To improve the response rate to treatment of severe acute GVHD (grade II-IV with gut involvement ) by adding infusion of Mesenchymal Stroma Cells to standard high dose prednisolone.
ID
Source
Brief title
Condition
- Other condition
- Haematological disorders NEC
Synonym
Health condition
stamceltransplantatie gerelateerde complicatie: Graft versus Host ziekte
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary
- 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)
Secondary outcome
Secondary
- Proportion of patients in each treatment arm who experience a CR-GVHD or
PR-GVHD at dindicated 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 (see Appendix E
and F)
- The immunological genotype of responders and non-responders as well as donors
in both groups (see Appendix E and F)
- 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
Background summary
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 stroma cells (syn., Mesenchymal stem cells) from others] and our
center.The so far published data as well as data of our cohort 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%.
Study objective
To improve the response rate to treatment of severe acute GVHD (grade II-IV
with gut involvement ) by adding infusion of Mesenchymal Stroma Cells to
standard high dose prednisolone.
Study design
Prospective, multicenter, double blind, placebo- controlled, randomized
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).
Study burden and risks
Burden consists of repetitive infusions of MSC, additional blood draws, bone
marrow apirate and biopsy of the organ of GVHD 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-threatining nature of GVHD and the side-effects of steroids, we expect an
overall-benefit in terms of improved survival and less use of steroids.
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
HOVON Centraal Bureau, VUMC, De Boelelaan 1117
Amsterdam 1081 HV
NL
Listed location countries
Age
Inclusion criteria
- Any age;
- Previously treated with allo-SCT/ DLI;
- Acute GVHD grade II iIV nvolving gut and/or liver,
- WHO performance 0-3 ;
- Negative pregnancy test (if applicable);
- Patients must be willing and capable to use adequate contraception during therapy ;
- Written Informed Consent by the patient and/or parent(s) or legal guardian(s);
Exclusion criteria
- Patients with active, uncontrolled infection;
- Rapid progressive hematological malignancy;
- Patients pre-treated with prednisolone > 1 mg/kg for GVHD, for more than 72 hours prior to randomization/application of MSC/placebo;
- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, cancer, etc.)
- Any psychological, familial, sociological and/or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
- Known uncontrolled toxicity for DMSO;
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-003237-33-NL |
| CCMO | NL41506.000.13 |
| OMON | NL-OMON29599 |