BackgroundAllogeneic stem cell transplantation is the only curative option for patients with hereditary bone marrow failure syndromes. Umbilical cord blood is an alternative source of stem cells for allogeneic transplantation. Design and MethodsThis multicenter, retrospective study is based on data reported to the Eurocord Registry about patients with hereditary bone marrow failure syndrome who underwent umbilical cord blood transplantation. ResultsSixty-four patients with hereditary bone marrow failure syndromes were transplanted from related (n=20) or unrelated donors (n=44). Diagnoses were Diamond-Blackfan anemia (21 patients), congenital amegakaryocytic thrombocytopenia (16 patients), dyskeratosis congenita (8 patients), Shwachman-Diamond syndrome (2 patients), severe congenital neutropenia (16 patients) and unclassified (1 patient). In the group of patients who received grafts from related donors, all patients but one received an HLA-matched sibling transplant. The median number of total nucleated cells infused was 5¥10 7 /kg. The cumulative incidence of neutrophil recovery at 60 days was 95%. Two patients had grade II-IV acute graft-versus-host disease, while the 2-year cumulative incidence of chronic graft-versus-host disease was 11%. The 3-year overall survival rate was 95%. In the group of patients who received grafts from unrelated donors, 86% had HLA-mismatched grafts and three received two umbilical cord blood units. The median number of total nucleated cells infused was 6.1¥10 7 /kg. The cumulative incidence of neutrophil recovery at day 60 in this group was 55%. The 100-day cumulative incidence of grade II-IV acute graft-versus-host disease was 24%, while the 2-year cumulative incidence of chronic graft-versus-host disease was 53%. The 3-year overall survival rate was 61%; better overall survival was associated with age less than 5 years (P=0.01) and 6.1¥10 7 /kg or more total nucleated cells infused (P=0.05). ConclusionsIn patients with hereditary bone marrow failure syndromes, related umbilical cord blood transplantation is associated with excellent outcomes while increasing cell dose and better HLA matching might provide better results in unrelated umbilical cord blood transplantation.Key words: cord blood transplantation, hereditary bone marrow failure syndromes, engraftment, HLA compatibility.Citation: Bizzetto R, Bonfim C, Rocha V, Socié G, Locatelli F, Chan K, Ramirez O, Stein J, Nabhan S, Miranda E, Passweg J, de Souza CA, Gluckman E, on

Serviço de Hematologia e Hemoterapia do HC-FM-USP, São Paulo. Correspondência: Renata Bizzetto Rua Matias Aires nº 300, 9440-9935 E-mail: rbizzetto@hotmail.com Revisão / ReviewIntrodução O LPSNC é um linfoma extralinfonodal raro que, por definição, ao diagnóstico, encontra-se restrito ao parênquima cerebral, à meninge e/ou medula espinhal e/ou olhos.1 Após ter sua incidência triplicada nas últimas três décadas, atingiu taxas atuais de 0,4/100.000 habitantes.2 Anteriormente respondia por 0,5% a 1,5% de todas as neoplasias do SNC, representando atualmente 4% a 7% destes tumores.3 O aumento da incidência ocorreu em indivíduos imunossuprimidos 4 e em imunocompetentes. 1Os casos de LPSNC não relacionados à SIDA acometem pacientes de 45 a 70 anos, com predomínio acima de 60 anos. Raramente ocorrem em crianças. 4,5,6 Há discreto predo-

Cyclophosphamide (CY) associated to high dose total body irradiation (TBI) or busulfan (BU) is the gold standard of myeloablative conditioning regimen (MAC) in allogeneic hematopoietic stem cell transplantation (HSCT). In unrelated transplants, anti-T cell serotherapy (ATG/ALG) is often added as immunosuppressive drug. Recently, new drugs such as fludarabine (FLU) or thiotepa (TT) have also shown their value in conditioning regimen. However, no MAC has shown to be significantly superior to the conventional TBICY or BUCY. Unrelated cord blood transplantation (UCBT) has been increasingly used in adult patients lacking a HLA-matched donor, but the impact of MAC in this setting is unknown. In order to do so, we analyzed 226 patients who underwent single UCBT after MAC for leukemia [acute lymphoblastic leukemia (n=80), acute myeloid leukemia (n=86), myelodysplasia (n=33), chronic myeloid leukemia (n=27)]. According to IBMTR classification, 60% of patients had early- or intermediate-risk disease status at transplantation. All patients were transplanted from January 2000 to February 2008 in Europe. Median age was 33 years (18–60) and median follow-up was 21 months (2–96). UCB grafts had ≥ 2 HLA incompatibilities in 62% of cases; median nucleated cell dose infused was 2.5 × 107/kg. Ninety-three percent of patients received ATG/ALG before day 0. Three groups of MAC were observed: group 1- TBICY or BUCY (n=82; 36%), group 2- CY+TT (mostly associated to BU) (n=73; 32%) and group 3- FLU based regimens (mostly associated to intravenous BU 9.6 mg/kg and TT 10 mg/kg) (n=71; 31%). Graftversus- host disease (GVHD) prophylaxis consisted of cyclosporine and corticosteroids in 77% of patients. Patients-, disease- and transplant-related factors were compared among the 3 conditioning groups. All 3 groups showed the same frequency of diagnosis and status of the disease at transplantation. Group 1 (TBICY or BUCY), included a higher number of patients with negative CMV serology, transplanted before 2004, ≥ 2 HLA disparity and higher number of infused cells compared to group 2 and/or group 3. There was no statistical difference of those characteristics between group 2 and 3. Cumulative incidence of 60 day-neutrophil recovery (>500/mm3), 180 day-platelet recovery (>20000/mm3), 100 day-acute GVHD, 100 day non-relapse mortality (NRM) and relapse at 2 years were 80±3%, 52±3%, 24±3%, 28±3% and 24±4%, respectively. Two-year disease-free survival (DFS) was 37%±5 for patients transplanted in remission and 22±5% for those in more advanced phase (p=0.001). The association of groups of MAC and outcomes are shown in the table below. In a center effect adjusted multivariate analysis, among other variables such as CMV recipient serology, disease status and HLA disparity, groups 2 and 3 confirmed an increased incidence of neutrophil recovery [hazard ratio (HR)=0.44 (95% CI 0.32–0.60)] and platelets recovery [HR=0.52 (95% CI 0.34–0.79)]. However, none of the conditioning regimens were associated with acute GVHD, 100-day NRM or DFS. Conclusion: these findings support the use of fludarabine and/or thiotepa based MAC as a strategy to improve neutrophil/platelet recovery after single UCBT in patients with leukemia. Further prospective randomized trials should be performed to address this issue. Conditioning regimens Neutrophil recovery (day+60) Platelets recovery (day+180) AGVHD (II–IV) (day +100) NRM (day +100) DFS (2 years) Group 1 - TBICY or BUCY (n=82) 71±5% 39±5% 17±4% 28±5% 28±6 Group 2 - CY+TT (± BU or TBI) (n=73) 78±5% 53±6% 37±6% 38±6% 29±5 Group 3 - FLU (+ BU + TT) (n=71) 92±4% 66±6% 18±5% 17±4% 35±7 P (overall) <0.001 0.003 0.001 0.021 0.400

2300 Poster Board II-277 Allogeneic stem cell transplantation is the only curative option for congenital bone marrow failure syndromes (CBMFS). Umbilical cord blood cells from related or unrelated donor are an alternative source of stem cell for allotransplantation. We studied 64 patients with CBMFS who underwent umbilical cord blood transplantation (CBT), from related (RCBT) (n=20) and from unrelated donor (UCBT) (n=44) who were registered in Eurocord. In the RCBT group, 13 (65%) patients had Diamond Blackfan anemia (DBA), 3(15%) amegakaryocytic thrombocytopenia (Amega), 2(10%) dyskeratosis congenita (DC), 1(5%) Schwachman Diamond syndrome (SDS) and 1(5%) Kostmann's disease (KD). The median age was 5.7 years, 60% were male, 52% were CMV positive and 52% had received more than 20 red blood cell (RBC) and/or platelet transfusions. The median time from diagnosis to transplant was 64 months. Ninety five percent received a HLA matched sibling transplant. Conditioning regimens varied by centers: 25% received reduced intensity conditioning regimens (RIC) and 75% received myeloablative conditioning regimens (MAC). All patients received graft-versus-host disease (GVHD) prophylaxis that included Cyclosporine; most patients also received additional agents. The median number of infused nucleated cells was 5×107/kg and median CD34+ cell count was 1.7×105/kg. Median follow up is 40 months. The cumulative incidence of neutrophil recovery was 95% by day 60 and platelet recovery was 85% by day 180. The cumulative incidence of acute GVHD (II-IV) was 5% at day 100 and chronic GVHD was 11% at 2 years. The 3-year overall survival was 95%. In the UCBT group, 8 (18%) patients had DBA, 13 (29%) had Amega, 6 (14%) DC, 1(2%) SDS, 13(29%) KD, 2(5%) congenital agranulocytosis, and 1(2%) had unclassified aplastic anemia. The median age was 5 years, 64% were male, 64% were CMV positive, and 49% had received more than 20 RBC and/or platelet transfusions. The median time from diagnosis to transplant was 29 months. Eighty six percent of patients received grafts mismatched at 1 or 2 HLA loci and 3 patients received double UCBT. Conditioning regimens also varied by center: 38% received RIC and 62% MAC. GVHD prophylaxis included Cyclosporine in 91% patients. The median infused nucleated cell count was 6.1×107/kg and median CD34+cell count was 3.0×105/kg. The median follow up was 32 months. The cumulative incidence of neutrophil recovery was 55% by day 60 and platelet recovery was 50% by day 180. The cumulative incidence of acute GVHD (II-IV) was 24% at day 100 and chronic GVHD was 53% at 2 years. Two-year overall survival was 61%. Younger patients (<5 year) and number of infused nucleated cell count ≥6.1×107/kg were associated with improved survival rates. In fact, 2 year overall survival was 81% for patients transplanted with a higher cell dose versus 37% for the others (p=0.02) and it was 82% for younger patients versus 39% for older patients (p=0.01). We conclude that CBT from a related donor is a feasible procedure for patients with non-Fanconi CBMFS. Outcomes of unrelated CBT are better in younger patients and in patients transplanted with CB units containing higher cell doses. Disclosures: No relevant conflicts of interest to declare.

Ao Prof. Dr. Carmino Antônio de Souza, por ter prontamente aceitado ser o orientador deste trabalho, pela atenção e pelos ensinamentos durante o desenvolvimento desta tese. Ao Dr. Vanderson Rocha e Dra. Eliane Gluckman por terem me recebido no Eurocord e terem iniciado a idéia deste projeto, e à toda equipe do Eurocord pelas orientações durante o período em que estive em Paris para a coleta de dados. À Eliana Miranda pela disponibilidade, pelo carinho e orientações estatísticas durante a execução deste trabalho.