Management of acute graft-versus-host disease in children

Abstract

Acute graft-versus-host disease (aGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) in children. Although 30% to 50% of children respond to corticosteroids as initial therapy, the optimal initial or second-line therapies have not yet been determined. Newer approaches with combination therapy, novel agents, monoclonal antibodies, and/or cellular therapies show some promise but require prospective well-designed trials that include children to establish their efficacy. This article reviews the clinical presentation, treatment, and practical management guidelines for children with aGVHD.

Figure 1

*Some centers choose to begin steroid dosing at < 2 mg/kg/day for grade II aGVHD (see text, Section 4) **Seattle uses nonabsorbable gut steroids for children with Grade IIa aGVHD defined by anorexia, nausea, emesis or diarrhea < 20 mL/kg/day, no liver involvement, and rash covering < 50% of the body surface area and not progressing rapidly within the first 6–24 hours. Grade IIa aGVHD may be treated with a 10-day induction course of MP 1 mg/kg plus a 50-day course of nonabsorbable glucocorticoids delivered to the GI tract. If GI manifestations are progressing after 3 days of 1 mg/kg and nonabsorbable glucocorticoids then prednisone should be escalated to 2 mg/kg/day. In this latter scenario, the continuation of nonabsorbable glucocorticoids is optional but often invoked as prednisone-sparing therapy. If GI symptoms of anorexia, nausea and diarrhea <10 mL/kg/day without cramping have completely resolved after 10 days, then prednisone is usually successfully tapered rapidly over 1 week to 0.0625 mg/kg/day (or hydrocortisone 7.5 mg/m² divided into 2–3 daily doses) and continued until 30 days after nonabsorbable glucocorticoids have stopped. This temporary physiological replacement therapy is arguably more relevant in small children compared to adults because adrenal suppression can be clinically relevant due to some amount of systemic absorption of the “nonabsorbable” glucocorticoids. A serum cortisol level < 19 mg/dL after cosyntropin-stimulation, or an early morning baseline cortisol < 3.6 mg/dL are often helpful to confirm a diagnosis of suspected adrenal insufficiency. Children with grade IIa GVHD whose diarrheal volumes are between 10–20 ml/kg/day, especially with abdominal cramping, may require a slower, more standard taper of prednisone. Obstacles that have likely prevented the widespread adoption of this approach, particularly in children, as a standard practice include the fact that landmark beclomethasone (BDP) trials were conducted with a unique BDP formulation, orBec® (Soligenix, Princeton, NJ), which is an equipotent mix of plain and enteric-coated tablets designed to deliver 1 mg of BDP to the upper and lower GI tracts respectively four times daily in adults. Because the FDA’s Oncology Drugs Advisory Committee voted 7 to 2 that the phase III study results were insufficient for orBec® to garner approval in 2007 (reviewed further in [75]) this therapy remains commercially unavailable. Seattle currently mimics the approach by prescribing one capsule twice daily of EntocortEC® (Prometheus Lab, San Diego, CA) which contains 3 mg of micronized, enterically coated BDE, with 1 mg four times daily of oral BDP (U.S.P. material, Gallipot, St. Paul, MN, www.gallipot.com) emulsion that is compounded typically in corn or olive oil. Only 11 children (5 to 17 years of age) received BPD therapy among 231 patients who were treated during the three orBec® GVHD studies. Therefore, the efficacy of short course prednisone induction and oral BDP therapy for this indication in children has not been validated. Lastly, it is unclear whether children should receive similar dosing of topical GI glucocorticoids as adults. At least two other aGVHD studies of BDP [76] or budesonide (BED) [50] have included children and used adult dosing of BDE and BDP. By analogy in mild to moderate pediatric Crohn’s disease, an international survey found that Europeans favored the use of BDE over conventional glucocorticoid therapy [77]. Randomized controlled studies in pediatric Crohn’s disease have indicated that remission rates were similar in children (mostly teenagers) treated with BDE 3 mg three times daily versus prednisone 40 mg daily but side effects were significantly lower in the BDE treated group (32% vs 71%, p>0.05). Induction dosing of BDE 3 mg four times daily for 1 month followed by a taper resulted in a trend to higher remission rates without an increase in steroid-associated side effects [78].