A Multicenter Retrospective Analysis on Pentostatin As Salvage Therapy of Severe Steroid Refractory Intestinal Acute Graft Versus Host Disease
Authors: Klein Stefan A. , Schmitt Thomas , Bug Gesine , Schetelig Johannes , Schwerdtfeger Rainer , Schaefer-Eckart Kerstin , Schmid Christoph , Wandt Hannes , Hofmann Wolf-Karsten , Bornhaeuser Martin , Martin Hans , Dreger Peter 
Published: October 2019

Abstract
Abstract 3048
Acute graft-versus-host disease (aGvHD) of the gastrointestinal (GI) tract is still a major clinical challenge after allogeneic stem cell transplantation. Patients with steroid-refractory disease have a poor prognosis. Pentostatin, an inhibitor of adenosine deaminase, has shown efficacy as salvage therapy in steroid-refractory aGvHD of the GI tract in small single center studies. Here we report on the experience with pentostatin in severe steroid-refractory aGvHD of the GI tract at seven German transplant centers.

PATIENTS:
A total number of 123 patients who had been treated with pentostatin due to intestinal steroid-refractory aGvHD between 2000 and 2011 were retrospectively analyzed. Steroid-refractory aGvHD was defined as progression or no improvement of diarrhea despite treatment with prednisolone (≥ 2mg/kg/d) for ≥ 3 days. Pentostatin was infused at a dose of 1mg/m2 for 3 consecutive days. In patients with impaired renal function the dose of pentostatin was reduced. Patients received 1–4 cycles. Steroids and calcineurin inhibitors (CNI) were continued. Response after therapy with pentostatin was classified as complete (CR, no ongoing symptoms of GvHD), very good partial (VGPR, residual symptoms only) or no response (NR). 50 females and 73 males with a median age of 50 (range: 19–70) years were included. The underlying diseases were AML (n=71), ALL (n=15), CML/MPS (n=6), lymphoma (n=12), MDS (n=10), and multiple myeloma (n=9). 85 patients received reduced intensity and 38 myeloablative conditioning. Patients had been transplanted from matched related (n=38), matched unrelated (n=53) or mismatched donors (n=32). All patients suffered from severe steroid-refractory intestinal aGvHD overall grade III (n=59) or IV (n=64). Patients received pentostatin as first line salvage (n=109) or beyond first line salvage therapy (n=14).

Results:
52 patients (43%) responded after salvage therapy with pentostatin. 39 patients (32%) achieved CR, 13 patients (11%) VGPR. Median survival was 104 days; 2-year and long term survival rates were 26 and 19% with a median follow up of 45 months. Among 109 patients who received pentostatin as first line salvage therapy 49 (45%) responded (37 × CR [34%] and 12 × VGPR [11%]). Median survival, 2-year and long term survival were essentially the same as in the total cohort of patients. After the first infusion of pentostatin clinical improvement occurred within a median of 14 (range: 1–58) days. 71 patients (57%) did not respond. Responding patients had a significantly (p<0.0001) higher probability of survival in comparison with non-responders (2 year survival 44 vs. 14%, long term survival 41 vs. 0%). 94 patients (76%) died (66% therapy related, 10% due to relapse of the malignant disease). Patients who had been transplanted from a matched related donor had a significantly (p=0.04) higher probability of survival in comparison with patients with other donors (2-year survival: 38 vs. 21%, long term survival 35 vs. 8%). 53% (n=20) of these patients responded. Out of the 109 patients who were treated with pentostatin as first line salvage therapy 15 received simultaneously additional immunsuppressive salvage therapies (infliximab, mesenchymal stem cells [MSC] or extracorporeal photopheresis [ECP]). None of these patients survived. 46 patients without CR after one cycle of pentostatin received further immunosuppressive salvage treatment: 28 of these patients were treated with 1–3 further cycles of pentostatin. 18 of the 46 patients received pentostatin plus simultaneous or subsequent additional immunsuppressive therapies (infliximab, alemtuzumab, basiliximab, MSC or ECP). In both groups the probability of survival was identical (2-year survival: 17%).

Conclusions:
The outcome after salvage therapy of III/IV° steroid-refractory intestinal aGvHD with pentostatin is at least within the range as reported for other salvage approaches. In this critical clinical situation pentostatin has some superior characteristics: a sustainable effect, moderate toxicity, easy application and cost-effectiveness. Moreover, this analysis suggests that the outcome of steroid-refractory aGvHD cannot be improved by the application of more than one immunosuppressive salvage drug in addition to steroids and CNI or by second line salvage approaches.

Disclosures:
Klein: Hospira: Honoraria, Research Funding. Off Label Use: pentostatin is not licensed for use in acute GvHD.