Salvage Therapy with Everolimus Reduces the Severity of Treatment-Refractory Chronic Graft-Versus-Host Disease without Impairing Disease Control: A Dual Center Experience

Chronic graft-versus-host disease (cGVHD) following allogeneic hematopoietic stem cell transplantation remains the most important cause of late non-relapse mortality. While first-line treatment of cGVHD can be based on controlled data evidence for second-line treatment remains challenging with no single agent having been approved for salvage treatment yet. Here, we report a dual center retrospective cross-sectional analysis on salvage treatment of refractory cGVHD with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR).

A total of 78 consecutive patients (51 males, 27 females) with a median age of 53 years (range: 20 – 71 years) who received everolimus for off-label treatment of refractory cGVHD were considered eligible for this analysis. Potential toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) were assessed in a retrospective manner using patients' records. Response to treatment was assessed using the cGVHD Global Severity Score according to NIH Consensus Criteria (NIH Severity Score). Possible response rates included complete remission (CR), partial remission (PR), mixed response (MR), stable disease (SD) and progressive disease (PD).

Out of 78 total patients 14 (18%) suffered from mild, 38 (49%) from moderate, and 26 (33%) from severe cGVHD before being commenced on an everolimus-based salvage regimen. Concomitant immunosupression included steroids, calcineurin inhibitors, inosine monophosphate dehydrogenase inhibitors, methotrexate and/or rituximab. Patients received daily oral doses of everolimus ranging from 0.125 to 6 mg resulting in median plasma levels of 4.1 ng/mL (range: 1.1 – 7.4 ng/mL). At time of analysis median follow-up after introduction of everolimus was 731 days (range: 14 – 2205 days). Median treatment duration with everolimus was 484 days ranging from 12 to 1250 days. Everolimus-based treatment was discontinued in 49 patients due to toxicity (n=14), CR (n=12), PR (n=6), MR (n=6), death (n=6), refractory cGVHD (n=3), relapse of underlying disease (n=1) or patient's request (n=1) while 29 patients (37%) were continued on everolimus. Most frequent grade 3/4 toxicities included infections (n=29) and thrombocytopenia (n=15). Infectious complications were the main cause of death. There was a single case of relapse of the underlying malignancy in the entire treatment series. NIH Severity Score improved in 34 patients (44%), remained stable in 36 patients (46%), and worsened in 8 patients (10%) resulting in a 21% CR and 31% PR rate of cGVHD. The total sum of NIH Severity Scores in all patients assessable was significantly reduced after treatment with everolimus (168 vs. 125; p<0.0001 [Wilcoxon signed-rank test]). The different levels of response are presented in [Figure 1].

Everolimus-based salvage treatment of refractory cGVHD results in significant improvement of the NIH Severity Score even including complete remissions. The observed toxicity profile highlights infectious complications and myelotoxicity while control of the malignant disease was not impaired in this series. However, disease control could be either contributable to enhanced graft-versus-malignancy effects in association with cGVHD and/or the beneficial anti-malignancy effects of everolimus itself. Finally, these promising results demand verification in a prospective clinical trial.

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Mielke:Novartis, Germany: Honoraria. Off Label Use: Everolimus for off-label treatment of refractory cGVHD. Wolff:Novartis, Germany: Research Funding.