Revisiting mycophenolate mofetil for steroid‐refractory acute graft‐versus‐host disease: Is higher dosing effective in children?

Survival following allogeneic hematopoietic stem cell transplantation (HSCT) has steadily improved over time in all age groups, including children, even with increasing use of non-sibling donors (1, 2). Much of the improvement in outcomes is due to more effective strategies that have reduced the incidence of acute graft-versushost disease (GVHD) (3). Nonetheless, acute GVHD remains the primary cause of non-relapse mortality (NRM) after allogeneic transplantation (4). It is steroid-refractory acute GVHD, primarily involving the lower gastrointestinal (GI) tract, that accounts for the vast majority of NRM (5). Unfortunately, there are no proven treatments for steroid-refractory acute GVHD despite over 40 yr of clinical trials. It is in this context that Inagaki et al. (6) studied mycophenolate mofetil (MMF) as a treatment for steroidrefractory acute GVHD as reported in this issue of Pediatric Transplantation. Inagaki et al. analyzed the effectiveness of oral MMF in 14 children with steroid-refractory acute GVHD that had not responded to at least two lines of treatment before beginning MMF. They report an impressive 83% response rate at eight wk after initiation, which included an equally high response rate in patients with GI GVHD. The vast majority of patients remained alive, in remission, and off all immunosuppression at a median of almost three yr of follow-up. Although second-line therapies are often associated with significant toxicities (7), MMF was very well tolerated in this study. The authors attribute the success of their treatment to the high starting dose (>40 mg/kg/day) and further dose escalation due to poor initial dose response, an approach supported by data showing a strong dose–response relationship between MMF and acute GVHD incidence and response to treatment (8, 9). Although the results from this study are promising, they are far from definitive, especially in light of the small numbers of patients studied. Only oral MMF was used despite the high incidence of voluminous diarrhea, and no pharmacokinetic studies were performed, so we cannot be sure whether the high dosing actually led to higher blood concentrations of active drug. Also, several patients responded despite cessation of steroid therapy prior to initiating MMF, a strategy that raises questions as to how steroid-refractory the GVHD was in some patients. We also do not know whether some of the responses observed were from ongoing or delayed response to secondor higher line therapy already administered. In addition, we need to reconcile the results of this study with the large, multicenter, phase III randomized, controlled trial that failed to show any benefit from MMF compared to placebo when used in combination with steroids to treat newly diagnosed acute GVHD (10). Although Inagaki et al. observed excellent responses to MMF in their patients, we do not know whether these results will be reproducible in future trials. If we can identify patients whose GVHD will be resistant to frontline therapy before treatment failure has occurred, we may be able to design better clinical trials in the future. There has been intensive effort recently to develop staging systems that will help us categorize patients for risk of treatment failure when they are diagnosed with GVHD. MacMillan et al. (11) developed a clinical risk score for acute GVHD that predicts response to treatment, NRM, and survival based on GVHD target organ involvement and clinical severity when treatment is begun. Patients with isolated, but severe skin, GI, or liver involvement, and most combinations of multi-organ GVHD, are classified as high risk and comprise approximately