LAUSR

Dear Editor, Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for patients with hematologic malignancies [1]. However, overall survival (OS) is often compromised by treatment-related complications such as graftversus-host disease (GVHD). Recipients of fully HLAmatched sibling donors (MSD) have an acute GVHD rates between 30 and 40% and severe life-threatening acute GVHD may occur in 15% of patients [2, 3]. Many patients who could potentially benefit from allo-SCT do not have a MSD or a matched unrelated donor (MUD) based on highresolution molecular matching techniques [4]. Partially, HLAmismatched unrelated donor (MMUD) transplantation is a viable option for patients lacking a fully matched donor; however, HLA mismatches significantly increase the risk of GVHD and confer an inferior OS [5]. Treatment for acute GVHD is not successful in all patients and may impact long-term survival. Patients with grade III–IV acute GVHD who do not respond to frontline therapy with corticosteroids have only a 30% 2-year overall survival [6]. Pharmacologic immunosuppression is the most commonly applied method for prevention of GVHD and has been traditionally performed using a calcineurin inhibitor in combination with a short course of methotrexate [7, 8]. These regimens effectively prevent severe GVHD in the majority of MSD andMUD transplantation. However, there is no uniformly accepted guideline for GVHD prophylaxis for MMUD transplants. Sirolimus is an immunosuppressant derived from Streptomyces hygroscopicus [9], which is structurally similar to tacrolimus [10]. Sirolimus binds mammalian target of rapamycin (mTOR), that inhibits co-stimulatory pathway (e.g., CD28-AKT) and IL-2 driven pathway [11]. Sirolimus has potent anti-rejection activity in solid organ transplantation [12] and demonstrated activity as therapy of steroid-resistant GVHD [13]. Since tacrolimus and sirolimus have distinct mechanisms of action, combination therapy confers a synergistic effect [14, 15] to inhibit rejection in human organ allografting. Sirolimus does not cause nephrotoxicity and neurotoxicity, and is therefore less likely to cause synergistic adverse effects with a calcineurin inhibitor. The combination of sirolimus, tacrolimus, and low-dose methotrexate was initially tested as GVHD prophylaxis in both matched related and limited numbers of mismatched related transplants, with reported rates of overall acute GVHD of 26% and severe acute GVHD (grades III–IV) of 13% [16]. Here, we aimed to study the activity of sirolimus/ tacrolimus/low-dose methotrexate solely in MMUD transplantation and performed extended follow-up of patients registered in our pilot study. This pilot study enrolled 25 recipients of MMUD allografts recruited at Yale University between 2008 and 2011.Wemonitored the efficacy of a regimen of sirolimus, tacrolimus, and methotrexate as GVHD prophylaxis for MMUD allo-grafting with extended follow-up until 2015. This study was approved by the Institutional Review Board of Yale University and * Stuart Seropian [email protected]