Program: Oral and Poster Abstracts
Session: 722. Clinical Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster II
Chronic graft-versus-host disease (cGvHD) is major cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation, with no established second-line treatment. Mesenchymal stromal cells (MSC) have been widely studied in the treatment of acute GvHD, but the clinical reports in cGvHD are scarse. In this study, we aim to evaluate the effects of multiple infusions of MSC on patients with severe refractory cGvHD, including long-term follow-up and immunological evaluations.
Patients and Methods
The study comprises 11 patients (6 female/5 male, with a median age of 49 (range 20-61)) with severe cGvHD from Karolinska University Hospital, Stockholm, Sweden. Inclusion criteria was cGvHD of grade moderate to severe, refractory to or not tolerating 3 months standard treatment of calcineurin inhibitor plus steroids. Median time from cGvHD diagnosis to study inclusion was 18 months (range 6-70), and median number of previous systemic cGvHD treatments was 4 (range 1-10). Median of cGvHD affected organs was 5 (range 3-6), of which NIH organ score >= 2 in a median of 4 (range 1-5). The global severity score median was 8 (range 6-9). Most commonly affected organs were skin (n=10), eyes (9) and joints (8).
Clinical grade MSC were harvested from bone marrow of unrelated healthy donors. MSCs were administered intravenously at a dose of 2x10^6 cells/kg at 4-6 weeks intervals. A minimum of 6 doses were given, where response to treatment after 6 doses was observed an additional 1-3 doses were given. All patients continued on their previous immunosuppressive regime to be tapered as clinically indicated.
Response evaluation was carried out every three months until the end of treatment. A final formal evaluation was made 12 months after the last dose of MSC, and patients were then followed clinically outside of the study for a median follow-up time of 30 months (range 4-48) from inclusion. Response was graded according to the NIH 2014 consensus criteria with one addition: in case of sclerodermatous disease a reduction in total sclerotic body surface area (BSA) by at least 25% was considered partial response (PR) of the skin.
Results
Main evaluation time point was after 6 infusions. 2 patients discontinued before this point due to death or increasing donor chimerism and one is still receiving treatment.
Of the 8 evaluable patients, 5 showed overall PR and were classified as responders and 3 showed mixed response and were classified as non-responders. In the responders, continuing improvement was noted at each follow-up during MSC treatment and at final evaluation at 12 months after finishing MSC treatment. Organ responses were seen in joints (7), skin (4), eyes (3), GI tract (2) and oral cavity, lungs and liver (n=1 each). With a median follow-up time of 29 months (range 21-48), 2 patients have discontinued all systemic immunosuppression and 2 are free of steroids and tapering calcineurin inhibitors. Quality of life was evaluated using the FACT-BMT questionnaire, and responders showed a mean increase in FACT-BMT total score of 6,6 points, or 8%, compared to baseline values, at last follow-up.
Clinical response was preceded by reduction in plasma levels of CXCL-9 and CXCL-10, proposed biomarkers for cGvHD, as well as pro-inflammatory cytokines IL-7 and IL-17a.
MSC treatment was well tolerated without immediate side effects. 5 events of grade 3 infections were recorded during follow-up. One patient died due to progressive cGvHD after receiving only one MSC infusion. One patient with CLL discontinued the study after 3 infusions due to increasing CD19 donor chimerism, and one year later suffered haematological relapse. One patient with multiple myeloma discontinued after 7 infusions due to reappearence of the M-protein.
Discussion
These promising results show that repeated doses of MSC could be effective in inducing durable responses in severe, refractory cGvHD. Early biomarkers indicative of response would be a useful tool for selecting patients benefiting from prolonged treatment. This study is limited in the number of patients and needs to be followed by larger trials in which the prospective predictive value of biomarker responses could also be evaluated. Close surveillance of patients regarding infectious complications as well as disease recurrence is necessary.
Disclosures: No relevant conflicts of interest to declare.
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