Treatment of severe acute GVHD after allogeneic hematopoietic stem cell
transplantation with steroids versus MSC and steroids.
A prospective double-blind placebo-controlled randomized phase III trial

Background of the study:

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is an established and powerful treatment modality for patients with multiple hematological malignancies and inborn errors. In particular, the immunotherapeutic effect, known as the graft versus leukemia (GVL) effect, significantly reduces the rate of relapse in leukemia patients, receiving their allograft as consolidation therapy in first or subsequent remission However, GVL is strongly associated with the occurrence of acute and/or chronic graft versus host disease (GVHD). GVHD occurs in 35%-50% of the transplanted patients, still substantially limiting the outcome and the more widespread use of allo-SCT .Thus, allo-SCT strategies which separate GVHD from GVL effects and therapies which treat effectively GVHD are urgently needed. The core of acute GVHD treatment consists of immunosuppression, with 1-2mg/kg/d prednisolone as the standard first line treatment. Several studies demonstrate an overall complete response rate to prednisolone in approximately 40-50% of all patients, with a lower response rate and a higher recurrence in patients with more severe GVHD. One interesting alternative therapeutic option for patients with severe GVHD comes from recent data of the application of mesenchymal stromal cells (syn., Mesenchymal stem cells). The data strongly support the notion that MSC need to be studied in larger and more stringent randomized clinical trials for patients with acute GVHD. They could be more effective when administered early in GVHD treatment thus leading to a better survival. This is the rational for this Phase lll trial comparing steroids and MSC as first line therapy against steroids alone. The study includes selectively patients suffering from gut and/or liver grade II-IV GVHD in first-line, thus patients with an expected survival of less than 25%.

Objective of the study:

To improve the response rate to treatment of severe acute GVHD (grade II-IV with gut and/or involvement) by adding Mesenchymal Stromal Cells to standard high dose prednisolone.

Study design:

Prospective, multicenter, double blind, placebo- controlled, randomized

Study population:

Patients who received an allo-SCT for malignant or non-malignant disorders who develop severe grade II-IV acute GVHD involving gut and/or liver .

Intervention:

Patients are randomized for treatment with

-high dose prednisolone 2 mg/kg/day i.v. and placebo

-high dose prednisolone 2 mg/kg/day i.v. and MSC at day 1, day 8, and day 22 i.v.

Cyclosporine A + Mycophenolate prevention regimens will be (re)started or continued according to prevention schedule (Cyclosporine A through levels 0.20-0,35 mmol/l).

Primary study parameters/outcome of the study:

- Proportion of patients in each treatment arm who experience a CR-GVHD or PR-GVHD at day 57, without treatment failure (initiation of secondary treatment)

Secundary study parameters/outcome of the study (if applicable):

- Proportion of patients in each treatment arm who experience a CR-GVHD or PR-GVHD at indicated timepoints (until 2 years), without treatment failure (initiation of secondary treatment)

- Time to CR-GVHD or PR-GVHD

- Amount of immune suppression at indicated days

- Adverse events

- The (immunological) phenotype before and after application of MSC/placebo of responders and non-responders in both groups at different sites

- The immunological genotype of responders and non-responders as well as donors in both groups

- Quality of life

- Cost-effectiveness

- Relapse of the underlying disease (e.g. hematological malignancy)

- Progression-free survival

- Incidence and severity of chronic GVHD

- Overall survival

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

Burden consists of repetitive infusions of MSC, additional blood draws, bone marrow apirate and biopsy of the skin or gut after resolution of GVHD. So far no severe side effects have been reported of MSC. Theoretical risks are support of leukemia-growth, and severe infection. However, considering the life-threatening nature of GVHD and the side-effects of steroids, we expect an overall-benefit in terms of improved survival and less use of steroids.

Multiple small clinical trials support the notion that Mesenchymal Stromal Cells (MSC) need to be studied in larger and more stringent randomized clinical trials for patients with acute GVHD. This is the rationale for this Phase lll trial comparing steroids and MSC as first-line therapy against steroids alone.
The study objective is to improve the response rate to treatment of severe acute GVHD (grade II-IV with gut and/or liver) by adding MSC to standard high dose prednisolone.

The patients will be evaluated at entry, day 8, 15, 22, 29, 57 and at 3, 4, 6, 12 and 24 months.
Beyond 2 years after registration patients will be followed according to local practice.
All patients will be followed until 10 years after registration.

Patients will be randomized to either standard treatment consisting of high dose prednisolone plus placebo (arm A) or high dose prednisolone plus MSC (arm B).