Figure 1.
Figure 1. Algorithm to manage idiopathic aplastic anemia. (a) Indications for treatment are severe AA (2 in 3 blood counts, including absolute neutrophil count <500/μL, absolute reticulocyte count <60 000/μL, and platelet count <20 000/μL) or, in cases of moderate AA, where the patient needs transfusion support or has infectious complications as a result of low neutrophil count. (b) For age limit, stated cutoff ages are recommendations and are thus discussable according to institution and patient specificities. (c) For refractory patients, first carefully reassess the diagnosis to eliminate a clonal evolution such as myelodysplastic syndrome (MDS), as well as to exclude constitutional BM failure.1 (d) Early BM HSCT after cyclophosphamide (CY) with an ATG-conditioning regimen and a combination of cyclosporine (CsA) plus methotrexate (MTX) as GVHD prophylaxis is recommended. (e) Centers match either for A, B, C, and DRB1 at allelic level, looking for 8/8 matched donors or for DQ looking for a 10/10 match. BM HSCT after FLU, CY, low-dose TBI, and an ATG conditioning regimen is recommended ideally in the first year between diagnosis and HSCT. GVHD prophylaxis should combine CsA with MTX. The consensus is now that an additional low-dose TBI is beneficial for engraftment and long-term survival in adults, because many studies agree that 2 to 3 Gy TBI appears both safe and effective.8-11,13 However,the addition of low-dose TBI in young patients <14 years does not seem crucial.9 ATG has been part of the conditioning regimen since the early 1970s2 and also continues to be a positive predictor of survival in the UD setting.4 CY doses are higher (30 mg/kg for 4 days) than in the original protocol (300 mg/m2 for 4 days) to minimize rejection. Others recommend a dose of 50 mg/kg,12 and all agree that 150 mg/kg may be hazardous in these patients.14 Of note, the effect of CY dose is obviously greatly affected by other agents in the preparative regimen. EBMT, Blood and Marrow Transplant Clinical Network, as well as Japanese publications are thus not comparable regarding CY dosage because of other agents’ different dosage, brand, or schedule.9-14 For refractory patients aged ≥30 years, MUD HSCT is possible after only 1 course of IST but should be discussed on an individual patient basis, according to comorbidities at the respective transplant center. (f) Donor/recipient CMV seronegative status, absence of donor-specific antibodies, no comorbidities, >4 × 107 frozen nucleated cells/kg for CB HSCTs, and no kidney dysfunction are all favorable factors to help physicians make decisions. The recommended conditioning regimen is FCC for MMUD, a combination of FLU, CY, low-dose TBI, and ATG (5 mg/kg total dose maximum) for CB and the Baltimore protocol regarding haplo HSCT.15 ATG, anti-thymocyte globulin; CB, cord blood; Haplo, haplo-identical family donor; HSCT, hematopoietic stem cell transplantation; MMUD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor.

Algorithm to manage idiopathic aplastic anemia. (a) Indications for treatment are severe AA (2 in 3 blood counts, including absolute neutrophil count <500/μL, absolute reticulocyte count <60 000/μL, and platelet count <20 000/μL) or, in cases of moderate AA, where the patient needs transfusion support or has infectious complications as a result of low neutrophil count. (b) For age limit, stated cutoff ages are recommendations and are thus discussable according to institution and patient specificities. (c) For refractory patients, first carefully reassess the diagnosis to eliminate a clonal evolution such as myelodysplastic syndrome (MDS), as well as to exclude constitutional BM failure. (d) Early BM HSCT after cyclophosphamide (CY) with an ATG-conditioning regimen and a combination of cyclosporine (CsA) plus methotrexate (MTX) as GVHD prophylaxis is recommended. (e) Centers match either for A, B, C, and DRB1 at allelic level, looking for 8/8 matched donors or for DQ looking for a 10/10 match. BM HSCT after FLU, CY, low-dose TBI, and an ATG conditioning regimen is recommended ideally in the first year between diagnosis and HSCT. GVHD prophylaxis should combine CsA with MTX. The consensus is now that an additional low-dose TBI is beneficial for engraftment and long-term survival in adults, because many studies agree that 2 to 3 Gy TBI appears both safe and effective.8-11,13  However,the addition of low-dose TBI in young patients <14 years does not seem crucial. ATG has been part of the conditioning regimen since the early 1970s2 and also continues to be a positive predictor of survival in the UD setting. CY doses are higher (30 mg/kg for 4 days) than in the original protocol (300 mg/m2 for 4 days) to minimize rejection. Others recommend a dose of 50 mg/kg,12  and all agree that 150 mg/kg may be hazardous in these patients.14  Of note, the effect of CY dose is obviously greatly affected by other agents in the preparative regimen. EBMT, Blood and Marrow Transplant Clinical Network, as well as Japanese publications are thus not comparable regarding CY dosage because of other agents’ different dosage, brand, or schedule.9-14  For refractory patients aged ≥30 years, MUD HSCT is possible after only 1 course of IST but should be discussed on an individual patient basis, according to comorbidities at the respective transplant center. (f) Donor/recipient CMV seronegative status, absence of donor-specific antibodies, no comorbidities, >4 × 107 frozen nucleated cells/kg for CB HSCTs, and no kidney dysfunction are all favorable factors to help physicians make decisions. The recommended conditioning regimen is FCC for MMUD, a combination of FLU, CY, low-dose TBI, and ATG (5 mg/kg total dose maximum) for CB and the Baltimore protocol regarding haplo HSCT.15  ATG, anti-thymocyte globulin; CB, cord blood; Haplo, haplo-identical family donor; HSCT, hematopoietic stem cell transplantation; MMUD, mismatched unrelated donor; MRD, matched related donor; MUD, matched unrelated donor.

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