How I treat refractory acute GVHD

Abstract

Graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with considerable morbidity and mortality, particularly in patients who do not respond to primary therapy, which usually consists of glucocorticoids (steroids). Approaches to therapy of acute GVHD refractory to "standard" doses of steroids have ranged from increasing the dose of steroids to the addition of polyclonal or monoclonal antibodies, the use of immunotoxins, additional immunosuppressive/chemotherapeutic interventions, phototherapy, and other means. While many pilot studies have yielded encouraging response rates, in most of these studies long-term survival was not improved in comparison with that seen with the use of steroids alone. A major reason for failure has been the high rate of infections, including invasive fungal, bacterial, and viral infections. It is difficult to conduct controlled prospective trials in the setting of steroidrefractory GVHD, and a custom-tailored therapy dependent upon the time after HCT, specific organ manifestations of GVHD, and severity is appropriate. All patients being treated for GVHD should also receive intensive prophylaxis against infectious complications. IntroductionGraft-versus-host disease (GVHD) is the most frequent complication after allogeneic hematopoietic cell transplantation (HCT). First described as "secondary disease" in mice 1 the syndrome was shown to be triggered by immunocompetent donor cells. 2,3 As soon as the clinical basis for human HCT was established, it was apparent that GVHD would be a formidable problem even with transplantation of marrow cells from sibling donors who were identical with the patient for the antigens of the major histocompatibility complex (MHC), termed HLA (human leukocyte antigen) in humans.The development of acute GVHD is dependent upon various risk factors, which affect the manifestations of the disease and, possibly, the response to first-line therapy. Furthermore, treatment responses may be incomplete or mixed, rendering the assessment of refractory acute GVHD difficult. It appears justified, therefore, to provide a brief background description of the pathophysiology and classification of GVHD and outline up-front therapeutic strategies, which often overlap with what we consider therapy for refractory GVHD. Pathophysiology and risk factorsUnderstanding the pathophysiology of GVHD is a prerequisite to designing effective prophylactic and therapeutic strategies. A 3-step process best reflects the current view of the development of GVHD (reviewed in Ferrara et al 4 ). In this model, total body irradiation (TBI) or other cytotoxic modalities used to prepare patients for HCT result in tissue damage and the release of inflammatory cytokines into the circulation. In this milieu, transplanted donor T lymphocytes (and other cellular compartments) are activated. Studies in mice have shown that host antigen-presenting cells, in particular dendritic cells, are essential, 5 and the cytokines released by tissue damage up-regulate ...

Dismal response to high-dose methylprednisolone after failure to respond to standard dose in patients with acute GVHD

“…Like other investigators 19,23 we did not observe a response when the MP dose was increased. Van Lint et al, however, did observe a response to higher corticosteroid doses.…”

“…Hypertension, infection, hyperglycemia and myopathy are commonly associated with corticosteroid therapy for aGVHD. 22,23 Substantial toxicity was found in adults with aGVHD treated with MP in doses of 5 mg/kg/day or more including viral and fungal infections. 21 In our cohort of patients, the use of high-dose MP therapy was associated with toxicity including four proven infectious episodes.…”

Daclizumab as useful treatment in refractory acute GVHD: a paediatric experience

“…[1][2][3][4] Patients who fail to respond to first-line steroid treatment have poor prognosis, and although various second-line treatments have been proposed, to date, no standard treatment has proven to be effective.…”

Stromal cells–are they really useful for GVHD?

“…[79][80][81] We were the first group to use MSCs for the treatment of life-threatening acute GVHD, and we reported dramatic responses in some patients, but unfortunately not all. 8,9 These results encouraged a multi-centre phase-II study involving five centres and 55 patients.…”