Conditions: Dyskeratosis Congenita Aplastic Anemia
Keywords: Dyskeratosis Congenita Hematopoietic Stem Cell Transplantation Severe Aplastic Anemia
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 36
Healthy volunteers: no

Brief summary:
Transplantation with stem cells is a standard therapy in many centers around the world. Previous experience with stem cell transplantation therapy for leukemias, lymphomas, other cancers, aplastic anemia and other non-malignant diseases, has led to prolonged disease-free survival or cure for some patients. However, the high doses of pre-transplant radiation and chemotherapy drugs used, and the type of drugs used, often cause many side effects that are intolerable for some patients. Slow recovery of blood counts is a frequent complication of high dose pre-transplant regimens, resulting in a longer period of risk for bleeding and infection plus a longer time in the hospital.

Recent studies have shown that using lower doses of radiation and chemotherapy (ones that do not completely kill all of the patient's bone marrow cells) before blood or bone marrow transplant, may be a better treatment for high risk patients, such as those with Dyskeratosis Congenita (DC) or Severe Aplastic Anemia(SAA). These low dose transplants may result in shorter periods of low blood counts, and blood counts that do not go as low as with traditional pre-transplant radiation and chemotherapy. Furthermore, in patients with Dyskeratosis Congenita or SAA, the stem cell transplant will replace the blood forming cells with healthy cells.

It has recently been shown that healthy marrow can take and grow after transplantation which uses doses of chemotherapy and radiation that are much lower than that given to patients with leukemia. While high doses of chemotherapy and radiation may be necessary to get rid of leukemia, this may not be important to patients with Dyskeratosis Congenita or SAA. The purpose of this research is to see if this lower dose chemotherapy and radiation regimen followed by transplant is a safe and effective treatment for patients with Dyskeratosis Congenita or SAA.

Detailed description:
This is an open label, single arm, phase II clinical trial designed to evaluate the safety and efficacy of the treatment regimen. Efficacy will be measured by long-term engraftment of the transplanted cells.The primary endpoint of neutrophil engraftment is defined as an absolute neutrophil count (ANC) \>5 x 108/L (first of three consecutive laboratory measurements on different days) with at least 10% donor cells by day 100. We will evaluate the proportion of success (P) and its 95% confidence interval (CI) for the entire group. The null hypothesis of 90% engraftment will be rejected if 4 or more patients fail to engraft out of 15 evaluable patients. The secondary endpoints of regimen related mortality, acute and chronic graft-versus-host disease (GVHD) and secondary malignancies will be estimated by cumulative incidence treating non-event deaths as a competing risk. Survival will be estimated by Kaplan-Meier methods. Immune reconstitution will be summarized with descriptive statistics.

SAA and DC arms will be analyzed separately.

Arms:
arm 1: Patients with dyskeratosis congenita (DC). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, total body irradiation and stem cell transplantation. arm 2: Patients with severe aplastic anemia (SAA). Patients are treated with alemtuzumab (Campath 1H), Cyclophosphamide, Fludarabine, antithymocyte globulin, total body irradiation and stem cell transplantation.

Interventions: intervention 1: Campath 1H intervention 2: Cyclophosphamide intervention 3: Fludarabine intervention 4: Total Body Irradiation intervention 5: Stem Cell Transplantation intervention 6: antithymocyte globulin intervention 7: Methylprednisolone
Intervention descriptions: intervention 1: 10, 9, 8, 7, and 6 days before transplant subjects will be given 1 dose of campath 1H given via catheter (0.2 mg/kg over 2 hours). intervention 2: 7 days before the transplant, 1 dose of cyclophosphamide is given via catheter (50mg/kg IV over 2 hours). intervention 3: 6, 5, 4, 3, and 2 days before the transplant, 1 dose fludarabine is given via catheter (40 mg/kg IV over 1 hour) intervention 4: 1 day before the transplant one dose (200 cGy) of total body irradiation is given intervention 5: Infusion of stem cells on Day 0. intervention 6: ATG (rabbit) 3 mg/kg for 3 days. intervention 7: 2mg/kg IV is given before each dose of antithymocyte globulin (ATG).

Protocol document: