Acute Gvhd

The treatment of acute GVHD, particularly severe (grade III-IV) GVHD, remains inadequate. Corticosteroids are the mainstay of therapy for acute GVHD, particularly if they are not utilized as prophylaxis.84 85 Several studies have established the response rates for treatment of GVHD with corticosteroids.8687 The highest response rates have been demonstrated in cutaneous GVHD (>60%). Sustained response rates of only 20-40% have been seen for visceral (gut and liver) GVHD. Long-term survival has been correlated with the grade of GVHD and response to medical therapy. Patients with grade

III or IV GVHD who do not achieve a complete remission of their GVHD with medical therapy have a less than 50% probability of long-term survival; mortality rates in excess of 90% have been reported for grade IV GVHD.5 Most patients who receive corticosteroids for grades II—IV GVHD require long-term corticosteroid administration. Substantial morbidity which usually accompanies long-term corticosteroid administration includes heightened infection risk, hypertension, diabetes mellitus, osteoporosis and aseptic necrosis of the hip and other bones, and proximal myopathy.85

Given the substantial morbidity with intensive cor-ticosteroid therapy of acute GVHD, attempts have been made to both improve the response rate of treatment and to provide a steroid sparing effect by adding additional immunosuppressive therapy (Table 98.4). In a randomized trial comparing prednisone with equine antithymocyte globulin and prednisone for the initial treatment for acute grades II—IV GVHD, response rates were the same.88 There were more infectious complications in the combined therapy group. No difference in survival was observed between the two groups at day 100 and after 6 months and 2 years. In a comparison of upfront methylprednisolone versus methylprednisolone/daclizumab (an anti-IL-2 receptor monoclonal antibody) for acute GVHD, response rates were also similar.89 Significantly worse 100-day and 1-year survival for the combined therapy group led to early closure of the trial. The increased mortality in the

Treatment strategies for GVHD

Acute GVHD

Chronic GVHD

Pharmacologic immunosuppression Corticosteroids Cyclosporine Tacrolimus Sirolimus Mycophenolate mofetil

Pharmacologic immunosuppression Corticosteroids Cyclosporine Tacrolimus Sirolimus Azathioprine Mycophenolate mofetil

T-cell modulation Extracorporeal photophoresis

Antibody Therapy Thalidomide

Polyclonal Clofazimine

Antithymocyte globulin (equine, rabbit) Monoclonal Anti-T-cell (anti-CD3, CD2, ect) Daclizumab (anti-IL-2 receptor) Infliximab (anti-TNF-salpha) Alemtuzumab (anti-CD52+)

Other biologic therapy

Denileukin diftitox

Gene therapy

Thymidine kinase suicide gene transduction/ganciclovir GVHD, graft-versus-host disease.

combination group was attributed to both relapse and GVHD-related mortality, possibly as a result of a negative impact on regulatory (CD4+CD25+) cells due to daclizumab.

Thus, corticosteroids alone (or in combination with a calcineurin inhibitor which is often still being administered at the onset of GVHD) remain the initial treatment of choice for grades II-IV GVHD. For patients who do not respond to methylprednisolone (or an equivalent corticosteroid) at a dose of 2 mg/kg/day, several possible strategies exist. Increasing the steroid dose to 5 mg/kg or higher has been evaluated in previous noncontrolled situations.90 While a dose—response relationship may exist for corticosteroids, higher doses (particularly those of 10 mg/kg/day or greater) are associated with increased steroid-related complications and transplant-related mortality. Equine or rabbit antithy-mocyte globulin has been used most frequently as second-line therapy. While transient responses are common, particularly in cutaneous GVHD, the mortality rate in patients requiring ATG for steroid refractory acute GVHD is very high (approximately 90%) owing primarily to opportunistic infections.8791 Several other therapies, on the basis of their targeting of cytokines and/or effector cell populations, have been evaluated in steroid refractory GVHD. Favorable response rates have been seen with monoclonal antibodies targeting tumor necrosis factor-alpha (inflix-imab)92 and the IL-2 receptor (daclizumab and basilix-imab).93 94 A fusion protein consisting of IL-2 and diphtheria toxin has shown promising activity in steroid refractory GVHD.95 The transient nature of the responses is not surprising given the complex, multi-factorial mechanisms of GVHD. The cumulative immunosuppressive effect of corticosteroids and other immunosuppressive agents to which these potent highly specific immunosuppressive agents are added is also not surprisingly notable for a very high risk of infectious complications. In an experience from the MD Anderson Cancer Center with infliximab for steroid refractory GVHD an overall response rate of 65% was seen, with most of the patients (62%) achieving a complete remission. Fungal, bacterial, and viral infections were seen in 46, 69, and 57% of the patients, respectively. Estimated overall survival probability from the time of the transplant was only 31%.91

In an effort to more specifically target effector T cells while avoiding the more broad immunosuppressive effects of pharmacologic immunosuppressive therapy, gene therapy approaches have been evaluated for the treatment of acute GVHD. T cells transduced with a herpes viral thymidine kinase gene have been evaluated in preclinical transplant models and in preliminary clinical trials with ganciclovir administered in the event of GVHD, resulting in death of the effector T cells and in some instances, reversal of the GVHD.96 Improving the efficiency of gene transduction and preservation of the cells that mediate a GVM effect remain important future goals of this strategy.

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