Management of adult patients older than 40 years refractory to at least one immunosuppressive course: HLA-identical sibling HSCT using fludarabine-based conditioning

Abstract

Allogeneic hematopoietic SCT (HSCT) from an HLA-identical sibling donor is the recommended upfront therapeutic option for young patients with SAA. The outcome of allogeneic sibling HSCT has remarkably improved during the last decade as a function of improvement in transplantation supportive care. However, there is still much debate concerning the upper age limit for sibling HSCT in SAA, particularly in patients who are refractory to at least one immunosuppressive course. Recent studies suggest that fludarabine-based conditioning may improve HSCT outcome in older patients with SAA. This review discusses available data about the use of fludarabine-based conditioning in transplantation of older patients with SAA. More definitive conclusions are needed from larger studies before the wide adoption of fludarabine-based conditioning as an alternative to the standard CY and ATG-based conditioning. (2013) 48, 196-197; doi:10.1038/bmt.2012.251; published online 10 December 2012 Bone Marrow TransplantationKeywords: aplastic anemia; sibling donor; conditioning regimen; impact of age HLA-IDENTICAL SIBLING HSCT IN OLDER PATIENTSAllogeneic hematopoietic SCT (HSCT) from an HLA-identical sibling donor is the first line treatment of choice for newly diagnosed patients with severe acquired idiopathic aplastic anemia (SAA) younger than 40 years.However, for older patients X40 years, the decision whether to treat with immunosuppressive therapy (IST), namely antithymocyte globulin (ATG) and cyclosporine, or to transplant upfront from an HLA-identical sibling donor remains a key question. Two large studies from Seattle 1 and the European Group for Blood and Marrow Transplantation (EBMT) SAA Working Party 2 that examined survival by age group did not show an advantage for either HSCT or IST in older patients. This was notably related to a lower long-term survival after HSCT for older patients, that is, 440 years in the Seattle cohort 1 and 420 years in the European study. 2 The negative impact of older age at transplant has been confirmed in several other studies. 3-5 A recently published large study from the CIBMTR performed on 1307 patients analyzed the impact of age on outcome after sibling donor HSCT for SAA. 6 Patients older than 40 years were more likely to (i) have had immunosuppressive therapy before HSCT, (ii) have a poor performance status, (iii) have an interval from diagnosis to HSCT of43 months and (iv) have received a PBSC graft. The mortality risk was higher in patients over 40 years than in patients 20-40 years (P ¼ 0.008) and patients less than 20 years old (Po0.0001). IMPACT OF CONDITIONING REGIMEN MODIFICATIONS IN OLDER PATIENTSThe standard conditioning regimen for HLA identical sibling HSCT relies on CY, with or without ATG. In order to improve survival in patients older than 40 years, the use of less cytotoxic but more immunosuppressive regimens including lowered dose of CY (below the standard dose of 200 mg/kg) in combination with ATG, while adding fludarabine, might be an option to explore with the aim of reducin...

Clinical evaluation of haploidentical hematopoietic combined with human umbilical cord-derived mesenchymal stem cells in severe aplastic anemia

“…Recent studies suggested that immunosuppressants improved the efficacy of HSCT in patients with SAA [ 16 , 17 ]. In HLA-matched transplantation for treatment of aplastic anemia, the conditioning regimen consisting of Cy, ATG, and Flu could remarkably decrease the failure rate of transplantation [ 18 , 19 ].…”

Immune Escape after Hematopoietic Stem Cell Transplantation (HSCT): From Mechanisms to Novel Therapies

“…In conclusion, since all of these studies have provided evidence that DLI produces a GvL effect at the expense of a higher GvHD incidence, various strategies aimed at modifying the DLI content including: Tregs [116,117], NK and γδ-T cells, have been developed [115][116][117].…”

Allogeneic transplantation using CD34+ selected peripheral blood progenitor cells combined with non‐mobilized donor T cells for refractory severe aplastic anaemia

“…We, and others, have shown that fludarabine‐based PBSC transplantation overcomes the risk of graft rejection in heavily transfused and allo‐immunized SAA patients refractory to IST (Gomez‐Almaguer et al , ; Srinivasan et al , ; Maury et al , ; Novitzky et al , ; Maury & Aljurf, ; Pantin et al , , ). However, improvement in engraftment with PBSC transplantation was offset by a higher incidence of acute and chronic GVHD compared with BMT.…”