Autologous Myoblasts for the Treatment of Fecal Incontinence: Results of a Phase 2 Randomized Placebo-controlled Study (MIAS).

OBJECTIVE: The aim of this study was to evaluate the efficacy of intrasphincteric injections of autologous myoblasts (AMs) in fecal incontinence (FI) in a controlled study. SUMMARY OF BACKGROUND DATA: Adult stem cell therapy is expected to definitively cure FI by regenerating damaged sphincter. Preclinical data and results of open-label trials suggest that myoblast therapy may represent a noninvasive treatment option. METHODS: We conducted a phase 2 randomized, double-blind, placebo-controlled study of intrasphincteric injections of AM in 24 patients. The study compared outcome after AM (n = 12) or placebo (n = 12) injection using Cleveland Clinic Incontinence (CCI), score at 6 and 12 months. Patients in the placebo group were eligible to receive frozen AM after 1 year. RESULTS: At 6 months, the median CCI score significantly decreased from baseline in both the AM (9 vs 15, P = 0.02) and placebo (10 vs 15, P = 0.01) groups. Hence, no significant difference was found between the 2 groups (primary endpoint) at 6 months. At 12 months, the median CCI score continued to ameliorate in the AM group (6.5 vs 15, P = 0.006), while effect was lost in the placebo group (14 vs 15, P = 0.35). Consequently, there was a higher response rate at 12 months in the treated than the placebo arm (58% vs 8%, P = 0.03). After delayed frozen AM injection in the placebo group, the response rate was 60% (6/10) at 12 months. CONCLUSIONS: Intrasphincteric AM injections in FI patients have shown tolerance, safety, and clinical benefit at 12 months despite a transient placebo effect at 6 months.

Reduced frequency of regulatory T cells in peripheral blood stem cell compared to bone marrow transplantations.

Peripheral blood stem cell transplantation (PBSCT) is an alternative to bone marrow transplantation (BMT). Although CD4(+)CD25(+)CD127(lo) regulatory T cells (Tregs) have been shown to play important roles in the control of T cell reactivity, the Treg contents of both graft types have not been analyzed comparatively to date. We report herein that Treg frequencies are significantly reduced in PBSC compared to BM transplants. Furthermore, most Tregs from PBSC transplants are CD62L(lo), a phenotype reported to have poor suppressor activity. Both granulocyte-colony stimulating factor (G-CSF) administration and leukapheresis were found to contribute to the loss of CD62L(+) Tregs. Although higher T cell numbers are infused in PBSCT than in BMT, it is possible that the reduced Treg content of PBSC transplants may represent 1 factor contributing to the higher risk of GVHD reported after PBSCT.

Impact of frontline fludarabine and cyclophosphamide combined treatment on peripheral blood stem cell mobilization in B-cell chronic lymphocytic leukemia.

Ongoing studies in B-cell chronic lymphocytic leukemia are evaluating autologous peripheral blood stem cell (PBSC) transplantation in first remission following fludarabine therapy. However, fludarabine could impair PBSC harvest. In 38 patients after frontline oral fludarabine and cyclophosphamide (FDR-CY) therapy, we prospectively evaluated steady state filgrastim- or lenograstim-primed PBSC mobilization to collect 2.0 x 106/kg or more CD34 cells. The first mobilization, performed a median of 178 days (range, 69-377 days) from the last FDR-CY course, was unsuccessful in 32 patients. This result was significantly associated with a low platelet count before mobilization but not with age, interval from last FDR-CY course, initial stage, remission status, or other blood parameters. Finally, after 1, 2, and 3 mobilizations in 27, 10, and 1 patients, 2.0 x 106/kg or more CD34 cells were collected in only 12. Explorations of the mechanism of poor mobilization and adaptation of PBSC harvest policies after fludarabine treatment are therefore warranted.