Prochymal Improves Response Rates In Patients With Steroid-Refractory Acute Graft Versus Host Disease (SR-GVHD) Involving The Liver And Gut: Results Of A Randomized, Placebo-Controlled, Multicenter Phase III Trial In GVHD

Abstract

CD127 expression on CD8 + T cells, consistent with their rapid clonal expansion and differentiation. Multiplexed Luminex cytokine analysis demonstrated high-level secretion of IL-18 and IL-1RA, with no increased secretion of TNF, IL-1b or IL-17 despite severe GvHD.The four treated recipients demonstrated rapid donor engraftment, but, unlike the controls, they were significantly protected against clinical and immunologic GvHD: They displayed neither the skin rash nor the profuse diarrhea noted in the control animals, and flow cytometric analysis demonstrated control of T cell proliferation, maintenance of CD127 expression levels, and inhibition of IL-18 and IL-1RA cytokine secretion. Conclusions: We have established a robust model of MHC haploidentical HSCT and GvHD using an MHC-defined Rhesus macaque colony. We find that unprotected primate GvHD is characterized by rapid T cell proliferation, with concomitant loss of expression of CD127 on CD8 + T cells. In addition, it is associated with high level secretion of IL-18 and IL-1RA. Finally, we find that CD28/CD40-directed costimulation blockade in combination with sirolimus can effectively inhibit the clinical, cellular and serum hallmarks of GvHD during primate haploidentical BMT. This approach thus may deserve close scrutiny as a possible clinical strategy for GvHD prevention. . Dose-level-C accrual is ongoing. Concurrent immunosuppression was allowed.11 patients accrued; 7 and 4 at dose-levels-A and -B. Median age was 44 years (30-57). Median time from HSCT and cGVHD was 1021 (420-4714) and 784 (117-2233) days. cGVHD sites were skin (11 pts), mouth (6 pts), eyes (4 pts), liver (3 pts), lung (2 pts), esophagus (1 pt). Patients had a median of 3 (range, 1-3) concurrent immunosuppressives: steroids (11 pts), sirolimus (5 pts), MMF (5 pts), tacrolimus (4 pts). Discontinued prior therapies were rituximab (6 pts), ECP (4 pts), MMF (2 pts), sirolimus (2 pts), cyclosporine (1 pt), thalidomide (1 pt), denileukin-diftitox (1 pt), alemtuzumab (1 pt).No dose-limiting toxicity (DLT) GVHD flare occurred. One patient (lvl-A) had CTC grade-4 hemolytic-uremic-syndrome after Hemophilus-B bacteremia at 5 weeks of IL-2 (and prednisone, tacrolimus, sirolimus), reported as a DLT. No other DLT occurred. Another patient (lvl-A) had CTC grade-4 MRSA pneumonia at 8 weeks, unrelated to IL-2 (on prednisone, sirolimus, MMF; also had MRSA pneumonia pre-IL-2). No other significant infection was documented. One patient (lvl-B) discontinued IL-2 at 4 days for CTC grade-1 fatigue.Of 9 evaluable patients, 5 had a partial response, 1 had a mixed response, and 3 had stable disease. Responses were scored in skin and liver (mouth, eye received topical therapy). 4 of 5 responders chose extended IL-2 (range, 1.5-15 months) given clinical benefit. The 5 th , with resolving liver cGVHD, had IL-2 withheld for MRSA pneumonia. He died of progressive liver cGVHD off IL-2.IL-2 induced a 3-5-fold increase in CD4 + CD25 + CD127-Tregs (Table). At 1, 2, 4, 6 and 8 weeks, IL-2 increased Treg significantly over ba...

Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey

“…Although the primary end point in that study was not achieved for the whole group of patients, there was a significant benefit over placebo group in the liver and GI tract. 41 Response rate in our cohort of patients is also similar to that reported by Introna et al 20 in a cohort of 12 pediatric patients; that study demonstrated an overall response of 66.7%. However, in their patient cohort, only 25% of the patients exhibited aGvHD over grade III, whereas in our series, 96% of the patients exhibited aGvHD grade III or IV.…”

Pentostatin for treatment of steroid-refractory acute GVHD: a retrospective single-center analysis

“…32 A large randomized phase III trial involving 244 patients with steroid-refractory GVHD revealed a trend in favor of the addition of MSCs to the salvage regimen in the per protocol population in comparison with placebo (CR 40 vs 28%; P ¼ 0.08). 33 Taken together, in the absence of convincing results from randomized phase III trials, it seems that there is no salvage treatment for steroid-refractory GI aGVHD with obviously outstanding efficacy. Therefore, secondary criteria might be considered when choosing the therapeutic regimen.…”

Stromal cells–are they really useful for GVHD?

“…26 The anticipation of using BM-MSCs as GVHD treatment dramatically declined in the scientific community when the negative results of the randomized clinical trial by Osiris Therapeutics were released. 27 BM-MSC administration for treatment of GVHD did not improve long-term survival 23 and have also failed to show effects on GVHD in animal models. [28][29][30][31][32] Some studies from academic institutions have shown positive results, but there is most likely a selection bias in the literature as negative results are seldom published.…”