Bone marrow failure (BMF) syndrome is a group of rare hereditary or idiopathic disorders occurring at all ages. For BMF patients under 40 years of age and having an HLA-identical related donor, allogeneic bone marrow transplantation (HSCT) is indicated. The use of cord blood transplantation (CBT) from an HLA-identical sibling donor is of interest in non-malignant disease due to the low risk of graft-versus-host disease (GVHD) associated with this type of stem cell source and the absence of risk to the donor.
We analyzed outcomes of 122 children and young adults with inherited or acquired BMF syndrome, who received a CBT from an HLA-identical related donor. Patients were transplanted in EBMT centers between 1988 and 2014 and reported to Eurocord and EBMT.
Ninety-six patients had an inherited and 26 patients had an acquired BMF. The specific diagnosis were: Fanconi anemia (n=48), Diamond Blackfan anemia (n=25), Amegakariocytic thrombocytopenia (n=6), Kostmann syndrome (n=4), Dyskeratosis congenital (n=3), Schwachman-Diamond syndrome (n=2), and unclassified inherited BMF (n=8) for the inherited group and severe aplastic anemia (n=25), pure red cell aplasia (n=1) for the acquired group.
Eighty-nine patients received a single cord blood (CB) unit, whereas 33 patients received a combination of CB and bone marrow (BM) cells from the same sibling donor. The main reason for adding BM was due to the low cell dose of the single CB unit alone. Of patients receiving CB+BM, 6 had an acquired and 24 had an inherited BMF.
Median age at CBT was 6.7 (range 1-16) years (5.6 years for patients with acquired and 6.9 years for those with inherited BMF). Median interval between diagnosis and CBT was 21 (range 2-114) months for the acquired and 55 (range 2-160) months for the inherited group, respectively.
Fifty-nine patients (53%) received a reduced intensity conditioning (RIC) and 52 (47%) were treated with myeloablative regimens (MAC) (data available for 111 of 122 patients). Fludarabine-based regimens were used in 54 patients (44%). For patients receiving a RIC the most common regimen was cyclophosphamide and fludarabine (56%), and for MAC, cyclophosphamide and busulfan (46%). Total body irradiation was used in 8 patients (both in RIC and MAC settings).
GVHD prophylaxis consisted mainly of cyclosporine alone (CSA) in 53 patients (43%), CSA + micophenolate mofetil in 11 patients (9%) and CSA + methotrexate in 23 patients (19%).
The median number of total nucleated cells (TNC) infused was 6.2x107/Kg (1-24.2x107/Kg) for patients receiving a single CB unit and 26.8x107/Kg (5.3-41x107/Kg) for those receiving CB+BM (median TNC was 3x107/Kg in CB, and 22x107/Kg in BM graft).
Median follow up is 5 (range 0.6-25) years. The cumulative incidence (CI) of neutrophil recovery at day 60 was 91%+9%, and the median time to engraftment was 21 (range 7-100) days. The CI of platelets engraftment at day 180 was 89+3% with a median time of 35 (range 7-138) days. Thirteen patients experienced primary graft failure (PFG) (12 patients after a single CB and one after a CB+BM graft). For those patients with available information, treatment of graft failure was second BM-HSCT (n=6), and growth factors (n=1).
Of the 13 patients with graft failure, 11 died within in a median time of 1.9 (0.3 to 6) months after CBT. Two patients are alive after the second HSCT.
The 100-day CI of grade II-IV acute GVHD was 11+3% (15 patients: grade II, n=8; grade III, n=6; grade VI, n=1), and the 1-year CI of chronic GVHD was 12+4%.
The 1-year CI of transplant-related mortality was 13+3%, 17 patients died: 11 due to PGF (infections (n=6) hemorrhagic syndrome (n=1) and other causes (n=4)) and the remaining 6 of acute respiratory distress syndrome (n=1), and infections (n=5).
Five-year overall survival (OS) for the whole population was 87+3%. OS was 80+8% for patients with acquired BMF, 87+3% for Fanconi anemia patients, 95+4% for those with Diamond Blackfan, and 86+7% for other inherited BMFs.
In pediatric and young adult patients with either inherited or acquired BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes with particular low rates of both acute and chronic GVHD, this latter observation being of particular importance for patients with non-malignant disorders. In case of inherited BMF, collecting cord blood unit at the birth of a new sibling is strongly recommended.
Asterisk with author names denotes non-ASH members.