Combination antithymocyte globulin and soluble TNFα inhibitor (etanercept) +/− mycophenolate mofetil for treatment of steroid refractory acute graft-versus-host disease

Abstract

Antitumor necrosis factor-a antibodies are increasingly being used for the treatment of steroid-refractory acute graft-versus-host disease (GVHD) complicating allogeneic stem cell transplantation. We retrospectively reviewed the outcomes of 16 patients with refractory acute predominantly visceral GVHD treated with combination antithymocyte globulin (ATG), tacrolimus and etanercept þ /À mycophenolate mofetil (MMF) at our institution. Overall response rate (CR þ PR) was 81%, with median survival post commencing salvage immunosuppression 224 days (range 20-1216 days). In total, eight patients (50%) died, including from progressive GVHD in two cases (13%), infection in five (31%) and relapse of underlying malignancy in one (6%). In comparison to our previous experience of ATG þ tacrolimus as treatment for refractory visceral GVHD, both response rate and overall survival were improved with addition of etanercept, with no apparent increase in infectious complications. As such, use of etanercept in combination with ATG þ /À MMF for treatment of steroid refractory acute GVHD appears to be associated with high response rates, significant survival and no unexpected toxicity. Further study of this immunosuppression combination in a larger cohort of patients in this setting is indicated.

Targeting mycophenolate mofetil for graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation

“…Although not officially licensed, many investigators have used the compound to treat acute and chronic GVHD. 20,21 In addition, MMF was shown to be synergistic with CYA in inducing a stable mixed chimerism after nonmyeloablative conditioning in a large animal model and in subsequent clinical studies. 22,23 Studies on the use of MMF as part of GVHD prophylaxis have been limited in size and mostly inconclusive, as most investigators reported insufficient plasma levels of the active metabolite MPA.…”

Transplantation-associated thrombotic microangiopathy: effect of concomitant GVHD on efficacy of therapeutic plasma exchange

“…Indeed, in a previously published series of refractory GVHD patients treated with etanercept-based therapy at our institution, the overall incidence of bacterial sepsis was 430%. 30 Despite the multiple publications assessing the efficacy of PE as treatment for TA-TMA, almost none detail non-lethal infectious complications occurring during therapy, and as such, the risk of PE-related complications in TA-TMA is typically inferred from data obtained from therapeutic PE in idiopathic TTP. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]32,33 Our experience suggests that the risk of catheter-related sepsis in TA-TMA is greater than previously considered, especially in the presence of acute GVHD.…”

“…Refractory acute GVHD was managed with etanercept-based therapy as previously published. 30 Concomitant infections were treated with appropriate antibiotics; if present, CMV reactivation (monitored by weekly quantitative PCR) was treated pre-emptively with i.v. ganciclovir.…”

Alemtuzumab as salvage therapy for steroid and ATG/etanercept-refractory acute GVHD

“…[1][2][3][4][5] Although several different agents have been proposed as therapy for steroid-refractory aGVHD, there remains no consensus as to optimal management following failure of corticosteroids. At our institution, steroid-refractory aGVHD is routinely treated with antithymocyte globulin (ATG), etanercept ± mycophenolate mofetil.…”

“…At our institution, steroid-refractory aGVHD is routinely treated with antithymocyte globulin (ATG), etanercept ± mycophenolate mofetil. 5 Although this approach is able to salvage a significant proportion of patients, prognosis is historically dismal in those patients refractory to second-line therapy. Given the reports of steroid-refractory aGVHD responding to alemtuzumab, [1][2][3][4]6,7 we have incorporated this agent as third-line therapy in patients failing the above strategies.…”