Clinical trial NCT02824653: Allogenic Bone Marrow Mesenchymal Stem Cells Infusion in Patients With Steroid-refractory GVHD
Official title: Allogenic Bone Marrow Mesenchymal Stem Cells Infusion in Patients With Steroid-refractory GVHD- A Phase I/II Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Graft Versus Host Disease
Keywords: acute GVHD
chronic GVHD
steroid-refractory
Mesenchymal Stem Cells
Lead sponsor: National Institute of Blood and Marrow Transplant (NIBMT), Pakistan
Sponsor class: OTHER_GOV
First posted: 2016-07-07
Enrollment: 10
Sex: ALL
Minimum age (years): 1
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Graft versus host disease is a serious and often life-threatening complication in allogeneic haematopoietic stem cell transplantation. Although corticosteroids are the first-choice of treatment in these patients, but about 30-50% patients do not respond to it and develop steroid-refractory GVHD. Mesenchymal stem cells (MSC) have emerged as a promising treatment option in these patients. This phase-I/II clinical trial aims at establishing the safety and clinical efficacy of allogenic ex-vivo cultured MSCs to treat steroid-refractory GVHD in a Pakistani HSCT cohort.

Detailed description: Allogeneic haematopoietic stem cell transplant has become first choice of treatment for many malignant and non malignant haematological disorders. Although great progress has been made to prevent and minimize transplant-associated complications, yet graft versus host disease (GVHD) remains a significant complication affecting these the outcome in these patients. It is a severe inflammatory condition that arises when recipient tissues are attacked by immune mediated donor T cells during transplantation. Acute GVHD predominately affects the skin, upper and lower GI tract, liver and occasionally the eye and oral mucosa, whereas chronic GVHD resembles more with autoimmune disorders in its clinical symptoms. These symptoms can be organ-specific or generalized throughout body.

The pathophysiology of GVHD shows that it has different phases. In first phase i.e., afferent phase, damage to host tissue occurs. In second phase i.e., Induction and expansion phase, donor T cells are triggered and activated by recipient and donor APC as well as the inflammatory cytokines. Activated T cells produce IL-2 and IFN-γ (or Th1 response). Allogeneic immune response is amplified by IL-2, which activates more T cells and natural killer cell responses, triggering macrophages to release TNF-α and further inflammation damages skin and gut. The third phase i.e., effector phase, is characterized by cytotoxic damage against host cells by activated donor T-cell-mediated through Fas-Fas ligand interaction, perforin-granzyme and TNF-α. The latter has a central role in the pathophysiology, stimulating cytokine production (IL-1, IL-6, IL-10, IL-12 and TNF-α). This dysregulation leads to the clinical manifestations of acute GVHD.

The cells involved in GVHD pathophysiology include CD4+ T cells; for maintaining the expansion of CD8+ T cells that mediate GVHD, APCs; these have role in the initiation phase of acute GVHD as described in murine models and Natural killer (NK) cells; contribute to tissue damage in the effector phase by releasing inflammatory cytokines and nitric oxide. However, natural killer cells mediate cell death by two important pathways: Fas-Fas-ligand-mediated apoptosis and perforin-granzyme-B-mediated cytolysis.

HLA differences between donor and recipient are the major predictor of GVHD. Other affecting factors include age, gender mismatch between donor and recipient, minor histocomapatability antigen expression difference(mHA) in otherwise identical HSCT, donor age, source and dose of stem cells (PBSCT greater risk than BM), intensity of conditioning and GVHD prophylaxis.

Steroids are the first line therapy for acute GVHD patients and are standard treatment for grade II-IV acute GVHD. Adverse effects of glucocorticoids include hypertension hyperglycemia and psychosis, immunosuppression, infections, myopathy, osteoporosis and avascular necrosis of bone, cataracts and fat re-distribution etc. If acute GVHD is not improved after 5-7 days treatment with steroids then it is considered as steroid-refractory. Various agents that are being investigated from last two decades as second line therapy include low-dose MTX, MMF, extracorporeal photopheresis, IL-2R targeting, antibody therapy against CD3, CD7, CD25, CD52, CD147, IL-2R, IL-1, and TNF-α (i.e., basiliximab, daclizumab, denileukin, diftitox and alemtuzumab), horse ATG, etanercept, infliximab, and sirolimus and recently infusions of mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are defined as self-renewing, multipotent progenitor cells with potential to differentiate into other cell types of mesodermal origin, such as adipocytes, osteocytes, and chondrocytes. Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy developed the minimal criteria for definition of MSCs which is as follows: first, adherence to plastic; Second, positivity for the cell-surface molecules CD105, CD73, and CD90 and negativity for CD45, CD34, CD14 or CD11b, CD79a or CD19, and human leukocyte antigen (HLA)-DR; and third, the ability to differentiate into osteoblasts, adipocytes, and chondroblasts under standard in vitro differentiation conditions. Since Le Blanc and colleagues first reported successful treatment of a patient with severe acute GVHD using third-party haploidentical MSCs in 2004, many clinical trials worldwide have described the benefits of MSC therapy in GVHD.

The proposed project is a phase I/II clinical trial of single group, open label, interventional study design. The objective is to observe the safety and efficacy of intravenous injection of ex-vivo expanded bone marrow mesenchymal cells from a third party donor for treating refractory GVHD. The study will also document the type and frequency of any adverse event or side effects, if discovered.

Eligibility criteria: Inclusion Criteria:

* Must fill Informed consent.
* Patient who has undergone allogeneic HSCT and has steroid-refractory grade II-IV acute GVHD.
* Patients who did not respond to treatment options including methylprednisolone, and or cyclosporine A or ATG.
* Patients who despite above mentioned treatment have unresponsive GVHD after 5 days or progressive acute GVHD for more than 72 hours.
* Patients who have received any other treatment and had discontinued for non-responsiveness.

Exclusion Criteria:

* Poor performance status, not expected to survive 5 days.
* Patients with hypersensitivity to penicillin and/or gentamycin.
* Poor compliance.

Primary outcomes:
measure: Incidence of treatment-emergent adverse events and complications [Safety and Tolerability]
timeFrame: 4 weeks
measure: Acute GVHD-restaging [Efficacy]
timeFrame: 4 weeks
measure: Chronic GVHD-restaging [Efficacy]
timeFrame: 3 months
Secondary outcomes:
measure: Survival analysis at six months after MSC infusion
timeFrame: 6 months
measure: Incidence free survival at six months after MSC infusion
timeFrame: 6 months
Other outcomes:
Locations:
city: Rawalpindi
country: Pakistan
facility: Armed Forces Bone Marrow Transplant Centre
state: Punjab
Study officials:
affiliation: Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan
name: Parvez Ahmed, FCPS, MCPS
role: PRINCIPAL_INVESTIGATOR
References: