reduced intensity conditioning

aGvHD treatment2

  • Systemic treatment should be given for Grade ≥ 2 aGvHD
  • Grade 2 aGvHD with isolated skin or upper GI manifestations: treat with lower steroid doses (Table 4)
  • Choice of second-line therapy for SR GvHD:
    • Little data are available to compare options
    • No standard second-line treatment exists
    • Options are shown in Table 4
    • Patients should be enrolled on clinical trials where possible
  • aGvHD with GI involvement: non-absorbable oral steroids (Table 4) in addition to systemic corticosteroids

Table 4. Treatment of aGvHD2

Setting

Recommendations

% approval

Evidence & consensus category

aGvHD

Treatment of aGvHD should be based on clinical signs. Biopsy prior to initiation of treatment is recommended, but treatment should not be delayed while awaiting histology

100

2C

Grade ≥ 2 aGvHD

Systemic treatment

100

1

First-line treatment for aGvHD

Methylprednisolone (2 mg/kg/day) or prednisone (2.0–2.5 mg/kg/day) 

100

1

Grade 2 aGvHD with isolated skin or upper GI manifestations

Lower steroid doses, e.g. 1 mg/kg/day methylprednisolone or prednisone

100

1

Tapering of steroid doses

No reduction in prednisolone for the first 7 days post-transplant but parenteral steroids can be stopped, and oral steroids used until signs of aGvHD have gone.

Tapering should be slow and dependent on response.

With CR: reduce dose to 10% of initial dose over ~4 weeks.

100

1

Skin aGvHD

Grade 1: topical steroids

More advanced disease: steroids + systemic treatment

100

2C

GI aGvHD

Non-absorbable oral steroids (budesonide [9 mg/day] or oral beclomethasone [1.3–2.0 mg four times/day]) in addition to systemic corticosteroids

100

1

Corticosteroid resistance or dependence

Second-line treatment

100

2C

Second-line treatment

Current practice, one of the following: alemtuzumab, α1-antitripsin, basiliximab, cellular therapies, daclizumab, extra-corporal photopheresis, fecal microbiota transfer, JAK inhibitors, MMF, MTX, pentostatin, rATG, sirolimus, and vedolizumab

100

2A

aGvHD, acute graft-versus-host disease; CR, complete response; GI, gastrointestinal; MMF, mycophenolate mofetil; MTX, methotrexate; rATG, rabbit anti-thymocyte globulin; SR, steroid refractory 

cGvHD treatment2

  • First-line treatment for newly diagnosed cGvHD: steroids
  • Severe cGvHD: addition of another immunosuppressant to reduce steroid use
  • No standard second-line treatment for cGvHD
    • Follow institutional guidelines
    • Enroll patients in clinical trials where possible
    • Most widely used second-line treatment, in addition to corticosteroids, are shown in Table 5

Table 5. Treatment recommendations for cGvHD2

Setting

Recommendations

% approval

Evidence & consensus category

cGvHD

Decision to start treatment based on symptom type, severity, and dynamics of progression, e.g. disease risk, chimerism, and MRD results

100

2C

Newly diagnosed cGvHD

First-line treatment: steroids

100

2A

Severe cGvHD

Addition of another immunosuppressant to minimize steroid use

95

2C

Corticosteroid choice

First-choice: prednisone, 1 mg/kg orally

100

2C

Treatment for patients who are already on corticosteroids

Dose of corticosteroid can be increased (if < 1mg/kg) and an alternative strategy applied, e.g. administration of calcineurin inhibitor or extracorporeal photopheresis

95

2C

Treatment for patients who are on full-dose corticosteroid and cyclosporin at cGvHD onset

No standard treatment available — continuation + supportive measures is an option, changing immunosuppressive therapy is often done — treatment in clinical trials is recommended

100

2C

Bronchiolitis obliterans syndrome

FAM regimen + systemic steroids

Prolonged use of azithromycin after resolution is not recommended

100

2A

Assessment of first-line efficacy of cGvHD

Wait at least one month after treatment start before assessment

100

2C

Second-line treatment of cGvHD

Follow institutional guidelines and enroll patients in trials where possible

Most widely used second-line treatment, in addition to corticosteroids are calcineurin inhibitors, extracorporeal photopheresis, ibrutinib, JAK inhibitors, MMF, rituximab, mTOR inhibitors, pentostatin, proteasome inhibitors, and tyrosine kinase inhibitors

95

2B

cGvHD, chronic graft-versus-host disease; FAM, fluticasone, azithromycin, and montelukast; MMF, mycophenolate mofetil; MRD, minimal residual disease; mTOR, mammalian target of rapamycin

Limitations

  • Conflicting evidence within publications
  • In SR aGvHD, novel agents have been added to the available treatment options, however none have been compared to existing second-line treatment options
  • Cord blood transplant recommendations have not been updated due to a decline in the number of cord blood transplants in Europe
  • Despite the common use of post-transplant cyclophosphamide in MRD and MUD allo-HSCT, no formal recommendation has been given in this review due to a lack of long-term outcome data

Conclusion

The updated guidelines established a high level of consensus (≥ 95%) in recommendations for the prevention and treatment of GvHD. However, it is likely that, as with the 2014 recommendations, implementation into clinical practice will not be standardized and adherence will vary. The authors plan to conduct an audit following the circulation of these amended guidelines to best understand any barriers to implementation and understand if clinicians are able to adhere to them.

References
  1. Ruutu T. et al. The EBMT–ELN working group recommendations on the prophylaxis and treatment of GvHD: a change-control analysis. Bone Marrow Trans. 2016 Nov 28. 52:357–362. DOI: 10.1038/bmt.2016.298
  2. Penack O. et al. Prophylaxis and management of graft versus host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow Transplantation. Lancet Haem. 2020 Feb 1. 7(2): e157–167. DOI: 10.1016/S2352-3026(19)30256-X
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