Graft-versus-host disease following marrow transplantation for aplastic anemia: different impact of two GVHD prevention strategies

136

107

Dyskeratosis congenita (DC) is characterized by reticular skin pigmentation, oral leukoplakia and abnormal nails. Patients with DC have very short telomeres and approximately one-half have mutations in telomere biology genes. A majority of patients with DC develop BM failure (BMF). Hematopoietic cell transplantation (HCT) represents the only known cure for BMF in DC, but poses significant toxicities. We report six patients who underwent allogeneic HCT with a novel nonmyeloablative conditioning regimen specifically designed for DC patients. Graft sources included related PBSCs (1), unrelated BM (2) and unrelated double umbilical cord blood (3). Complete donor engraftment was achieved in five of six patients. One patient had initial autologous hematopoietic recovery, which was followed by a second transplant that resulted in 88% donor chimerism. With a median follow-up of 26.5 months, four patients are alive, three of whom were recipients of unrelated grafts. We conclude with this small study that encouraging short-term survival can be achieved with HCT in patients with DC using a preparative regimen designed to promote donor engraftment and minimize life-threatening disease-specific complications such as pulmonary fibrosis. Long-term follow-up will be crucial with respect to individualized patient care with each of the transplanted individuals.

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Disease-specific hematopoietic cell transplantation: nonmyeloablative conditioning regimen for dyskeratosis congenita

Dietz

Orchard

Baker

et al. 2010

136

107

“…The superiority of the alemtuzumab-based conditioning for AA transplants in terms of decreased incidence of acute and chronic GVHD has been brought out by previous work from our centre as well as other studies from Toronto and Houston. [29][30][31][32] Most of our patients (36 out of 46; 78.3%) had donor marrow as the stem cell source, as recommended by the national guideline. 33 This is another likely explanation for the low incidence of GVHD in our analysis.…”

Section: Discussionmentioning

confidence: 99%

Implications of CD34+ cell dose on clinical and haematological outcome of allo-SCT for acquired aplastic anaemia

Islam

Anoop

Datta-Nemdharry

et al. 2009

The precise effects of CD34 þ cell dose on the outcome of allogeneic transplantation for aplastic anaemia (AA) are not known. Previous studies have used the total mononuclear cell count to quantify stem cell dose. We evaluated the effects of CD34 þ cell dose on the clinical and haematological end points of transplantation. The transplant variables and outcome parameters on 46 patients with acquired AA were assessed by comparing low vs high CD34 þ cell doses. Infusion of less than 2 Â 10 6 /kg of CD34 þ cells was associated with an increased incidence of graft failures (P ¼ 0.03), higher incidence of bacterial infections (P ¼ 0.006) and a delay in the engraftment of neutrophils (P ¼ 0.046). The latter was found to be an effect of stem cell source (non-PBSC) rather than the CD34 þ count. Other parameters, such as plt engraftment (P ¼ 0.63), red cell (P ¼ 0.94) and plt (P ¼ 0.31) transfusion independence, chimerism, acute and chronic GVHD (P ¼ 1.0) and OS (P ¼ 0.57), were not significantly influenced by the CD34 þ cell dose. These findings are different to the published studies on the relevance of CD34 þ cell dose in allogeneic transplantation for haematological cancers.

“…1,2 Better selection of HLA-matched donors has probably had a major role, but also significant changes in the conditioning regimen have occurred, including the use of fludarabine (FLU)-based conditioning, the addition of low-dose (2 Gy) [3][4][5][6] TBI in adults, and the use of Alemtuzumab as an alternative to ATG. [7][8][9][10] OS is currently 475%. 6,10 Results of UD transplants have improved to such an extent that treatment recommendations should be adapted: UD transplantation is now considered after failure to respond to one course of immunosuppressive therapy, and in children UD haematopoietic SCT (HSCT) may be considered as first line treatment in severe aplastic anaemia (SAA).…”

mentioning

confidence: 99%

“…[14][15][16] The combination of FLU-CY and ATG is used most often for the conditioning regimen in UD HSCT for acquired AA, 5,6 although Alemtuzumab is an emerging alternative option to ATG (FCC). [7][8][9][10] Low-dose TBI, 2 or 3 Gy, was added following the Japanese and USA studies. 3,4 The dose of CY was originally set at 300 mg/ m 2 Â 4.…”

mentioning

confidence: 99%

Unrelated donor search and unrelated donor transplantation in the adult aplastic anaemia patient aged 18–40 years without an HLA-identical sibling and failing immunosuppression

Bacigalupo

Marsh

2012

Currently at least 75% of patients with severe aplastic anaemia can be successfully transplanted using a matched unrelated donor (UD) haematopoietic SCT (HSCT). For children, outcomes are similar to matched sibling donor (MSD) HSCT. This improvement in outcome over time is likely due to improved HLA tissue typing to identify better matched donors, improvements in the conditioning regimen, particularly fludarabine-based regimens, and improved supportive care. Graft rejection occurs in B15% of adults, but is less frequent in children. Chronic GVHD remains a concern but may be reduced by using Alemtuzumab instead of ATG. UD HSCT should be considered early after failure to respond to one course of immunosuppressive therapy, but for children who lack a MSD up front matched UD HSCT may be considered. (2013) 48, 198-200; doi:10.1038/bmt.2012.233; published online 26 November 2012 Bone Marrow TransplantationKeywords: aplastic anaemia; HSCT The outcome of unrelated donor (UD) transplants for patients with aplastic anemia (AA) has improved in the last decade. 1,2 Better selection of HLA-matched donors has probably had a major role, but also significant changes in the conditioning regimen have occurred, including the use of fludarabine (FLU)-based conditioning, the addition of low-dose (2 Gy) 3-6 TBI in adults, and the use of Alemtuzumab as an alternative to ATG. 7-10 OS is currently 475%. 6,10 Results of UD transplants have improved to such an extent that treatment recommendations should be adapted: UD transplantation is now considered after failure to respond to one course of immunosuppressive therapy, and in children UD haematopoietic SCT (HSCT) may be considered as first line treatment in severe aplastic anaemia (SAA). 11 Centres match either for A, B, C and DRB1 at the allelic level, looking for 8/8 matched donors 12 or for DQ looking for a 10/10 match. In a recent European BMT (EBMT) analysis, we showed an effect of mismatching (o8/8 vs 8/8 match) only for patients prepared with FLU-CY and ATG (FCA), but not for patients receiving FCA supplemented with low-dose TBI 2 Gy (FCA-TBI). 13 In general, an 8/8 (A, B, C and DRB1) matched donor would be ideal, but a 7/8 (or 9/10) match would probably be also acceptable if low-dose TBI is used. [14][15][16] The combination of FLU-CY and ATG is used most often for the conditioning regimen in UD HSCT for acquired AA, 5,6 although Alemtuzumab is an emerging alternative option to ATG (FCC). 7-10 Low-dose TBI, 2 or 3 Gy, was added following the Japanese and USA studies. 3,4 The dose of CY was originally set at 300 mg/ m 2 Â 4. 5,6 This was associated with a significant risk of rejection, so the current indication is to increase the dose of CY to 120 mg/kg. The working party SAA currently recommends FLU 30 mg/m 2 Â 4, CY 30 mg/kg Â 4 and ATG. TBI (2 Gy) can be added on day À 1 for patients aged 414 years, 6 but can be considered also for children sensitized after numerous blood transfusions. Alemtuzumab used with FLU and CY 300 mg/m 2 Â 4 (FCC) has recently been reported to show enco...