High Overall Response Rate in Calcineurin Inhibitor-Free Treatment with the mTOR Inhibitor Everolimus in Advanced Extensive Chronic GvHD after Allogeneic Stem Cell Transplantation.
Authors: Klink Anne , Schilling Kristina , Rapp Katrin , Höffken Klaus , Sayer Herbert G. 
Published: April 2020

Abstract
Background: The mammalian target of rapamycin (mTOR) inhibitor Everolimus (RAD001, Certican®) is a new immunosuppressive drug and beside of sirolimus used and approved in solid organ transplantation. Recently, it was reported that mTOR-inhibitors in combination with calcineurin inhibitors (CNI) showed clinical responses in chronic graft-versus-host disease (cGvHD). In this single centre retrospective analysis, we report on 29 patients (pts) with severe cGvHD treated with Everolimus without CNI.
Patients and Methods: Twenty-nine pts (17 AML, 3 CML, 4 ALL, 3 CLL, 2 NHL) with a median age of 44 years [range: 25–61] underwent allogeneic stem cell transplantation between September 1999 and August 2007. Myeloablative conditioning was used in 21 pts, reduced-intensity conditioning in 8 pts. Except for one patient receiving bone marrow, all pts received peripheral blood stem cells for transplantation. Family donors (2 non-fully HLA matched) were used in 7 pts (24%) and unrelated donors (7 non-fully HLA-matched) in 22 pts (76%). GvHD-prophylaxis consisted of CNI (cyclosporine or tacrolimus) in 4 pts, CNI+Methotrexate (MTX) in 8 pts, CNI+Mycophenolate (MPA) in 8 pts and CNI+MPA+MTX in 9 pts. Antithymocyte globulin (ATG) as in vivo T-cell depletion was used in 9 pts. Cytomegalovirus (CMV)-serostatus was positive in 14 pts, with seronegative donors in 5 pts. Acute GvHD occurred in 27/29 (93.3%), grade II-IV in 25 (86.2%). At the same time, CMV reactivation/infection was observed in 11 pts and thrombotic microangiopathy (TMA) in 3 pts. All pts developed severe cGVHD with extensive disease. Organ involvement included skin with scleroderma in 21 pts, mucous membranes in 22 pts, eyes in 22 pts, lungs in 8 pts, liver in 11 pts, gut in 9 pts and arthralgia in 6 pts. At the time of treatment start with everolimus (0.75 mg Certican ® twice a day orally), CNI medication was stopped. The intended plasma therapeutic levels of everolimus were 3–8 mg/l. In addition all pts received prednisone and in 18 pts (62%) MPA as third immunosuppressive agent was continued.
Results: Median treatment duration was 8.4 months [range: 2.5–21.7]. None of the pts developed CMV disease or TMA. Adverse events were: arterial hypertension in 1 patient, atrial fibrillation in 1 patient, pneumonia in 1 patient, sinusitis in 1 patient, herpes labials infection in 1 patient, renal insufficiency grade II in 2 pts and myalgia in 2 pts. 96.6% are still alive, 1 patient (3.4%) died due to relapse of ALL. Two pts (6.9%) achieved a complete response of their cGvHD and 18 pts (62.1%) a partial response resulting in an overall response rate of 69.0% (n=20) according to the recent consensus NIH report (Biol. Blood Marrow Transplant. 2006 May; 12(5): 491–505). No change was observed in 3 pts (10.3%) and progression occurred in 6 pts (20.7%). Complete response in HLA-identical related donors was 20% (1/5) and with HLA-matched unrelated donors was 6.7% (1/15). 100% (n=2) of pts with a HLA-mismatched related donor achieved a partial remission and 85.7% (n=6) of pts with a HLA-mismatched unrelated donor. The gender of recipient or donor did not impair the observed responses with everolimus. Prednisone could be tapered in 62.1% of all pts (18/29). In the triple combination with MPA, MPA could be tapered in 22.2% (4/18) and could be stopped in 38.9% (7/18).
Conclusions: A CNI-free treatment of advanced extensive cGvHD with everolimus seems to be feasible and effective with a high overall response rate of nearly 70 %. It should be emphasized that a low toxicity profile without TMA was observed. Our data supports further clinical and immunological investigations with m-TOR inhibitor everolimus in treating GvHD.