HOW TO TAKE THE POST-TEST: To obtain CE credit, please click here after reading the article to take the post-test on myCME.com.
The most common adverse event following allogeneic hematopoietic stem cell transplantation (HSCT) is graft-versus-host disease (GVHD), which can increase morbidity and mortality in HSCT patients. The three sources of stem cells include bone marrow, umbilical cord blood, and peripheral blood.1 HSCT is most commonly used as a treatment option for malignant conditions. Allogeneic transplants involve grafts from a genetically nonidentical donor of the same species and are the transplant type most often used in children. Chemotherapy, radiation, or both are initiated prior to transplantation to enable engraftment of the transplanted cells, decrease tumor size, and reduce immunoreactivity of the recipient.2
Continue Reading
An environment for GVHD is formed when antigen-presenting cells are activated by the patient’s disease and the pretreatment destruction of cells caused by chemotherapy and radiotherapy.1 After transplantation, donor T cells are activated by antigen-presenting cells. Donor T-cells proliferate and inflammatory mediators are recruited. Cytotoxic T cells mount a response on the body and target recipient cells are lysed. This overactive immune response can cause significant damage to healthy tissue. GVHD can involve any organ; but the skin is the most affected organ, with the GI tract and liver also commonly involved organs.1 A typical cutaneous reaction manifests as macular lesions first appearing on the upper back and lateral neck, jaw, ears, palms, and soles. A severe cutaneous reaction may include blisters with full-thickness necrosis. Diagnosis of GVHD is difficult because of its broad presentation that may manifest similar to other conditions such as drug reactions and viral infections.2
To date, no standard treatment is established for GVHD and no therapies are FDA approved for this indication in pediatric or adult patients.3 Currently, prednisone in combination with cyclosporin or tacrolimus (Prograf, Protopic, generics) is used as a first-line preventive therapy. Treatment focuses on blocking the expansion of donor T cells, as GVHD develops from the expansion of these cells. Other treatments are extracorporeal photopheresis, pentostatin (Nipent, generic), tumor necrosis factor (TNF) antagonists, and CD20 antagonists. Extracorporeal photopheresis inactivates antigen-presenting cells and T cells, whereas TNF antagonists decrease cellular activation and local tissue damage. CD20 is an antigen expressed on the surface of B cells. CD20 antagonists deregulate B cells, which are believed to contribute to the pathogenesis of GVHD.4 One of the primary pathways in which T cells are activated is through antigen-presenting cells such as B cells. When CD20 antagonists decrease the amount of circulating B cells, the body may not produce as many cytotoxic T cells that can potentially induce GVHD.1
Recent studies are investigating the efficacy of rituximab (Rituxan) for GVHD in pediatric HSCT patients. This article discusses the current status of clinical trials of rituximab to treat GVHD in the pediatric population.
HISTORY OF CLINICAL USE
Rituximab was developed in 1986 and received FDA approval for the treatment of B cell non-Hodgkin lymphomas in 1997. Rituximab attaches to the CD20 surface of mature B cells and destroys both normal and malignant B cells. The versatile drug is now also approved for the treatment of B-cell Hodgkin lymphoma, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and rheumatoid arthritis in the adult population.
The package insert states that use of rituximab in children has not been studied;5 however, it has been used to treat many pediatric hematologic conditions, including chronic immune thrombocytopenic purpura, posttransplant lymphoproliferative disease, juvenile rheumatoid arthritis, and other blood dyscrasias. Therapeutic response has been beneficial and resulted in successful treatment of these diseases.6
Several studies are analyzing the effectiveness of rituximab in improving morbidity and mortality in pediatric transplant patients. Although not a first-line treatment for GVHD, rituximab may offer an alternative treatment option for GVHD in pediatric patients.6
CLINICAL TRIALS
Several studies currently in progress analyze the effectiveness of rituximab on improving health outcomes in pediatric HSCT patients. The National Institutes of Health (NIH) references one such study in which rituximab improved symptom management in pediatric patients with chronic GVHD.7 Participants received one dose of rituximab 375 mg/m2 per week for the first 4 weeks of treatment, and those who did not respond well received an additional weekly dose. At 1-year follow-up, 70% of participants had improved symptoms. Two of the 21 participants had no signs of disease. Rituximab demonstrated the most benefit for patients who had GVHD of the skin. The NIH recommends further investigation of this medication as a prophylactic and initial treatment regimen.
In addition to being a treatment option for GVHD, rituximab is also an antineoplastic agent. M.D. Anderson Cancer Center in Houston, Texas, is sponsoring a study to determine if cord blood is safe for transplantation in patients with leukemia or lymphoma.8 In this study, which is not yet recruiting participants, researchers plan to use a rituximab dose of 375 mg/m2 via intravenous (IV) route. This study will include participants aged 1 to 80 years, and completion is anticipated for April 2015.
