An overview of EBMT recommendations on prophylaxis and treatment of acute and chronic GvHD

This article is a summary of the European Society for Blood and Marrow Transplantation (EBMT) webinar entitled ‘Prophylaxis and management of GvHD’ delivered by Olaf Penack, Charité - Universitätsmedizin Berlin, Berlin, DE, on May 11, 2020.

EBMT recommendations¹

Prophylaxis

Graft-versus-host disease (GvHD) is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a significantly negative impact on recipient morbidity and mortality. In order to minimize the risk of developing GvHD patients should be given prophylactic therapy.

The EBMT has developed a set of recommendations on GvHD prophylaxis, which apply to the most common allo-HSCT settings of standard risk malignancy, adult patients, matched related (MRD) and matched unrelated (MUD) donors. However, those recommendations do not apply to pediatric patients, haploidentical transplantations, or mismatched unrelated donor transplants.

• Tacrolimus or cyclosporine A (CsA) can be used in transplants involving siblings or MUD, depending on the center experience
• A calcineurin inhibitor with an antimetabolite should be used in patients undergoing MRD or MUD transplant:
  • For patients receiving myeloablative conditioning, addition of methotrexate (MTX) is recommended as increased survival probability is observed with MTX + CsA vs CsA alone²
  • For patients receiving non-myeloablative conditioning, addition of mycophenolate mofetil (MMF) is recommended, although comparative data for MMF vs MTX are lacking in this setting
• Anti-thymocyte globulin (ATG) is recommended in patients undergoing MUD and MRD allo-HSCT, due to the ability to reduce the incidence of chronic (c) GvHD^3,4

Recommendations on drug management

CsA

Retrospective studies demonstrated that higher levels of CsA during the first weeks after allo-HSCT were associated with a lower incidence of acute (a) GvHD.⁵ Therefore, the EBMT recommends 200–300 µg/L CsA target concentration in the first 4 weeks after transplantation. Decision on the subsequent CsA target level should balance the risk of GvHD and tumor relapse. With transplants carrying a standard GvHD risk according to the current practice and expert opinion, the EBMT recommends the use of CsA 100–200 µg/L, twice daily for up to 3 months after transplantation.

The recommended duration of CsA prophylaxis is 6 months, with dose tapering from 3 months onwards if no GvHD is detected. However, in cases where signs of aGvHD or cGvHD are present, except for mild skin involvement, tapering should not be considered.

MMF

MMF prophylaxis is usually used for 30 days in transplants from MRD and for 2–3 months in transplants involving MUD and should be adapted according to individual risk of tumor and GvHD relapse, such as sex match and dose of infused T cells. An earlier withdrawal of MMF may be considered in patients with a persistent disease or tumor relapse with no signs of GvHD.

Treatment of aGvHD

EBMT- National Institutes of Health (NIH)- Center for International Blood & Marrow Transplant Research (CIBMTR) Task Force position statement on steroid resistance and dependence in aGvHD:⁶

Steroid refractoriness or resistance is defined as

• Progression in any organ within 3–5 days of therapy onset with ≥ 2 mg/kg/day of prednisone equivalent
• Failure to improve within 5–7 days of treatment initiation
• Incomplete response after > 28 days of immunosuppressive treatment including steroids

Steroid dependence is defined as

• The inability to taper prednisone < 2 mg/kg/day after an initially successful treatment of ≥ 7 days
• The recurrence of aGvHD activity during steroid tapering

Systemic treatment is recommended to be initiated for aGvHD of Grades ≥ II. The advice is based on studies showing no benefit of 1 mg prednisolone vs observation treatment for Grade I aGvHD⁷ and no difference in response, treatment‐related mortality (TRM), or incidence of infections between 2 and 10 mg/kg/day of methylprednisolone.⁸

Additionally, Grade II aGvHD with isolated skin or upper gastrointestinal (GI) tract can be treated with lower steroid doses of 1 mg/kg/day methylprednisolone or prednisone without reduced benefit on response, TRM, or incidence of infections.⁹

Recommendations on steroid dose tapering and resistance include:

• Steroid dose should not be reduced during the first 7 days of treatment
• Dose tapering should be done gradually and dependent on the response
• In patients who achieve a complete response, dose should be reduced gradually to 10% of the starting dose over a period of 4 weeks
• In patients with steroid resistance or dependence, second-line treatment should be initiated
  • Currently, there is no standard, second-line treatment for GvHD and centers should follow institutional advice, with treatments available including
    • Alemtuzumab
    • Alpha-1 antitrypsin
    • Basiliximab
    • Cellular therapies, including mesenchymal cells and regulatory T cells
    • Daclizumab
    • Extracorporeal photopheresis (ECP)
    • Fecal microbiota transplant
    • Janus (JAK) 1/2 inhibitors
    • MMF
    • MTX
    • Pentostatin
    • ATG
    • Sirolimus
    • Vedolizumab

Treatment of cGvHD

It is recommended to base treatment decisions for cGvHD on the symptom type and severity, as well as the speed of progression, disease risk, chimerism, and minimal residual disease.

Prednisone at a dose of 1 mg/kg should be used as a first-line treatment of newly diagnosed cGvHD. However, in patients who are already on doses < 1 mg/kg of corticosteroid treatment, the dose can be increased and an alternative strategy, such as calcineurin inhibitor or ECP can be added. For initial assessment of efficacy of the therapy, the treatment should last ≥ 1 month.

There is a lack of evidence that addition of azathioprine, CsA, thalidomide, MMF, or hydroxychloroquine to prednisone offers benefit. However, in severe cGvHD, addition of immunosuppressants other than steroids may be considered.

For the treatment of bronchiolitis obliterans syndrome, combination of fluticasone, azithromycin and montelukast (FAM) in combination with systemic steroids is recommended. However, FAM should not be used in the prophylaxis setting.

In the case of aGvHD, currently there is no standard second-line treatment for cGvHD. Centers should follow their institutional guidelines, and where possible enroll patients on clinical trials. The most commonly used treatment options in addition to corticosteroids include:

• Calcineurin inhibitors
• ECP
• Ibrutinib
• JAK1/2 inhibitors
• MMF
• Rituximab
• Mammalian target of rapamycin (mTOR) inhibitors
• Pentostatin
• Proteasome inhibitors
• Tyrosine kinase inhibitors

Highlighted new aspects of the 2019 version of recommendations

• ATG is recommended for GvHD prophylaxis in all patients undergoing MUD allo-HSCT and in patients with a high risk of developing GvHD undergoing MRD transplant
• A lower steroid dose, such as 1 mg/kg/day methylprednisolone or prednisone can be used in patients with Grade II aGvHD displaying isolated skin or upper GI tract involvement
• FAM in combination with steroids is recommended as initial treatment for bronchiolitis obliterans syndrome
• More therapeutic agents have been added to the list of treatment options for steroid-refractory (SR)-GvHD, aGvHD, and cGvHD (e.g. JAK1/2 inhibitors and ibrutinib) when compared to the previous version
• Recommendations for GvHD management in cord blood transplantation have been removed from the 2019 version due to the considerable decline in the use of cord blood as a graft source

Novel therapies

The search for novel druggable targets and therapies for GvHD continues, with 125 clinical trials currently recruiting patients. Treatment options in development and recently approved for aGvHD and cGvHD that were highlighted by the speaker are presented in Table 1.

Table 1. Novel therapies⁹

aGvHD, acute graft-versus-host disease; BTK, Burton kinase inhibitor; CCR5, CC chemokine receptor 5; cGvHD, chronic GvHD; CTLA4, cytotoxic T-lymphocyte-associated protein 4; HDAC, histone deacetylase; IgG, immunoglobulin G; IL, interleukin; JAK, Janus kinase; SYK, spleen tyrosine kinase; SR-(a)GvHD, steroid-refractory (a)GvHD
Therapeutic agent	Mode of action	Indication
Ruxolitinib	JAK1/2 inhibitor	SR-aGvHD
Tocilizumab	Antibody against IL-6 receptor	aGvHD prophylaxis and treatment of SR-GvHD
Alpha-1 antitrypsin		SR-GvHD
Brentuximab vedotin	Anti-CD30 antibody–drug conjugate	SR-GvHD
Vorinostat	HDAC inhibitor	aGvHD
Abatacept	Fusion protein of CTLA4 and heavy chain IgG	SR-GvHD
Vedolizumab	α4β7 integrin inhibitor	aGvHD prophylaxis and treatment of SR-aGvHD
Maraviroc	CCR5 inhibitor	aGvHD prophylaxis
Rituximab	Antibody against CD20	cGvHD
Ibrutinib	BTK inhibitor	cGvHD
Fostamatinib	SYK inhibitor	Potentially cGvHD

You can read the more on the updated consensus of the EBMT on prophylaxis and management of post-transplant GvHD here.