Unmanipulated Bone Marrow Transplantation From Haploidentical Related Donor for Patients with High-Risk Hematological Malignancies

Between August 2005 and May 2010, 71 patients were transplanted for acute myeloid leukemia (AML) (n=42), acute lymphoblastic leukemia (n=13), chronic myeloid leukemia (n=5), Hodgkin lymphoma (n=5), plasmacell leukemia (n=3), myelofibrosis (n=2) and myelodisplastic syndrome (n=1). Their median age was 35 years (5-71). At time of BMT, all patients were at very high risk: 39 were in early (complete remission 1 or 2) and 31 in more advanced stage of disease. Seventeen of them were given a previous transplant either autologous (n=14) or allogenic (n=3). All donors were HLA identical at 1 haplotype and mismatched for 2 (n=24) or 3 (n=47) loci on the unshared haplotype. As pretransplant regimen, 10 patients received a reduced intensity conditioning consisting of Fludarabine (Flu) alone (n=1), Flu + Thiotepa (Thio) + Melphalan (n=2) or Flu + Thio + i.v.Busulphan (Bu) (n=7), and 61 patients received a myeloablative therapy consisting of Aracytin + Cyclophosphamide combined with TBI (n=7) or Treosulphan (n=11) or Bu (n=11), whereas the last 32 consecutive patients underwent transplant after conditioning with the association of Thio + Flu + i.v. Bu. All patients received an identical graft-versus-host disease (GvHD) prophylaxis consisting of Fresenius Antithymocyte Globulin (5 mg/Kg/d from day -4 to -1) combined with Cyclosporine (1,5-3 mg/Kg/day i.v. from day -7 to +28 and orally 5 mg/Kg until day +365), Methotrexate (15 mg/sqm on day +1 and 10 mg/sqm on day +3, +6 and +11), Mycophenolate Mofetil (1 g/d from day +7 to +100) and the anti-CD 25 monoclonal antibody Basiliximab (20 mg i.v. on day 0 and +4). Bone marrow cells were harvested from all donors after priming with Filgrastim at 3–4 microg/Kg/d from day -7 to -1. Bone marrow cells were infused fresh and unmanipulated on day 0.

The median dose of total nucleated, CD34⁺ and CD3⁺ cells infused was 7.8 (1-28) ×10⁸/kg, 2.1 (0.8-11) ×10⁶/Kg and 28 (10-98) ×10⁶/Kg, respectively. One patient had a primary graft failure and 5 patients died too early to be evaluated for engraftment. Results in terms of cumulative incidence (CI) of PMN engraftment, acute and chronic GvHD, relapse, transplant related mortality (TRM) and overall survival (OS) estimated with the Kaplan Meyer method are given in the Table. After a median follow-up of 16 (3-56) months, the 3 years probability of OS and disease-free survival (DFS) was 43% and 37% respectively for all patients (see Figure). The 3 years OS for the 42 patients with AML was 48% (61% for 30 patients transplanted in early stage and 18% for 12 patients transplanted in advanced stage, P=0.01). The 1 year OS for the 32 patients transplanted with the conditioning therapy employed in the last 2 years (Thio + Flu + i.v. Bu) was 72% in 18 patients transplanted in early stage and 52% in 14 patients transplanted in advanced stage (P=0.47).

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BMT from haploidentical donor using G-CSF primed, unmanipulated bone marrow cells and an intensive regimen for GVHD prophylaxis is correlated with high engraftment rate, low incidence of acute and chronic GVHD, acceptable TRM and favourable patient outcome. The results seem particularly encouraging for AML patients grafted at an early disease stage. In alternative to transplant from matched unrelated donor or cord blood, this approach can be offered to high risk patients with hematological malignancies particularly for those who are on urgency for a transplant.

Results are given as % ± standard error

No relevant conflicts of interest to declare.