Treatment of severe steroid-refractory acute GvHD with mesenchymal stromal cells.
A phase III randomized double-blind multi-center HOVON study.

Allogeneic stem cell transplantation (SCT) is the only curative option for many patients
suffering from hematological malignancies. Although providing cure for many patients, SCT
may be accompanied by severe treatment-related side-effects, including acute Graft-versus-Host Disease (GvHD). Acute GvHD is a major cause of SCT-related morbidity and mortality.
First line treatment consists of usually protracted immunosuppressive therapy with high dose corticosteroids often in combination with calcineurin inhibitors. A variety of second line immunosuppressive agents has been investigated for patients failing on corticosteroids, but no optimal treatment has emerged. Steroid-refractory acute GvHD has a high mortality rate and surviving patients often develop chronic GvHD, which severely reduces quality of life.
Therefore, there is an urgent need for new and better treatment modalities. Several studies have indicated that third-party mesenchymal stromal cells (MSC) might be an effective therapy for steroid-refractory GvHD. MSC play a role in the regulation of hematopoiesis but also have putative immunomodulatory properties. Pilot studies have yielded encouraging results suggesting that MSC treatment may induce responses in the majority of patients. We therefore propose a phase III prospective randomized double-blind multicenter study, comparing early treatment with MSC to placebo in patients with steroid-refractory acute
GvHD.

The study will focus on:

i) improving the response rate to treatment with MSC,

ii) studying safety,

iii) assessing progression-free survival,

iv) assessing GvHD-free survival,

v) evaluating the possibility to reduce the time required for pharmacological
immunosuppression,

vi) assessing the incidence of severe bacterial, viral and/or fungal
infections,

vii) reducing the incidence and severity of chronic GvHD,

viii) evaluating the quality of life of patients receiving MSC compared with controls,

ix) developing a predictive score allowing the identification of patients with acute GvHD that will respond to MSC treatment.

The hypothesis to be tested is that the outcome in arm B is better than in arm A.

Clinical, laboratory and QoL evaluations:

• At entry,

• At day 8, 15, 22 and 29,

• Thereafter at 6 weeks and at 2, 3, 6, 12, 18 and 24 months

All patients will be followed until 10 years after randomization.

Eligible patients will be randomized to either standardized second line treatment only, consisting of mycophenolate mofetil (MMF) in combination with a placebo for MSC infusion, or MMF in combination with MSC at a dose of 2 x106 MSC per kg bodyweight IV. The first gift of MSC or placebo will be administered the day following randomization. The second gift will be administered 7 days after the first gift.
In addition, all patients will continue systemic treatment with steroids and a calcineurin-inhibitor.