stem cell transplant (sct) for dyskeratosis congenita or saa

Conditions: Dyskeratosis Congenita; Aplastic Anemia

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.

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.

Eligibility criteria:
inclusion criteria: * patients with dyskeratosis congenita (dc) or severe aplastic anemia (saa) 0-70 years of age with an acceptable hematopoietic stem cell (hsc) donor * hsc source * human leukocyte antigen (hla) identical or 1 antigen mismatched sibling or other relative eligible to donate bone marrow (bm), umbilical cord blood (ucb) or mobilized peripheral blood (pb) at cell doses that meet current institutional standards. * hla identical or up to a 1 antigen mismatched unrelated donor. * two units of unrelated umbilical cord blood (ucb) that are (a) up to 2 hla antigens mismatched to the patient (b) up to 2 hla antigens mismatched to each other, (c) minimum cell dose of ≥ 3.5 x 10\^7 nucleated cells/kg and optimal cell dose ≥ 5 x 10\^7 nucleated cells/kg. * if two units are not available: single unrelated ucb unit selected according to minnesota bone marrow transplant (bmt) program guidelines * disease characteristics for dc (both of the following): * evidence of bm failure: * requirement for red blood cell and/or platelet transfusions, * requirement for granulocyte colony-stimulating factor (g-csf) or granulocyte-macrophage colony-stimulating factor (gm-csf) or erythropoietin, or * refractory cytopenias defined as two out of three: platelets \<40,000/microliter (ul) or transfusion dependent, absolute neutrophil count \<500/ul without hematopoietic growth factor support, hemoglobin \<9g/ul or transfusion dependent * diagnosis of dc: * a triad of mucocutaneous features: oral leukoplakia, nail dystrophy, abnormal reticular skin hyperpigmentation. * or one of the following: short telomeres (under a research study), dyskerin mutation, telomerase rna (terc) mutation * disease characteristics for saa (both of the following): * evidence of bm failure: * refractory cytopenia defined by bone marrow cellularity \<25-50% (with \< 30% residual hematopoietic cells) * diagnosis of saa: * refractory cytopenias defined as two out of three: platelets \<20,000/ul or transfusion dependent, absolute neutrophil count \<500/ul without hematopoietic growth factor support, absolute reticulocyte count \<20,000/ul * patients with early myelodysplastic features. * patients with or without clonal cytogenetic abnormalities. patient exclusion criteria: * patients with one or more of the following: * decompensated congestive heart failure; left ventricular ejection fraction \<35% * acute hepatitis or evidence of moderate or severe portal fibrosis or cirrhosis on biopsy * carbon monoxide diffusing capacity (dlco) \<30% predicted, and oxygen requirement * glomerular filtration rate (gfr) \<30% predicted * pregnant or lactating female * active serious infection whereby patient has been on intravenous antibiotics for at least one week prior to study entry. any patient with aids or hiv seropositivity. if recent mold infection e.g. aspergillus - must have \>30 days of appropriate treatment before hsc transplantation and infection must be controlled and cleared by the infectious disease consultant. * cannot receive total body irradiation (tbi) due to prior radiation therapy * diagnosis of fanconi anemia based on diepoxybutane (deb). * dc patients with advanced myelodysplastic syndrome (mds) or acute myeloid leukemia with \>30 blasts. * history of non hematopoietic malignancy within 2 years except resected basal cell carcinoma or treated carcinoma in situ.

Keywords: dyskeratosis congenita hematopoietic stem cell transplantation severe aplastic anemia