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Monthly theme | GvHD prophylaxis

Oct 8, 2019

Graft-versus-host disease (GvHD) is a common complication of allogeneic hematopoietic stem cell transplant (allo-HSCT). GvHD can be acute (aGvHD) or chronic (cGvHD); the latter is the most common long-term complication post-transplant and is the leading cause of non-relapse mortality (NRM) in transplant survivors who are otherwise cured of their disease.1 The specific risk for GvHD depends upon multiple factors including; stem cell source, patient age, the choice of conditioning regimen and the GvHD prophylaxis used.2 There are several options for GvHD prophylaxis, with many more under investigation.

This month, the GvHD Hub are focusing on the topic of GvHD prophylaxis. This article provides an insight into the current standard of care (SOC) regimens for GvHD prophylaxis, therapies under investigation, and expert interviews on the topic.

EBMT-ELN working group recommendations for GvHD prophylaxis3,4

The European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN) guidelines recommend patients receiving allo-HSCT, with standard-risk disease, from a matched-related donor (MRD) or matched-unrelated donor (MUD), with bone marrow (BM) or peripheral blood stem cells (PBSCs) as the stem cell source, are treated with:3,4

  • A calcineurin inhibitor, commonly tacrolimus or cyclosporine A (CsA)
  • An antimetabolite such as methotrexate (MTX) or mycophenolate mofetil (MMF) for patients requiring rapid engraftment
  • In MUD, antithymocyte globulin (ATG) is recommended

To read more about the EBMT-ELN guidelines from the 1st EBMT GvHD Summit, click here.

Clinical trials and analyses for GvHD prophylaxis

In addition to current SOC regimens, there are many ongoing clinical trials and investigations that are aiming to define the optimal prophylaxis treatment for each transplant situation and test new novel agents and combinations. The GvHD Hub has summarized some of these in Tables 1–3, with links to the original coverage from the GvHD Hub.

Table 1. Studies investigating post-transplant cyclophosphamide (PtCy) alone, or in combination, as GvHD prophylaxis 

Therapy and link to article


Trial details




Patients with sickle cell disease

Case series of four patients. Promising results using PtCy as GvHD prophylaxis with good one-year survival outcomes and reasonable toxicity



Phase II study using PBSC in patients with severe aplastic anemia

Encouraging results for PtCy as a single agent in SD transplants using PBSC. There were lower rates of aGvHD and cGvHD in the PtCy group compared to historical cohorts using MTX

ATG + PtCy

MUD and mismatched unrelated donor (MMUD)


PtCy + ATG in patients undergoing MUD allo-HSCT with PBSCs resulted in low rates of grade III–IV aGvHD and cGvHD with acceptable safety and relapse rates

Low-dose (LD) ATG + LD PtCy with CsA and MMF


Phase II study using unrelated cord blood + PBSC as stem cell source

LD ATG + LD PtCy is a promising prophylaxis regimen in the haplo-setting.

ATG + PtCy + CsA

MUD, MRD, haploidentical and MMUD

Patients with acute myeloid leukemia (AML) treated with reduced intensity conditioning (RIC) and given PBSC

Following RIC, ATG + PtCy led to low rates of aGvHD and cGvHD

ATG + PtCy + CsA


RIC with low-dose bulsulfan, fludarabine, total body irradiation +

Encouraging results for patients receiving RIC + ATG + PtCy + cyclosporine after haploidentical transplant, with lower rates of grade II–IV GvHD. However, there were higher rates of viral reactivation

PtCy vs calcineurin inhibitor (MMF or MTX)



Single-agent PtCy was superior to MMF or MTX in relation to grade II–IV and III–IV aGvHD with improved overalls survival (OS), event-free survival (EFS) and GvHD/relapse-free survival (GRFS)

During the EBMT annual meeting, Frankfurt, DE, 2019, the GvHD Hub spoke to Arnon Nagler, Tel Aviv University, Tel Aviv, IL, regarding whether PtCy or ATG should be used as prophylaxis in haploidentical SCT. Watch the video below:

Should we use PTCy or ATG as GvHD prophylaxis in haploidentical stem cell transplantation?

Table 2. Studies investigating calcineurin inhibitor combinations for GvHD prophylaxis 

Therapy and link to article


Trial details


Tacrolimus + ATG


Prospective phase II study

The use of tacrolimus + ATG did not meet the primary endpoint (reduction of grade II–IV aGvHD below the pre-determined threshold). 12/20 patients developed aGvHD and the study was terminated after the first stage

MMF + tacrolimus

Not reported (NR)


Pediatric, adolescent and young adults

MMF + tacrolimus prophylaxis was safe and efficient in this population

MMF-tacrolimus, MMF-CsA, MTX-tacrolimus and MTX-CsA


GvHD prophylaxis after RIC with PBSC as stem cell source

All four regimens yielded equal benefits in relation to outcome. In MUD, RIC, allo-HSCT, MMF-cyclosporine was inferior compared to MTX-based regimens for aGvHD prophylaxis, but no difference in cGvHD and OS.

Sirolimus + CsA + MMF (CMMS) vs standard treatment alone


Multicenter, randomized phase III trial

CMMS reduced the incidence of aGvHD and improved OS and progression-free survival (PFS) compared to standard treatment alone. Results indicate the CMMS combination should be used for patients receiving MMUD transplant who are treated with non-myeloablative conditioning

 Table 3. Studies investigating novel agents and other regimens as GvHD prophylaxis 

Therapy and link to article


Trial details


Azacitidine + mini-MMF and tacrolimus


Interim phase II results

Azacitidine can be used safely as GvHD prophylaxis after day +7 after MUD

Mesenchymal stromal stem cells (MSCs)


Meta-analysis on MSCs to prevent cGvHD

Using MSCs as prophylaxis was safe and effective in preventing cGvHD

Tocilizumab + tacrolimus + MTX


Phase II study

Addition of tocilizumab to SOC reduced rates of aGVHD, though OS and transplant-related mortality (TRM) rates were unaffected

Invariant natural killer T-cells (iNKT)



Preclinical and clinical data support the use of iNKT cells in aGvHD prophylaxis

Abatacept or placebo + calcineurin inhibitor and MTX


Multicenter, randomized, double-blind, placebo- controlled phase II study, ABA2,

Short course abatacept is safe and effective in preventing aGvHD without compromising relapse, meaning matched donor transplant may be able to become more widely available

Vedolizumab + tacrolimus + MTX


Phase Ib study

Treatment-emergent adverse events were consistent with the expected risks with no dose-limiting toxicities. Promising results with low cumulative incidences of grade II–IV aGvHD and severe lower gastrointestinal aGvHD. Watch the GvHD Hub interview with Yi-Bin Chen below

Maraviroc + tacrolimus + MTX


Phase II study in patients receiving RIC

Maraviroc administered for three months prevents aGvHD and cGvHD, providing superior GRFS compared to patients receiving maraviroc for one month



Japanese, nationwide, retrospective analysis in pediatric patients

MMF was found to be safe and effective in pediatric patients

The GvHD Hub were also pleased to speak to Yi-Bin Chen at the American Society of Hematology (ASH) meeting, 2018, about vedolizumab + SOC for GvHD prophylaxis.

Vedolizumab plus standard of care for GvHD prophylaxis

Over the coming weeks, the GvHD Hub will be publishing new content surrounding GvHD prophylaxis, featuring the latest data and educational content – stay tuned!

  1. Lee S.J. Classification systems for chronic graft-versus-host disease. Blood. 2017 Jan 05. DOI: 10.1182/blood-2016-07-686642
  2. Jacobsohn D.A. and Vogelsang G.B. Acute graft versus host disease. Orphanet J Rare Dis. 2007 Sep 04. DOI: 10.1186/1750-1172-2-35
  3. Ruutu T. et al. Prophylaxis and treatment of GVHD: EBMT-ELN working group recommendations for a standardized practice. Bone Marrow Trans. 2014 Jul 29. DOI: 10.1038/bmt.2013.107
  4. Penack O. Prophylaxis and treatment of GvHD: EBMT-ELN working group recommendations for standardized practice. 1st EBMT GVHD Summit. Warsaw, PL. 2019 May 16–18. Oral presentation