Chronic GVHD: Where are we? Where do we want to be? Will immunomodulatory drugs help?

Abstract

Chronic GVHD (cGVHD) is an important problem after allotransplants. Some risk factors for cGVHD are similar to those of acute GVHD (aGVHD) but others are distinct indicating sometimes overlapping but unique pathogeneses. Precise incidence and prevalence data of cGVHD are lacking because of diverse diagnostic criteria but a 50% risk is a reasonable estimate. Incidence and prevalence of cGVHD are probably growing because of increased use of unrelated donors, blood rather than bone marrow (BM) grafts, decreased early transplant-related mortality (TRM) and increasing frequency of allotransplants. Pathophysiology of cGVHD is complex and poorly understood. Notably, no reliable surrogate end point to predict mechanism(s) of cGVHD has been identified. Therapy of cGVHD is unsatisfactory. Corticosteroids are effective but other drugs are controversial and few are rigorously tested in randomized trials. Highly variable response rates are reported because of small sample sizes and inconsistencies in eligibility, diagnostic and response criteria. We focus on the possible role of immunomodulatory drugs (IMiDs), thalidomide lenalidomide and pomalidomide, in preventing and treating cGVHD. The data suggest activity of thalidomide but at doses not clinically practical in many instances. There are few data with lenalidomide. Trials of pomalidomide, which has immune activities like thalidomide but with fewer adverse effects, are beginning. Because cGVHD is not recently reviewed in Bone Marrow Transplantation, we give a brief background and discuss challenges in diagnosing, understanding and treating cGVHD including the recently proposed National Institutes of Health consensus criteria for cGVHD. 1-3 It occurs in about 50% of persons surviving 41 year post transplant and causes substantial morbidity and mortality. There has been little progress over the past 30 years in preventing and/or treating cGVHD. Moreover, incidence and prevalence are increasing because of several factors including: (1) increased use of blood cell rather than BM grafts; (2) increasing use of incompletely HLA-matched related and unrelated donors; (3) increased use of donor-lymphocyte infusions, especially in the context of reduced-intensity allotransplants; (4) increased number of transplants done each year; and (5) increased proportion of transplants in older persons. [4][5][6] The focus of our review is on the use and potential of IMiD-class drugs to prevent and/or treat cGVHD. These drugs have unique, complex immune regulatory activities. As a prelude, we review some relevant definitional, laboratory and clinical features of cGVHD.

Phase-1/-2 study of pomalidomide in chronic GvHD

“…Consequently, it is impossible to predict the impact of pomalidomide on cGvHD except in a clinical trial. 11 This was a single institution, open label, pilot study of safety and efficacy of pomalidomide in subjects with corticosteroid-refractory cGvHD (NCT00770757). Approval was obtained from the Institutional Review Board and subjects gave written informed consent.…”

Long‐term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta‐analysis

“…Chronic GVHD is currently a tough problem with few prophylaxis interventions effective (27). Our results showed ATG was effective in prevention of overall cGVHD in myeloablative conditioning (6,10,11,(14)(15)(16)(17)(18)(24)(25)(26), and this effect was more obvious in extensive cGVHD (10,11,14,16,18,25).…”

Association of Killer Cell Immunoglobulin-Like Receptor Genes with the Graft versus Host Disease after Related Haematopoietic Stem Cell Transplantation in Patients with Haematological Malignancies from Republic of Macedonia

“…It is clear by now, that the GVHD involves different effector's cells, several cytokines in abundant quantities and affects the skin, liver and digestive tract but also produces a long-term immune deficiency [9]. However, it should be noted that not all the recipients of even partially unmatched transplants develop clinical disease, while the characteristic exanthema may occur in syngeneic (identical twin) transplants.…”