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In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.

In this retrospective collaborative study, we have analyzed long-term outcome and donor cell engraftment in 194 patients with Wiskott-Aldrich syndrome (WAS) who have been treated by hematopoietic cell transplantation (HCT) in the period 1980- 2009. Overall survival was 84.0% and was even higher (89.1% 5-year survival) for those who received HCT since the year 2000, reflecting recent improvement of outcome after transplantation from mismatched family donors and for patients who received HCT from an unrelated donor at older than 5 years. Patients who went to transplantation in better clinical conditions had a lower rate of post-HCT complications. Retrospective analysis of lineage-specific donor cell engraftment showed that stable full donor chimerism was attained by 72.3% of the patients who survived for at least 1 year after HCT. Mixed chimerism was associated with an increased risk of incomplete reconstitution of lymphocyte count and post-HCT autoimmunity, and myeloid donor cell chimerism < 50% was associated with persistent thrombocytopenia. These observations indicate continuous improvement of outcome after HCT for WAS and may have important implications for the development of novel protocols aiming to obtain full correction of the disease and reduce post-HCT complications.

Immunosuppressive therapy is the best alternative for patients with severe aplastic anemia (SAA) without matched sibling donor or with age > 40 years. Since 1988, an alternative protocol was developed with cyclosporine (CSA) and prednisone (PRED) due to irregularity in distribution of anti-thymocyte globulin (ATG) in Brazil. This study aims to show the results of this treatment on the quality of response, overall survival and development of clonal evolution.384 patients diagnosed with SAA (Camitta and Bacigalupo criteria) were evaluable by medical records review from 12/1988 to 12/2008. The immunosuppressive therapy consisted of CSA: 12mg/kg/day BID from day (D)1- D8, then 7mg/kg/day BID until 1 year. After that CSA was progressively tapered (5% each month) and ultimately stopped usually by two years. CSA levels were kept between 200–400ng/ml. PRED: 2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on PRED dose was tapered 20% each week. Sulfamethoxazole-trimethoprim and fluconazole were used for prophylaxis against Pneumocystis jiroveci (P carinni) and fungal diseases, respectively. Treatment response was defined as Table 1.Treatment evaluation was performed at 6 weeks, 3, 6 and 12 months and then yearly. At diagnosis: median age was 21 years (2-75), disease duration 95 days (2-4749), and median number of transfusions were 12 (0-200). Etiology was idiopathic in 78%. In peripheral blood, median hemoglobin was 7.4g/dL, granulocytes 580/uL, platelets 12.000/uL and reticulocyte 0.5% (corrected value). 60% of the patients had not been treated previously.Overall survival was 61% ± 3 with a median follow-up of 7 years (range: 2 months - 23 years). Response to treatment: 51% had some degree of response, with good quality of life and transfusions independent (143 patients with complete response and 53 partial response). 36 patients had no response and there were 96 deaths. Fifty six patients have lost follow-up. Most patients achieved response between 3 and 6 months of therapy. In multivariate analysis the number of neutrophils ≥ 200/uL (p = 0.009), platelets ≥ 12.000/uL (p = 0.018), reticulocyte ≥ 0.5% (p <0.001) and starting treatment after 1997 (p = 0.002) had an impact on overall survival. Patients with 15 or more previous transfusions (p = 0.006) and age ≥ 40 years (p = 0.003) had lower survival. Overall survival was 63% ± 4 and 42% ± 6 for for patients with severe disease and very severe aplastic anemia (p <0.001). The subgroup analysis of patients under 10 years old had similar results. Among patients with response, thirty-four remained dependent of CSA. Cumulative incidence of relapse was 28% ± 4 within a median of 4.4 years. Hypertension, gingival hypertrophy and diabetes mellitus were common, but easily controlled. The rate of clonal evolution among this cohort was 7.81% (16 patients developed Paroxysmal Nocturnal Hemoglobinuria, 9 Myelodysplastic Syndrome and 5 Acute Myeloid Leukemia).This study, with a long follow-up, has demonstrated that the overall survival using CSA and PRED is similar to that reported with ATG therapy. Even patients with partial responses had achieved good quality of life, free from transfusions and infections. Survival was influenced by the neutrophils, platelet counts, reticulocyte, number of transfusions, age at diagnosis, and therapy started after 1997. The incidence of clonal evolution was lower when compared to reported trials with ATG + CSA.Oliveira: Alexion: Speakers Bureau. Funke: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pasquini: Novartis, Bristol: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract 2234

No relevant conflicts of interest to declare.

Abstract 1211

Introduction: Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) leading to gradual axonal degeneration. It is a classical auto-immune disease, thus high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) could “reset” the immune disorder by controlling autoreactive clones and by restoring self-tolerance after immunological recovery. Objectives: Describe the experience of the Brazilian Cooperative Group of AHSCT for Autoimmune Diseases in 41 MS patients followed-up to five years. Methods: Stem cells were mobilized from the bone marrow with Cy (2g/m2) and Filgrastim (10μg/kg/d SC), collected by leukapheresis and cryopreserved. Patients were conditioned with BEAM (BCNU 300 mg/m2, cytarabine 200 mg/m2, etoposide 200 mg/m2 ×4, melphalan 140 mg/m2) and horse antilymphocyte globulin (ATG) 90 mg/kg) or cyclophosphamide (CY) 50 mg/kg ×4 and rabbit ATG (rATG) 4.5 mg/kg, followed by stem cell infusion. Quality of life was assessed by the Short Form-36 Health Survey Questionnaire (SF-36). Results: Between January 2001 and June 2006, 21 patients received BEAM/ATG and 20 received CY/ATG. Medium age was 42 years (27–53 years), 24 (58.5%) were females, 33 (80.4%) had secondary progressive MS form, 80.95% had EDSS (Expanded Disability Status Scale) 6.0 or higher. No significant difference was seen between the groups regarding age, sex, disease presentation and EDSS. The mean number of CD34+ infused cells was 8.8×106/kg (2,5– 25.13×106/kg). Mean engraftment was 9,3 days (7–10 days) for neutrophils and 13 days (7–24 days) for platelets. 18 patients (46%) had neutropenic fever, 8 (20.0%) had pneumonia and 5 (12.5%) had allergic reactions to lymphoglobulin. Three patients (14.3%) died in the BEAM group due to conditioning regiment toxicity, sepsis and alveolar hemorrhage. Mean hospital stay was 35.47 days (20–168 days) in the BEAM group and 20.15 days (14–32 days) in the CY group (p<0,0001). EDSS-based disease progress in six months to a year was similar in both groups (p = 0.54). Disease worsening was detected in 6/18 patients in the BEAM group and 4/14 in the Cy group. Median follow-up was 17 months. Disease-free survival 4 years post-transplant was 65%. 31/41 patients completed SF-36 after transplantation and they exhibited improvement in their general health status at 100 days post-transplant (p = 0.02). Conclusion: In our study, a less intensive conditioning regimen (CY + rATG) was associated with similar neurological outcomes but also with less toxicity when compared to BEAM regimen. The majority of patients had an improvement in their quality of live. Longer follow-up is required to assess the therapeutic effectiveness of both regimens in MS progression.

Introduction: Multiple sclerosis (MS) is a chronic, inflammatory and demyelinating disease of the central nervous system (CNS) leading to gradual axonal degeneration. It is a classical auto-immune disease, thus high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) could “reset” the immune disorder by controlling autoreactive clones and by restoring self-tolerance after immunological recovery.

Introduction: Chronic myeloid leukemia (CML) accounts for 2–3% of the leukemias in childhood. The only potential curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT), although promising results achieved with imatinib mesylate in adults substantiate its use as a therapeutic alternative for children. The aim of this study is to analyze the outcomes of HSCT in pediatric patients regarding overall survival (OS) and main causes of death. Materials and methods: Retrospective analysis of children aged 1–17 years, diagnosed with CML who underwent HSCT in a single institution in Brazil between jan/1984 and aug/2005. Survival was estimated by Kaplan-Meier curves. Log Rank test was used for comparison of continuous variables. Results: Fifty patients were assessed, 31 male and 19 female. Median age of 13,5 years (1–17). Forty one patients (82%) were in first chronic phase (CP1) and 9 in advanced phases. The interval between diagnosis and HSCT had a median time of 17,5 months (5–84). The source of stem cells was bone marrow in 44 patients (88%), umbilical cord blood in 5 (10%) and peripheral blood stem cell in 1 (2%). Thirty nine patients (78%) underwent related HSCT and 11 (22%) unrelated donor HSCT. Conditioning regimens: busulfan and cyclophosphamide in 35 patients (70%) and TBI containing regimens in 15 (30%). Complete engraftment occurred in 82% of the transplants. Acute (a) graft-versus-host-disease (GVHD) grades II–IV occurred in 44% of the patients, with 20% grade IV. Extensive chronic (c) GVHD occurred in 15/40 patients (38%). Fifteen patients (32%) relapsed after HSCT. Mortality in the study population was 48% and the main causes of death were: relapse in 6 patients (25%), a-GVHD in 6 (25%) and c-GVHD in 4 (17%). Estimated OS in 20 years was 50%, with a median survival of 1926 days. When analyzed separately, patients in CP1 who received related HSCT and immuneprophilaxis with three drugs (steroids, cyclosporine and methotrexate) had an estimated OS in 20 years of 70%. Conclusions: Long term follow up of these children with CML who underwent allogeneic HSCT demonstrate an OS of 50%, reaching 70% in low risk patients. Main causes of death were relapse, acute and chronic GVHD.

Introduction: Unrelated donor hematopoietic stem cell transplantation (HSCT) has been carried out in Brazil since 1995, with an increasing number of procedures among the transplant centers. Evaluating this experience is important to improve the outcomes of this therapeutic modality. The aim of this study is to assess risk factors for survival in 125 patients who underwent unrelated donor HSCT for malignant diseases. Material and methods: 125 patients with malignant diseases who received unrelated donor HSCT between july/95 and june/2005 in a single institution in Brazil were analyzed. Kaplan-Meier curves were used to estimate overall survival, log-rank test for comparison of continuous variables and Fisher exact test for categorical variables. Cox proportional hazard model was used for analyzing risk factors for survival. Analyzed risk factors: sex, age, acute graft-versus-host-disease (a-GVHD) grades II-IV, extensive chronic (c) GVHD, diagnosis, stage of disease, source of stem cells, number of infused cells/Kg and HLA matching. Median age was 17 years (range 1–55), male (n=78) and female (n=44). Diseases: CML (n=46), AML/MDS (n=40), ALL (n=34), other (n=5). Source of stem cells: bone marrow (n=95), umbilical cord blood (n=30). ATG or ALG containing regimens were used in 25 patients. Advanced disease was detected in 66 patients (53%) and was defined as CML in advanced phases, AML and ALL ≥ second clinical remission (CR2), relapsed or refractory. Results: Acute GVHD II-IV was observed in 51 (41%) patients and extensive c-GVHD in 32 (26%). Main death causes: a-GVHD (9%), c-GVHD (13%), infections (41%) and relapse (27%). Estimated overall survival (OS) in 10 years was 40%, with a median survival of 189 days. Sex, diagnosis, stem cell source, type of conditioning, number of infused cells/Kg and HLA matching did not influenced survival. OS in 10 years was higher in patients with early stage disease compared to advanced diseases (55% × 20%; p=.0005) and in patients under 18 years of age compared to those ≥ 18 years-old (60% × 20%; p=.0012). The presence of extensive c-GVHD had a positive influence in OS (OR 0,1758 – 0,9092). Conclusions: The OS in 10 years was 40% for this group of patients. Patients in early stage disease and under 18 years of age have a higher OS in 10 years (55% and 60% respectively). Extensive c-GVHD had a positive impact in survival, probably due to graft versus leukemia effect.

Background: PNH is a clonal acquired disease characterized by poor expression of CD55 and CD59, adding higher lytic activity to the complement pathway, ending up in hemolysis, pancytopenia and thrombosis. The clinical variability and the lack of effective therapeutics make the treatment of PNH a real challenge. Material and methods: A retrospective analysis of 48 patients diagnosed with PNH between feb/1997 and march/2006 admitted to our center was performed. Before 1999, diagnosis was made by HAM and SACAROSIS tests. From this point immunophenotyping analysis was used to establish diagnosis. Bone marrow aspirate and biopsy, cytogenetic and biochemistry analysis were performed for exclusion of comorbities. Patients were divided in two groups: 1) de novo PNH associated with marrow failure (MF) and 2) PNH as an evolution of severe aplastic anemia (SAA) or mielodysplastic syndrome (MDS). Response was defined as reduction at hemolytic episodes as well as improvement of CBC and transfusion requirements. Results: Median age was 24 years (range 9–75); male patients constituted 58% of the sample (male/female: 1,4:1). De novo PNH with associated marrow failure occurred in 22 patients (group 1) and evolutive PNH in 15, being 13 from previous SAA and 2 from previous hypoplastic MDS (group 2). Thirty seven patients were followed at our clinic during this time: 25 (67,5%) received immunesupression with cyclosporine and steroids. Overall response (partial or complete) after one year of therapy was 84% (31/37). The remaining 11 patients (32,5%) received steroids alone, androgens or only observation, four of them remained with stable disease. HLA match hematopoietic stem cell transplantation (HSCT) was performed in 18/48 (38%), being 11 from group 1 and 7 from group 2. Main indications were: pancytopenia (77%), thrombosis (17%) and AML (6%). Only nine patients died (19%): five after HSCT and 4 of those followed at our clinic (massive thrombosis and hemolysis). Overall survival after HSCT was 72% with median follow-up of 890 days. Overall survival among outpatient clinic patients was 86% with a median follow-up of 2340 days. Most frequent outpatient events were: hemolysis (48%), pancytopenia (13%), thrombosis (13 %), renal failure (9%) and infection (8%).Fourteen patients (37%) remained without symptoms. Conclusions:Immunosuppressive therapy with cyclosporine and corticosteroids is an excellent strategy in patients with PNH and associated marrow failure, leading to durable clinical responses.The present data supports previous published indications for HSCT: ASS and thrombosis.Overall survival of PNH patients who received HSCT achieved 72%.

Introduction: Unrelated donor hematopoietic stem cell transplantation (HSCT) has been carried out in Brazil since 1995, with an increasing number of procedures among the transplant centers. Evaluating this experience is important to improve the outcomes of this therapeutic modality. The aim of this study is to assess risk factors for survival in 125 patients who underwent unrelated donor HSCT for malignant diseases.

Introduction: Chronic myeloid leukemia (CML) accounts for 2–3% of the leukemias in childhood. The only potential curative treatment is allogeneic hematopoietic stem cell transplantation (HSCT), although promising results achieved with imatinib mesylate in adults substantiate its use as a therapeutic alternative for children. The aim of this study is to analyze the outcomes of HSCT in pediatric patients regarding overall survival (OS) and main causes of death.

Background: PNH is a clonal acquired disease characterized by poor expression of CD55 and CD59, adding higher lytic activity to the complement pathway, ending up in hemolysis, pancytopenia and thrombosis. The clinical variability and the lack of effective therapeutics make the treatment of PNH a real challenge.

Introduction: Allogeneic Stem Cell transplantation from an HLA identical sibling is considered the treatment of choice for young pts. For pts without a suitable donor, immunosupressive treatment with cyclosporine (Csa) + prednisone (Pred) + Antithymocyte globulin (ATG) is an effective alternative treatment. In 1988, as ATG supply was not regular in our country, we decided to initiate a trial using only Csa +Pred to treat SAA without a matched sibling donor.

Introduction: Allogeneic Stem Cell transplantation from an HLA identical sibling is considered the treatment of choice for young pts. For pts without a suitable donor, immunosupressive treatment with cyclosporine (Csa) + prednisone (Pred) + Antithymocyte globulin (ATG) is an effective alternative treatment. In 1988, as ATG supply was not regular in our country, we decided to initiate a trial using only Csa +Pred to treat SAA without a matched sibling donor. Material and Methods: All pts had the diagnosis of SAA according to established criteria (Camitta et al Blood1976; 48:63–70) and 95 pts had received previous treatment (androgens, Csa alone or steroids). Treatment: Csa: 12mg/kg/day BID from day(D)1- D8, then 7mg/kg/day BID until 1 year. After 1 year, Csa was slowly weaned (5% each month) until definitively stopped. Csa levels were maintained between 200-400ng/ml. Pred:2mg/kg/day from D1-D14 then 1mg/kg/day from D15- D45. From that day on Pred dose was weaned 20% each week until stopped. Prophylactic antibiotics were given according to common practice. Number of pts: 287. Period: 12/1988 to 01/2004. Age: 2-74y (Median: 22). Disease duration: 10–4015days (Median:100). Previous transfusions: 0-160UI (M:10). At diagnosis, granulocytes counts ranged from 0-3110/ul(M:540/uL) and platelet counts from 1000-53000/uL(M:11000/uL). Treatment evaluation was performed at 6weeks, 3,6 and 12 months and then yearly after. Definition of response: Type I: independence of red cells and platelets transfusions and improvement of hematological parameters (Hb>10g/dL, platelets>50.000/uL and granulocytes>1000/uL). Type II: Improvement of hematological parameters (not enough to reach the hematological counts previously specified) with or without dependence of blood transfusions. Type III: No evidence of improvement and dependence of blood transfusions. Results: Overall survival is 63% with a median follow-up of 7 y(6months- 15 years). Response to treatment: TypeI was achieved in 138pts (48%) and all but one pt is alive. These pts have a normal life, free of infections and are transfusion independent. TypeII occurred in 21 pts(7,3%) and 13 pts are alive with only 1 pt dependant of red blood cell transfusions every 45 days. TypeIII occurred in 128pts (44%) and 50 pts are still alive. Most pts responded between 3 and 6m of treatment. Response to treatment was significantly influenced by: Granulocytes at diagnosis >500/uL (p=0,0001); platelets at diagnosis >12000/ul (p=0,01); age>22y(p=0,0061) and previous transfusions < 10UI (p=0,008). Granulocytes at diagnosis >500/uL (p=0,02), platelets at diagnosis >10000/uL (p=0,01)and disease duration >45 days (p=0,02) significantly affected survival. Toxicity was tolerated and well controlled. Hypertension, gingival hypertrophy and diabetes mellitus were frequent complications. Relapse occurred in 19% (31pts) and twenty-two pts(70%) responded to a second treatment using the same drugs but 9pts became cyclosporine dependant. Clonal or malignant disease occurred in 5 pts (2AML and 3 PNH). Conclusion: This data demonstrates that Csa +Pred is an effective treatment for pts with SAA without a suitable donor. Pts may become free of infections and transfusion independent and are able to live normal lives even though their blood counts are still subnormal

Introduction: FA is an autossomal recessive syndrome that usually presents with congenital abnormalities, progressive pancytopenia and an increased risk of cancer.The first stem cell transplant for FA was performed in Latin America in 1983 and since then the BMT center from Curitiba, Brazil became a reference center for this disease. From 1983 until June 2004, 140 pts received a stem cell transplant for FA and most of them were in aplastic phase. In this study we performed a retrospective analysis of 36 patients who received an unrelated stem cell transplant for FA in our BMT center. Patients and methods: Period: 04/1996 to 06/2004, age 4 to 19 year old (median: 9y), sex: 20F/16M. Disease duration: 7 to 122 months (Median: 45), Previous transfusions: 0 to 400 (Median of 21). Aplastic phase: 35 pts. Myelodysplastic syndrome:1pt.Stem cell source : bone marrow 15 pts ( 6/6 : 12pts; 5/6 : 3pts) , cord blood : 20 pts ( 6/6: 3pts , 5/6 :8 pts and 4/6 : 9 pts) and peripheral stem cell : 1 pt ( 6/6). Preparatory regimen: 9 pts received only Cyclophosphamide (CY), 15 pts received CY + Fludarabine + Thimoglobuline, 4 pts received Fludarabine + TBI (200cGy), 4 pts received CY+ TBI ± ATG and 4 pts Fludarabine + CY. GVHD prophylaxis: Cyclosporine (Csa) + MTX: 18 pts, Csa + steroids: 14 pts and other: 4pts. All pts received prophylactic antibiotics according to common practice. Results: 13 pts are alive and well 45 to 1579 days after transplant (median 303 days). 34 pts were evaluable for engraftment (2 pts died before day 28 due to bacterial sepsis and CNS hemorrhage). Median time to reach PMN> 500/uL was 21 days after transplant (+ 12 to + 57) and platelets> 20.000/uL was 22, 5 days (+14 to + 49). Pts who received CY + Fludarabine + Thimoglobuline had a better survival (56%) but it did not reach statistical significance when compared to other preparatory regimens. Acute graft versus host disease (A-GVHD) occurred in 9 pts (grade III: 4 pts, grade IV: 5 pts). Three pts with grade III A-GVHD developed C-GVHD (2 were extensive and severe). VOD was diagnosed in 3 pts (moderate/severe). Mucosytis grade III- IV occurred in 16 pts. Twenty-three pts died at a median time of 58 days after transplant (7 to 226 d). All pts with primary graft failure (11) and 5 pts with only a neuthrophil engraftment died. Causes of death: 15 pts: infections or hemorrhage related to rejection; 4 pts: GVHD, 3 pts:VOD , 1 pt: P carinii and 1 pt EBV lymphoproliferative disease. Transplant related mortality (TRM) was 55% for the whole group (38% for the pts who received CY+ Fludarabine + ATG). It was also lower (35%) for the pts who received cord blood transplants but it did not reach statistical significance regarding survival rate. Conclusions: Treatment of FA pts with unrelated stem cell transplant must be directed at a more effective control of rejection and GVHD. Transplant related mortality is still very high in this group of pts. Our study shows that the use of CY + Fludarabine + Thimoglobuline may improve survival but we still need more pts and a longer follow up to confirm this data.

Introduction: FA is an autossomal recessive syndrome that usually presents with congenital abnormalities, progressive pancytopenia and an increased risk of cancer.The first stem cell transplant for FA was performed in Latin America in 1983 and since then the BMT center from Curitiba, Brazil became a reference center for this disease. From 1983 until June 2004, 140 pts received a stem cell transplant for FA and most of them were in aplastic phase. In this study we performed a retrospective analysis of 36 patients who received an unrelated stem cell transplant for FA in our BMT center.