The Best GVHD Prophylaxis: or at least progress towards finding it.

Available online 20 October 2023, 101520

Best Practice & Research Clinical Haematology

Author links open overlay panel, , Abstract

Options for GVHD prophylaxis after allogeneic hematopoietic cell transplantation can best be chosen by understanding the pathophysiology of GVHD. Interventions to limit T cell activation, expansion and subsequent tissue injury can each be utilized in designing successful GVHD prevention strategies Depleting, tolerizing or blunting T cells or host antigen presenting cells (APCs), blocking co-stimulation or more broadly suppressing inflammation have all been used. Interventions which spare regulatory T cells (Tregs) may prevent GVHD and facilitate controlled allo-responses and not compromise subsequent relapse risks. Graft manipulations and pharmacologic interventions each have potential to limit the morbidity of GVHD while permitting the immunocompetence to prevent infection or relapse.

Section snippetsGVHD Pathogenesis

The pathogenesis of graft versus host disease (GVHD) starts with host tissue injury which activates or damages host antigen-presenting cells (APCs), augments class I HLA and adhesion molecule expression and creates an inflammatory milieu. Secondly, donor T cells recognize host polypeptides as foreign recognizing major and minor HLA histocompatibility molecules plus tissue antigens as targets. Thirdly, T-cell recognition, activation, expansion and host tissue injury follows with migration of

Defining GVHD

Clinical challenges in GVHD prophylaxis include discrimination of GVHD from other clinical mimics that simulate the symptomatology (drug-associated skin eruptions, other causes of cholestasis and alternative etiologies for diarrhea). Not only does the diagnosis need specific documentation, but its onset and what clinical components of the immune activation syndrome we call GVHD actually need therapy. Some components of this alloreactivity can be associated with favorable alloactivation that can

Options for Prophylaxis

Therapeutic interventions for either prophylaxis or early therapy fall in at least 3 therapeutic categories. To deplete, tolerize or inactivate donor T cells, investigators have used techniques of graft modulation such as ex vivo T-cell depletion, blocking co-stimulation most recently with abatacept, addback or enhancement of T reg numbers or function or adoptive transfer with NK, NKT, mesenchymal stem cells or others-- all to reduce the allogeneic signals and limit donor T cell activation.

The

Novel GVHD Prophylaxis

The newest and strikingly popular approach to GVHD prevention is the use of posttransplant cyclophosphamide (PTCy), generally given on day +3 and +4 as originally developed at Johns Hopkins (13). This approach deletes the allo-reactive expanding donor T cells and clinically can limit both acute and chronic GVHD (1417). Concerns about relapse, particularly with reduced intensity conditioning remain a subject of clinical study yet the therapy is easy to deliver, relatively inexpensive and has

PTCy

For RIC transplants in BMT CTN 1203, Tac + MTX (with/without bortezomib or marivaroc) versus PTCy (with Tac/MMF) compared with a control (CNI, methotrexate (Mtx)) from the CIBMTR. PTCy was preferred approach with the best GVHD-free, relapse free survival (GRFS) and thus was retained for future study (24) (Figure 3).

After ablative conditioning (BMTCTN 1301), Tac/Mtx and a bone marrow graft and single-agent PTCy with a bone marrow graft was compared to CD34 selection of peripheral blood stem

Co-stimulation blockade

Another promising approach developed from sophisticated understanding of how co-stimulation is essential for T cell activation and the toxic manifestations of GVHD. This involves abatacept as a supplement to calcineurin inhibitor (CNI) therapy to limit GVHD. In a prospective trial testing abatacept vs. placebo with CNI/Mtx (randomized/blinded in HLA matched related and URD) and open label single arm in 7/8 matched URD transplants comparing outcomes versus CIBMTR controls who received no ATG (27

Implications and Conclusions

These new promising approaches of PTCy and abatacept are great advances. PTCy can be considered as a current standard though it has not been fully tested in all settings. Its efficacy, easy administration and low cost all support its potential to help many more patients. Concerns with immune recovery and risks of infection or possible increased risks of graft failure in some subsets of recipients needs more careful evaluation and study. Co-stimulation blockade is similarly promising and newly

Uncited References

17.

References (28)Toshihito Hirai et al.Negrin; Activation of natural killer T cells enhances the function of regulatory T-cell therapy in suppressing murine GVHD

Blood Adv

(2021)

R.E. Fletcher et al.Posttransplantation cyclophosphamide expands functional myeloid-derived suppressor cells and indirectly influences Tregs

Blood Adv

(2023 Apr 11)

J. Bolaños-Meade et al.Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203)

Lancet Haematol

(2019 Mar)

Amandeep Salhotra et al.Waller, Mwe Mwe Chao, J Scott McClellan, Nathaniel B Fernhoff, Robert Lowsky, Mehrdad Abedi; Orca-Q Demonstrates Favorable GvHD-andRelapse-Free Survival in Haploidentical Transplants without Post-Transplant Cyclophosphamide