• Skin: Maculopapular skin rash on the face, truck, extremities, palms, soles, and ears which may progress to generalized total-body erythroderma, bullous formation, and skin desquamation

• GI: Ileus, malnutrition, dehydration and electrolyte abnormalities due to nausea, vomiting, and diarrhea

• Hepatic: Jaundice due to hyperbilirubinemia Laboratory Tests

• Hepatic: Elevation of bilirubin, alkaline phosphatase, and hepatic transaminases

• GI: send stool for bacterial, viral, and parasitic cultures to rule out infectious causes Other Diagnostic Tests

• Biopsy of affected site for pathologic review

Prophylaxis of acute GVHD for nonmyeloablative preparative regimens is varied, but a calcineurin inhibitor with either methotrexate or mycophenolate mofetil is used. To date, trials evaluating the optimal acute GVHD prophylaxis regimen have not been conducted.

Adaptive Dosing of the Calcineurin Inhibitors Most HSCT centers have their own standardized approach to dose adjust the calcineurin inhibitors cyclosporine and tac-

rolimus to target concentration ranges. Cyclosporine trough concentrations are associated with the acute GVHD and nephrotoxicity. Cyclosporine trough concentrations usually are maintained between 150 and 400 ng/mL (125-333 nmol/L) in patients undergoing allogeneic HSCT. Tacrolimus trough concentrations are targeted to a range of 10 to 20 ng/mL (10-20 mcg/L).34 Dosage adjustments to either calcineurin inhibitor also should be made for elevated serum creatinine (SrCr) regardless of their serum concentrations. Nephrotoxicity can occur despite low or normal concentrations of the calcineurin inhibitor cyclosporine and may be a consequence of other drug- or disease-related factors known to influence the development of nephrotoxicity (e.g., genetic risk factors, concurrent use of other nephrotoxic agents, and sepsis). Careful monitoring for drug interactions via cytochrome P-450 3A4 and p-glycoprotein is also warranted. The calcineurin inhibitor doses are adjusted based on serum drug levels and the calculated creatinine clearance. Common adverse effects to these agents include neurotoxicity, hypertension, hyperkalemia, hypomagnesemia, and/or nephrotoxicity (which may lead to an impaired clearance of methotrexate).

Tapering schedules for the calcineurin inhibitors after myeloablative HSCT vary widely. In patients without GVHD, the calcineurin inhibitor doses usually are stable to day +50 and then are tapered slowly with the intent of discontinuing all immunosuppressive agents by 6 months after HSCT. By this time, immunologic tolerance has developed and patients no longer require immunosuppressive therapy. There is a paucity of information regarding the optimal duration of GVHD prophylaxis after nonmyeloablative HSCT, with data suggesting that a two month duration of cyclosporine with a four month taper lowers the rate of severe acute GVHD.35

Treatment of Acute GVHD The most effective way to treat GVHD is to prevent its development. Corticosteroids, usually in combination with a calcineurin inhibitor, are the first-line therapy for treatment of established acute GVHD. Corticosteroids indirectly halt the progression of immune-mediated destruction of host tissues by blocking macrophage-derived IL-1 secretion. IL-1 is a primary stimulus for T-helper-cell-in-duced secretion of IL-2, which, in turn, is responsible for stimulating proliferation of cytotoxic T lymphocytes. The recommended dosage of methylprednisolone in this setting is 2 mg/kg/day; there is no advantage to higher corticosteroid doses (i.e., 10 mg/

kg/day). A partial or complete response is seen in approximately 50% of patients treated with corticosteroids. Once a clinical improvement occurs, there is no consensus on the optimal method for tapering the corticosteroids. Patients with steroid-refractory acute GVHD have a poor prognosis and a number of medications are being studied for salvage therapy.

Chronic GVHD Occurring in 20% to 70% of HSCT recipients surviving over 100 days, chronic GVHD is the most frequent and serious late complication of allogeneic HSCT.36 Chronic GVHD is the major cause of nonrelapse mortality and morbidity. The clinical course of chronic GVHD is multifaceted, involving almost any organ in the body and its symptoms resemble autoimmune and immunologic disorders (e.g., scleroderma). Chronic GVHD symptoms usually present within 3 years of allogeneic

HSCT and often are preceded by acute GVHD. Traditionally, the boundary between acute and chronic GVHD was set at 100 days after HSCT; however, more recent defin-

itions hinge on different clinical symptoms rather than the time of onset. A consensus document regarding the diagnosis and scoring of chronic GVHD has been published recently which proposes a clinical scoring system to describe chronic GVHD as opposed to historical descriptions of chronic GVHD which described the phenomen-

on as being "limited" versus "extensive" in nature. The diagnosis of chronic GVHD requires (a) distinction from acute GVHD, (b) presence of at least one diagnostic clinical sign of chronic GVHD or presence of at least one distinctive manifestation confirmed by pertinent biopsy or other relevant tests, and (c) exclusion of other possible diagnoses.

Prevention and Treatment of Chronic GVHD Chronic GVHD is not a continuation of acute GVHD and separate approaches are needed for its prevention and management. Prevention of chronic GVHD through prolonged use of immunosuppressive medications has been unsuccessful.36 Thus, its prevention is focused on minimization of factors associated with higher rates of chronic GVHD. Several recipient, donor, and transplant factors are relevant. Recipient risk factors that are not modifiable include older age, certain diagnoses (e.g., chronic myeloid leukemia), and lack of an HLA-matched donor. Modifiable factors that may lower the risk of chronic GVHD include selection of a younger donor, avoidance of a multiparous female donor, use of umbilical cord blood or bone marrow grafts rather than PBPCs, and limitation of CD34+ and 36

T-cell dose infused. Development of acute GVHD is a major predictor for chronic GVHD, with 70% to 80% of those with grade II to IV acute GVHD developing chronic GVHD.36

Relative to no treatment, survival in those with chronic GVHD is improved by extended corticosteroid therapy; however, multiple long-term adverse effects are associated with corticosteroid use. The prednisone dosage is 1 mg/kg/day administered orally in divided doses for 30 days and then slowly converted to an alternate-day therapy by increasing the "on day" and decreasing the "off day" dose until a total of 2 mg/kg/day on alternate days is administered. Once therapy is initiated, one to two months may pass before an improvement in clinical symptoms is noted and therapy usually is continued for 9 to 12 months. Therapy can be tapered slowly after resolution of signs and symptoms of chronic GVHD. If a flare of chronic GVHD occurs during the tapering schedule or after therapy is discontinued, immunosuppressive therapy is restarted. Other potential approaches for patients who are refractory to initial therapy include etanercept (Embrel), infliximab (Remicade), mycophenolate mofetil (Cellcept), rituximab (Rituxan), extended use of calcineurin inhibitors, or extracor-poreal photochemotherapy.36 When immunosuppressive therapy is administered for long periods, the patient must be monitored closely for chronic toxicity. Cushingoid effects, aseptic necrosis of the joints, and diabetes can develop with long-term corticosteroid use. Other severe complications include a high incidence of infection with encapsulated organisms and atypical pathogens such as Pneumocystis jiroveci, cytomegalovirus (CMV), and varicella-zoster virus (VZV).

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