Current Approaches for the Prevention and Treatment of Acute and Chronic GVHD

Abstract

Whereas aGVHD has strong inflammatory components, cGVHD displays autoimmune and fibrotic features; incidence and risk factors are similar but not identical; indeed, the aGVHD is the main risk factor for cGVHD. Calcineurin Inhibitors (CNI) with either Methotrexate (MTX) or Mycophenolate (MMF) still represent the standard prophylaxis in HLA-matched allogeneic stem cell transplantation (HSCT); other strategies focused on ATG, Post-Transplant Cyclophosphamide (PTCy), Abatacept and graft manipulation. Despite the high rate, first-line treatment for aGVHD is represented by corticosteroids, and Ruxolitinib is the standard second-line therapy; investigational approaches include Microbiota transplant and the infusion of Mesenchymal stem cells. GVHD is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. It is a pleiotropic disease involving any anatomical district; also, Ruxolitinib represents the standard for steroid-refractory cGVHD in this setting. Extracorporeal Photopheresis (ECP) is still an option used for steroid refractoriness or to achieve a steroid-sparing. For Ruxolitinib-refractory cGVHD, Belumosudil and Axatilimab represent the most promising agents. Bronchiolitis obliterans syndrome (BOS) still represents a challenge; among the compounds targeting non-immune effectors, Alvelestat, a Neutrophil elastase inhibitor, seems promising in BOS. Finally, in both aGVHD and cGVHD, the association of biological markers with specific disease manifestations could help refine risk stratification and the availability of reliable biomarkers for specific treatments.

Keywords: graft versus host prophylaxis; graft versus host treatment; transplantation.

Figure 1

Pathogenesis of aGVHD and main targetable pathways for prophylaxis and treatment. Simplified outline of the aGVHD pathogenesis and the possible specific interventions according to some targetable steps. 1—The conditioning damages host tissues and causes the release of inflammatory mediators with the activation of host APCs; this process is amplified in the GIT lumen, where the altered microbiota and the destruction of the intestinal barrier facilitate the stimulation of innate immunity. 2—Host APCs activate donor T cells in the secondary satellite lymphoid organs 3—After expansion in the lymph nodes, activated T cells are primed, differentiating to type 1 T helper (Th1)/type 1 CD8+ T (Tc1) or Th17/Tc17 cells, and become able to target specific organs; 4—The lymphocyte traffic to the target organs is mediated by adhesion molecules such as L-selectin, CCR7, integrin a4b7; 5—activated T-cells can induce the tissue damage, both directly and by recruiting non-immune effector cells, (such as monocytes, PMN and NK) cells, and cytokines, such as TNF. The progressive loss of Treg contributes to the uncontrolled expansion of alloreactive T cells. Targetable pathways for Prophylaxis: 1—alloreactive T-cell depletion (in vivo/ex vivo): ATG; Campath; 2—early PTCy blocks alloreactive donor T cell expansion; 3—CD34 + selection/a-b depletion; 4—inactivating TCR (CNI: CSA, Tac); Sirolimus is a mTOR inhibitor which inhibits effector T-lymphocytes; 5—Abatacept (CTLA4-Ig) blocks T cell-APC co-stimulation; 6—Anti-homing compounds interfere with the alloreactive T-cell migration in the target organs (Vedolizumab; Maraviroc). Targetable pathways for Therapy: 1—anti-inflammasome treatment (Prednisone; Ruxolitinib/Itacitinib; Tocilizumab; Etanercept/Infliximab; 2—blocking T-cell priming: anti-IL2 (Basiliximab); 3—Primed T cells are susceptible to the Jak1/2 inhibitor Ruxolitinib or anti-IL-6R-antibodies (Tocilizumab) anti-TNF-antibodies; 4—Begelomab (anti-CD26) blocks alloreactive T cell migration to target organs; 5—treatments aimed to protect or regenerate target organs: IL22, FMT, anti-1 anti-trypsin; 6—Agents with pleiotropic activity: MSC; PDSC; multitarget treatments (ECP induces tolerogenic dendritic cells; reduces inflammasome; augments Treg). Abbreviations: aGVHD, acute GVHD; GIT, gastrointestinal tract; GIsc, gastrointestinal stem cells; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; HP APC, hematopoietic antigen-presenting cell; non-HP APC, non-hematopoietic antigen-presenting cell; TCR, T cell receptor; IFN, interferon; IL, interleukin; Th, helper T lymphocyte; Tc, cytotoxic T lymphocyte; T reg; regulatory T cells; PMN, polymorphonucleated cells; NK, natural killer cells; PTCY, post-transplant cyclophosphamide; CNI, Calcineurin Inhibitor; CSA, cyclosporine A; Tac, Tacrolimus; MTX, Methotrexate; MMF, Mycophenolate; ECP, Extracorporeal Photopheresis; FMT, fecal microbial transplant; MSC, mensenchimal stem cell; PDSC, placenta-derived stem cells.

Figure 2

Pathogenesis of cGVHD and main targetable pathways for prophylaxis and treatment. The three-step development of c-GVHD with the treatment targeting the specific pathways. Phase I: Inflammasome is the starting point of cGVHD and could be clinically undetectable; conditioning and aGVHD cause thymus injury with loss of central tolerance. Phase II: T and B cell dysregulation; thymic dysfunction impairs donor Treg generation and the negative selection of autoreactive donor T cell clones that escape into the periphery. Tfh cells expand in lymphoid organs and promote the development of allo/autoreactive B cells in germinal centers; BAFF facilitates survival and expansion of the aberrant B cell clones; the aberrant B cells produce auto or allo-antibodies which induce macrophage polarization in presence of IL17/GM-CSF Phase III: Fibrosis and tissue remodeling; activated macrophages produce high levels of profibrotic cytokines (TGF-b, PDGF) with continuous stimulation of fibroblast which in turn produce exaggerated collagen matrix with tissue fibrotic remodeling. Targetable pathways: 1—The inflammasome and the subsequent phase of deregulation can be targeted by drugs/treatments with anti-inflammatory properties (PDN/ECP/Ruxolitinib); 2—Immune dysregulation and aberrant B-cell activity. The imbalanced Treg/T effector cell reconstitution (and the altered ROCK-2 signal) can be restored by Belumosudil, low-dose IL-2 treatment or by Treg infusions; ECP preserves Treg function. Belumosudil blocks Th17 differentiation and GC reactions by inhibiting Tfh cell generation (like Ruxolitinib); constitutive B cell receptor signaling (BTK) and intracellular downstream Syk can be inhibited by BTK Ibrutinib or Fostamatinib, while Rituximab blocks auto-antibodies production and Bortezomib inhibits long-lived autoreactive plasma cells. 3—Macrophage polarization and fibroblast activation with exaggerated collagen production: fibrosis and tissue remodeling. Axatilimab inhibits CSF1-R+ macrophages secreting profibrotic cytokines; -TGF-β production is inhibited by Belumosudil, Nintedanib, Pirfenidone or by Imatinib; these compounds also inhibit the fibrotic process via PDGF-R. Abbreviations: cGVHD, chronic GVHD; aGVHD, acute GVHD; T reg, regulatory T cell; Tfh, helper T follicular lymphocyte; GC, germinal center; BAFF, B cell activating factor; PDN, prednisone; ECP, Extracorporeal Photopheresis; BTK, Bruton tyrosine kinase; TKI, tyrosine kinase inhibitor.

Figure 3

How we manage GIT-GVHD. Proposal of a clinical algorithm for managing patients with grade II–IVlower GIT aGVHD: first of all, do not wait for histologic confirmation in case of suspected GIT GVHD; check the chance to enroll the patient in a clinical trial: if not, start immediately standard first-line therapy with PDN 2 mg/kg and monitor response every day. If worsening after 72 h or without improvement after 5–7 days, a treatment change is strongly suggested (check again for a clinical trial availability). In the case of CR, a quick steroid tapering (or a slow tapering in the case of PR) should be considered; in our personal view, we consider the early ECP association in order to allow an easier steroid tapering, preventing possible flares and reducing the risk of infections. The standard second-line treatment is represented by Ruxolitinib (Etanercept or ECP represents possible alternative treatments), but enrollment in clinical trials (if available) is a valuable option both in steroid-refractory and in Ruxolitinib-refractory aGVHD. Fecal Microbiota Transplant or Mesenchymal Stem cell infusions are currently under evaluation: 1—NCT04769895: MaaT013 as Salvage Therapy in Ruxolitinib Refractory GI-aGVHD Patients; 2—NCT06075706 Treatment Of Steroid-Refractory Acute Graft-versus-host-Disease With Mesenchymal Stromal Cells Versus Best Available. GIT, gastro-intestinal tract; Neg, negative; PDN, Prednisone; CR, complete response; PR, partial response; ECP, Extracorporeal Photopheresis.

Figure 4

Approach to the patient with suspected pulmonary GVHD involvement: the onset of dyspnea on (with or without other symptoms) and/or the deterioration of the LFTs require a careful work-up based on both imaging and Bronchoalveolar lavage, in order to exclude infectious complications; DLCO testing, although not mandatory, is useful since its reduction is frequent in restrictive syndromes. An isolated reduction in FEV1 (or FEV1/VC ratio) of at least 10% over 3 months, if associated with distinctive imaging findings (bronchiectasis, air trapping; bronchial wall thickening) points towards typical lung GVHD (BOS). Alteration of the LFTs, but with a preserved FEV1/VC ratio (often with reduced DLCO) instead points towards a restrictive syndrome or a mixed form (which may be referred to an atypical form of cGVHD). In this case (in the absence of microbiological/virological isolations) radiological imaging can be indicative of either rare forms (PPFE; NSIP) or may show consolidations indicative of COP. Steroid treatment can be rapidly curative in COP while it rarely is in BOS; in the case of SR-cGVHD or steroid-dependence, the association of ECP for 10-12 months is an option; Ruxolitinib is indicated in any case in SR-cGVHD forms, while in Ruxolitinib-refractory forms, consider the use of Belumosudil (if available); other options include the use of Imatinib and Ibrutinib. Ancillary treatment with FAM is generally recommended in BOS forms, while in young patients with severe impairment of lung function the option of a lung transplant should be considered. Abbreviations: LFT: lung functional test; BAL: Broncho-Alveolar Lavage; DLCO: Diffusion Lung Carbon Monoxide; FEV1: Forced Expiratory Volume in the first second; VC: vital capacity; BOS: Bronchiolitis obliterans syndrome; RLD: Restrictive Lung Disease; PDN: Prednisone; FAM: Fluticasone-Azithromycin-Montelukast; ECP: Extracorporeal Photopheresis; CT: Computed Thomography; PPFE: Pleuropaenchimal fibroelastosis; NSIP: Non-specific interstitial Pneumonia; BOOP: Bronchiolitis obliterans organizing pneumonia; COP: Cryptogenic organizing pneumonia; SR-cGVHD: Steroid-refractory chronic GVHD.