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Large numbers of patients now survive long term following stem cell transplantation (SCT). The late clinical effects of SCT are thus of major concern in the 21st century. Secondary malignant diseases are of particular clinical concern as more patients survive the early phase after transplantation

Hepatitis C virus (HCV) infection is frequent among patients with hematologic malignancies and unapparent routes of infection may be important in this setting. Moreover, the impact of this infection on the outcome of the hematologic disease needs to be better defined.To define sources and clinical courses of HCV infection, an epidemiologic study was performed on 13 patients newly admitted over one year who showed transaminase elevation and anti-HCV seroconversion. The investigation, started in August 1998, included laboratory tests and molecular analysis of virus isolates, and was extended to staff and blood donors. Clinical, hematologic and serologic surveillance of all infected patients were part of the subsequent follow-up study which started in September 1998 and was completed in December 2001.Anti-HCV seroconversion was observed in 13 of 294 patients (4.4%), admitted to the unit from August 1997 and August 1998; 11 of the seroconverted cases had central catheters, 12 received transfusions. Transmission via blood derivatives and staff was ruled out. All patients were infected by genotype 1b and 11 harbored the same viral variant. HCV infection did not influence the course of the underlying disease or the use of specific therapies. Forty months after the outbreak, five patients are alive (one after autologous and one after allogeneic stem cell transplantation), while eight have died, seven of hematologic disease, and one of cardiac failure. None died of liver disease.The molecular data suggest a patient-to-patient nosocomial HCV transmission. After having analyzed all the possible routes of transmission, a series of preventive measures were adopted: search for HCV RNA in newly admitted patients, protection of mucosae and isolation of patients during neutropenic phases, and avoidance of multidose vials. As regards the impact of HCV infection on the outcome of the hematologic diseases, changes in the scheduled therapy, including stem cell transplantation, were not required.

Acquired aplastic anemia is a rare disease. The incidence ranges from two to six new cases per 1 million inhabitants per annum. Bone marrow transplantation (BMT) in case of available human leucocyte antigen (HLA)-identical sibling and immunosuppressive therapy are the main therapeutic modalities currently used in pediatric patients. In large cooperative studies carried out in Europe, overall survival was not significantly different in children with aplastic anemia treated with allogeneic BMT from an HLA-identical sibling (85%) and those treated with immunosuppressive therapy (83%). Survival was significantly worse for patients treated with BMT from an alternative source (26%; p < 0.00001) versus immunosuppressive therapy. Based on these results, therapeutic strategies recommended for aplastic anemia are allogeneic BMT as a first-line therapy for children with an HLA-identical sibling, and immunosuppressive therapy in patients without. In children who do not respond, alternative therapies include BMT from unrelated or mismatched family donors and, more recently, the use of hematopoietic growth factors. Therapeutic choice in childhood severe aplastic anemia should also take into account the possible late effects, such as growth failure and other endocrine problems, that are peculiar to pediatric patients, as well as the risk of malignancies occurring mostly when irradiation is given as part of the conditioning regimen before BMT. As aplastic anemia is such a rare disease, improvements in current treatment strategies can only be achieved by joint efforts between treatment centers. Therefore, patients should be referred to experienced centers early in the course of the disease in order to offer the patient the best therapeutic options presently available.

14 leukemic children, who underwent Bone Marrow Transplantation (BMT), were evaluated for oral and dental status. 11/14 (78.6) patients had dental abnormalities (agenesia, crown opacity and ipoplasya, impaired root development). 11/14 presented multiple caries. Temporomandibular joint function was altered in 1/14 patient. Parodontal abnormalities incidence was similar to a normal population. In conclusion we found an increased incidence in agenesis and root abnormalities.

Allogeneic blood or bone marrow transplantation is a successful treatment for leukaemia and severe aplastic anaemia (SAA). Graft rejection following transplantation for leukaemia is a rare event but leukaemic relapse may occur at varying rates, depending upon the stage of leukaemia at which the transplant was undertaken and the type of leukaemia. Relapse is generally assumed to occur in residual host cells, which are refractory to, or escape from the myeloablative conditioning therapy. Rare cases have been described, however, in which the leukaemia recurs in cells of donor origin. Lack of a successful outcome of blood or bone marrow transplantation for severe aplastic anaemia (SAA), however, is due to late graft rejection or graft-versus-host disease. Leukaemia in cells of donor origin has rarely been reported in patients following allogeneic bone marrow transplantation for SAA. This report describes leukaemic transformation in donor cells following a second allogeneic BMT for severe aplastic anaemia. PCR of short tandem repeats in bone marrow aspirates and in colonies derived from BFUE and CFU-GM indicated the donor origin of leukaemia. Donor leukaemia is a rare event following transplantation for severe aplastic anaemia but may represent the persistence or perturbation of a stromal defect in these patients inducing leukaemic change in donor haemopoietic stem cells.

Granulocyte-colony stimulating factor (G-CSF) is being increasingly used in healthy volunteers to harvest haemopoietic stem cells. A possible role of G-CSF in the development of clonal disorders or leukaemia has been suggested. We analysed 144 patients with aplastic anaemia treated with immunosuppression protocols with or without G-CSF, with normal cytogenetics at diagnosis or immediately after immunosuppression. Our findings indicated that the risk of developing myelodysplasia or leukaemia was similar in patients with aplastic anaemia on immunosuppressive treatment with or without G-CSF. Therefore, it seems unlikely that G-CSF causes leukaemia in healthy volunteers.

Several groups have reported the results of Allo-SCT following a RIC regimen in relapsed and refractory lymphomas. However, the long-term efficacy of this strategy is still unknown. We report herein the results of a prospective multicenter phase II trial at median follow-up of 5 years. A total of 194 relapsed/refractory lymphomas received the same RIC regimen (thiotepa, cyclophosphamide and fludarabine) followed by Allo-SCT from sibling donors. Histologies were non-Hodgkin’s lymphomas (NHL) [indolent (LG-NHL, n=68), including follicular lymphoma (FL, n=29), chronic lymphocytic leukemia (CLL, n=35), other (n=4); aggressive (HG-NHL, n=87), including B-cell phenotype (n=43), T-cell phenotype (n=28), mantle cell lymphoma (MCL, n=16)] and Hodgkin’s lymphoma (HL, n=39). 133 (68%) of 194 patients (pts) had chemosensitive disease and 100 (52%) of 194 failed a previous autologous transplantation. Median follow-up was 60 months (range, 15–113). At last follow-up, 116 pts are alive (59%) and 78 died from any cause [n=47 for disease progression, n= 30 for non-relapse mortality (NRM), n=1 not assessable]. The 5-year overall survival (OS) and progression-free survival (PFS) were 62% and 70% for LG-NHL, 61% and 59% for HG-NHL, and 42% and 19% for HL, respectively. The median time to relapse was 7 (range, 2–30), 4.5 (range, 1.6–33), and 5.5 (range, 0.4–42) months for LG-NHL, HG-NHL, and HL respectively. Pts with chemosensitive disease at Allo-SCT had 5-year OS and PFS of 69% and 61%, while those with refractory disease had 5-year OS and PFS of 35% and 45%, respectively. Status of disease at Allo-SCT influenced significantly long-term outcome in HG-NHL and HL [chemosensitive versus chemorefractory: 73% versus 32% (p

A randomized trial was carried out comparing cyclosporin A (CsA) and short-term methotrexate (MTX) versus CsA alone for graft versus host disease (GVHD) prophylaxis in patients with severe aplastic anemia (SAA) undergoing allogeneic bone marrow transplantation (BMT) from a compatible sibling. Seventy-one patients (median age, 19 years; range, 4-46 years) were randomized to receive either CsA and MTX or CsA alone for the first 3 weeks after BMT. Subsequently, both groups received CsA orally, with gradual drug reduction until discontinuation 8 to 12 months after BMT. Patients randomized in both arms had comparable characteristics and received the same preparative regimen (ie, cyclophosphamide 200 mg/kg over 4 days). The median time for neutrophil engraftment was 17 days (range, 11-31 days) and 12 days (range, 4-45 days) for patients in the CsA/MTX group and the CsA alone group, respectively (P =.01). No significant difference was observed in the probability of either grade 2, grade 3, or grade 4 acute GVHD or chronic GVHD developing in the 2 groups. The Kaplan-Meier estimates of 1-year transplantation-related mortality rates for patients given either CsA/MTX or CsA alone were 3% and 15%, respectively (P =.07). With a median follow-up of 48 months from BMT, the 5-year survival probability is 94% for patients in the CsA/MTX group and 78% for those in the CsA alone group (P =. 05). These data indicate that the use of CsA with MTX is associated with improved survival in patients with SAA who receive transplants from compatible siblings. (Blood. 2000;96:1690-1697)

One hundred consecutive patients with severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), 6-methylprednisolone (6Mpred), and granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 16 years (range, 1-72 years) and median neutrophil count was 0.2 x 10(9)/L (range, 0-0.5 x 10(9)/L). Trilineage hematologic recovery (at a median interval of 96 days from treatment) was seen in 77 patients (48 complete, 29 partial) after 1 (n = 50) or more courses of ALG (n = 27). Of the 23 nonresponders, 11 patients died at a median interval of 83 days (range, 16-1132 days), 6 were considered treatment failures and underwent transplantation, and 6 were pancytopenic. Cytogenetic abnormalities were seen in 11% of patients, clonal hematologic disease in 8%, and relapse of marrow aplasia in 9%. The actuarial survival at 5 years was 87% (median follow-up 1424 days): 76% versus 98% for patients with neutrophil counts less than versus greater than 0.2 x 10(9)/L (P =.001) and 88% versus 87% for patients aged less than versus more than 16 years (P =.8). The actuarial probability of discontinuing CyA was 38%. Patients who did not achieve a white blood cell (WBC) count of 5 x 10(9)/L during G-CSF treatment have a low probability of responding (37%) and a high mortality rate (42%). This update confirms a high probability for SAA patients of becoming transfusion independent and of surviving after treatment with ALG, CyA, 6Mpred, and G-CSF, with a significant effect of neutrophil counts on outcome. Problems still remain, such as absent or incomplete responses, clonal evolution, relapse of the original disease, and cyclosporine dependence. Early transplantation, also from alternative donors, may be warranted in patients with poor WBC response to G-CSF. (Blood. 2000;95:1931-1934)

The occurrence of infection with Hepatitis B (HBV) or Hepatitis C virus (HCV) in patients undergoing allogeneic or autologous stem cell transplantation (SCT) poses several clinical problems, as these infectious complications can jeopardize the ultimate prognosis, due to the possibility of progression to fulminant hepatic failure and also of possible evolution to chronic active hepatitis and cirrhosis. Although the risk of acquiring HBV and HCV infection from blood transfusion is nowadays greatly reduced, SCT patients still represent a group at high risk, being extremely prone to becoming infected due to the ‘lack of immune competence given both the hematological disease and the conditioning regimen they receive before SCT. Moreover, these patients may already be infected at transplant. Lastly, patients undergoing allogeneic SCT may have a single related donor who is an HBV or HCV carrier, and this event is far from exceptional, especially in geographic areas where these viruses are endemic. The behavior of HBV and HCV infection and related disease is often unpredictable in this cohort of patients both in the short-term and long-term outcome. Before describing in detail the impact of HBV and HCV infection in this clinical setting, it may be pertinent to briefly summarize the pathogenesis and clinical expression of these infections in the immune competent host.

We have analyzed 2,002 patients grafted in Europe between 1976 and 1998 from an identical twin (n = 34), from an HLA-identical sibling (n = 1,699) or from an alternative donor (n = 269), which included unrelated and family mismatched donors. The proportions of patients surviving in these three groups are, respectively, 91, 66 and 37%: major causes of failure were acute graft-versus host disease (GvHD) (11%), infection (12%), pneumonitis (4%), rejection (4%). In multivariate Cox analysis, factors predicting outcome were patient's age (p0.0001), donor type (p0.0001), interval between diagnosis and bone marrow transplantation (BMT) (p0.0005), year of BMT (p = 0.0005) and female donor for a male recipient (p = 0.02). Patients were then divided in two groups according to the year of BMT: up to or after 1990. The overall death rate dropped from 43 to 24% (p0.00001). Improvements were seen mostly for grafts from identical siblings (from 54 to 75%, p0.0001), and less so for alternative-donor grafts (from 28 to 35%; p = 0.07). Major changes have occurred in the BMT protocol: decreasing use of radiotherapy in the conditioning regimen (from 35 to 24%; p0.0001) and increasing use of cyclosporin (with or without methotrexate) for GvHD prophylaxis (from 70 to 98%; p0.0001). In conclusion, the outcome of allogeneic BMT for patients with severe aplastic anemia has considerably improved over the past two decades: young patients, grafted early after diagnosis from an identical sibling, have currently an over 80% chance of long-term survival. Transplants from twins are very successful as well. The risk of complications with alternative donor transplants is still high.

Patients with severe aplastic anemia (SAA) can be successfully treated with bone marrow transplantation (BMT) or immunosuppressive therapy (IS). The current outcome using both forms of therapy among 3,669 patients treated in Europe between 1976 and 1998 is reviewed. Significant progress has been made and the overall risk of failure is now low, with survival rates greater than 80% for both treatments. Chronic graft-versus-host disease (GvHD) remains a problem for BMT patients, and carries a high risk of lethal complications. On the other hand, IS patients are exposed to late failure due to relapse or clonal/malignant diseases. First-line BMT from identical siblings is compared with IS therapy in an intent-to-treat analysis of 1,765 patients, regardless of subsequent transplant status. The outcome of SAA patients has improved considerably over time and is influenced by patient variables such as severity of the disease and age, but also by the choice of the initial treatment.

Antibody to the recently identified hepatitis C virus was investigated in sera of 128 patients treated with allogeneic bone marrow transplantation, to determine the prevalence of HCV infection and its role in post-transplant liver complications. The overall prevalence of anti-HCV positivity was 28.6% (38/128 patients). The presence of pretransplant anti-HCV positivity (in 10/35 tested patients) did not seem to predict a more severe liver disease. In fact 8/10 anti-HCV+ and 15/25 anti-HCV- patients had elevated transaminases at BMT, and posttransplant liver failure (due to VOD or subacute hepatitis), and post-BMT rises in transaminases occurred regardless of anti-HCV serology (P = 0.6 and 0.2, respectively). In patients tested for anti-HCV after BMT (n = 128), only two (one anti-HCV+ and one anti-HCV-) experienced VOD; the number of patients in whom liver failure contributed to death was comparable in anti-HCV-positive and anti-HCV- negative patients (P = 0.4). Among 17 patients with documented posttransplant seroconversion (from anti-HCV- to anti-HCV+) the appearance of anti-HCV was concomitant with hepatitis exacerbation in 9 (53%). Histologic changes demonstrated a more severe liver damage in anti-HCV+ patients: a chronic hepatitis was diagnosed in 9/11 anti-HCV+ versus 1/7 anti-HCV- cases. Based on these observations, we conclude that hepatitis C virus has a role in liver disease in such patients, although its evaluation by the anti-HCV test is still of limited accuracy, due to low sensitivity and incomplete specificity.

Introduction Bone marrow transplantation (BMT), when HLA-identical siblings are available, and immunosuppressive therapy are the main therapeutic modalities currently used to treat pediatric patients with acquired aplastic anemia. Children who fail to respond can be treated with alternative therapies, including transplantation of bone marrow from unrelated or mismatched family donors and, more recently, hemopoietic growth factors. Reports on the outcome of immunosuppressive therapy in children are often controversial. Some authors have illustrated good response rates in adults and children older than 5 years, while others have shown the opposite (Doney et al., 1997; Matloub et al., 1994). When choosing which therapy to use to treat children with severe aplastic anemia (SAA), one should consider the possible late effects that are peculiar to pediatric patients, such as growth failure and other endocrine problems, as well as the risk of malignancies, which may occur if the conditioning regimen before BMT involves irradiation. This chapter will cover the results and possible consequences of these treatments in childhood acquired aplastic anemia. BMT from HLA-identical siblings Allogeneic BMT from an HLA-identical sibling is thought to be the main treatment choice for young patients with acquired SAA. We analyzed the results of this therapeutic procedure in a large series of pediatric patients (less than 16 years of age) treated in Europe between 1970 and 1996. The SAA Registry of the European Blood and Marrow Transplantation Group (EBMT) contains data on 935 such patients, of whom 497 have received transplants from an HLA-identical sibling.

Immunosuppressive therapy has been used for successful treatment of severe aplastic anemia, but little information is available on outcome in older patients.To evaluate outcome in patients older than 50 years of age who received immunosuppressive therapy for aplastic anemia.Retrospective cohort study.56 centers of the European Group for Blood and Marrow Transplantation (EBMT).810 patients with aplastic anemia reported between 1974 and 1997. Patients were evaluated according to age group: 60 years of age or older (n = 127), 50 to 59 years of age (n = 115), and 20 to 49 years of age (n = 568; reference group).Antilymphocyte globulin, cyclosporine, or both.Survival, cause of death, response to treatment, relapse rate, and risk for late complications were analyzed in all patients and by age group.The 5-year survival rate was 57% (95% CI, 46% to 66%) in patients 50 to 59 years of age and 50% (CI, 39% to 60%) in patients 60 years of age or older compared with 72% (CI, 68% to 76%) in patients younger than 50 years of age (P0.001). Response to therapy, relapse rate, and risk for clonal complications were similar in all three age groups (P0.2). Age was significantly associated with an increased risk for death (relative risk compared with patients 20 to 49 years of age, 1.80 [CI, 1.29 to 2.52] for patients 50 to 59 years of age and 2.57 [CI, 1.87 to 3.53] for patientsor = 60 years of age), mainly because of bleeding or infection (P = 0.02). Response to immunosuppressive therapy in all patients at 12 months was 62% (CI, 58% to 66%); no difference was seen among the age groups in multivariate analysis (P0.2). Sixty-six of the 379 responding patients (17%) subsequently had relapse. The risk for clonal disorders at 10 years was 20% (CI, 15% to 27%).Response to immunosuppression in aplastic anemia is independent of age, but treatment is associated with increased mortality in older patients.

Ninety-five patients undergoing an allogeneic bone marrow transplant (BMT) and developing acute graft-versus-host disease (aGvHD) were randomized to receive low-dose intravenous 6-methylprednisolone (6MPred; 2 mg/kg /d; n = 47) or high-dose 6MPred (10 mg/kg/d; n = 48) for 5 days, with subsequent tapering doses. On day 5 patients not responding or progressing on low-dose 6MPred could be switched to high-dose 6MPred. All patients, aged 1 to 55 years, were recipients of unmanipulated BMT from HLA identical sibling donors. Patients were stratified at randomization for age (//= 20 years), disease (acute leukemia, chronic myeloid leukemia [CML], nonneoplastic disease), disease status (early/advanced), and GvHD prophylaxis (cyclosporin/cyclosporin + methotrexate). Primary endpoints were response to treatment and evolution of aGvHD to grade III-IV. Secondary endpoints were cytomegalovirus (CMV) infections, transplant-related mortality (TRM), and relapse. The median interval between BMT and treatment was 12 days (6 to 43). Results in the two groups (2 v 10 mg/kg) were as follows: response of aGvHD 68% versus 71% (P = .9), evolution to aGvHD grade III-IV 17% versus 20% (P = . 6), CMV infections 55% versus 60% (P = .7), 3-year actuarial TRM 28% versus 32% (P = .7), relapse 17% versus 7% (P = .1). The actuarial survival at 3 years was 63% versus 62% (P = .9) with a median follow up of 580 and 778 days. On day 5 of therapy, 26 patients assigned to low-dose (2 mg/kg) 6MPred were switched to a higher dose of 6MPred because of no response or progression. Their actuarial TRM was 46%, which is significantly higher than TRM of patients who responded on 2 mg/kg and continued with tapering doses (TRM = 16%, P = .007). In conclusion, early treatment of acute GvHD with 6MPred 10 mg/kg/d does not improve the response rate as compared with 2 mg/kg/d, nor does it prevent evolution to aGvHD grade III-IV. CMV infections, TRM, and survival were also comparable. A group of patients at high risk of TRM can be identified after 5 days of treatment with 6MPred 2 mg/kg and could be eligible for alternative forms of therapy.

Purpose: Advances in bone marrow transplantation (BMT) have consistently improved long-term survival. Therefore, evaluation of late complications such as cataracts is of paramount importance. Methods and Materials: We analyzed data of 2149 patients from the EBMT registry. A cohort of 1063 patients were evaluable for survival and ophthalmologic status after transplant for acute leukemia (AL) in first or second complete remission. Conditioning therapy included either single-dose total body irradiation (STBI) or fractionated TBI (FTBI) grouped in different dose rates (low: LDR ≤ 0.04 Gy/min; high: HDR > 0.04 Gy/min). Results: The overall 10-year estimated cataract incidence (ECI) was 50%. It was 60% in the STBI group, 43% in the FTBI group ≤ 6 fractions, and 7% in the FTBI group > 6 fractions ( p −4 ). It was significantly lower (30%) in the LDR than in the HDR groups (59%; p −4 ). Patients receiving heparin for veno-occlusive disease prophylaxis had fewer cataracts than those who did not (10-year ECI: 33% vs. 53%, respectively; p = 0.04). The 10-year ECI was 65% in the allogeneic vs. 46% in the autologous BMT patients ( p = 0.0018). Factors independently associated with an increased risk of cataract were an older age (> 23 years), higher dose rate (> 0.04 Gy/min), allogeneic BMT, and steroid administration (> 100 days). The use of FTBI was associated with a decreased risk of cataract. Heparin administration was a protective factor in patients receiving STBI. In terms of cataract surgery, the unfavorable factors for requiring surgery were: age > 23 yr, STBI, dose rate > 0.04 Gy/min, chronic graft-vs.-host disease (cGvHD), and absence of heparin administration. Among the patients who required cataract surgery (111 out of 257), secondary posterior capsular opacification was observed in 15.7%. Conclusion: High dose rate and STBI are the main risk factors for cataract development and the need for surgery, and the administration of heparin has a protective role in cataractogenesis.

Patients treated with BMT are extremely susceptible to infection with blood-borne viruses that can cause liver disease of variable clinical severity, from minimal biochemical changes to fulminant hepatic failure. Facing a patient with liver disfunction after BMT, one must bear in mind that more than one cause of liver disease, of viral and/or non-viral origin, may coexist. Moreover, besides the most important hepatotropic viruses, other agents, like herpesviruses (including CMV, adenoviruses, Epstein-Barr virus) may also be implicated, sometimes causing a life-threatening fulminant hepatitis, due to their cytopatic effect. Liver disease history and viral markers before transplant, together with the accurate assessment of the timing and type of clinical and biochemical deterioration are useful tools for a differential diagnosis. Liver biopsy, if taken in the early posttransplant period, is often difficult to interpret, while in case of liver disease occurring during immunosuppression tapering, histologic examination may discriminate between an exacerbation of viral hepatitis and an acute onset of chronic liver GVHD. While it seems that hepatitis G virus does not cause liver disease, the presence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a matter of concern for its consequences both early after BMT and for long-term survivors. Despite screening for blood and marrow donors for HBV and, more recently, for HCV markers, the rate of post-transplant infection (4% and 4-15% respectively, confirmed in prospective studies) with those viruses indicates that viral hepatitis still remains an important clinical problem in this setting, although the prognosis of chronic HCV and HBV infection appears more benign than expected, especially in children.

Chronic graft-versus-host disease (cGVHD) is a frequent complication of allogeneic bone marrow transplantation (BMT). Thalidomide was found to have immunosuppressive properties and it has been used in a limited number of children with cGVHD. We report our experience with refractory and/or high-risk cGVHD in 14 children. Six children showed complete clinical response to thalidomide in a median time of 2 months. Four children had partial responses and four failed. Side-effects were usually mild (somnolence, constipation) and only two patients developed sensory peripheral neuropathy. An increased incidence of infectious complications attributable to thalidomide was not observed. Nine out of 10 responding patients are alive 49-111 months post-BMT. Thalidomide can be effective particularly in children with prevailing mucocutaneous cGVHD. All patients should be carefully monitored to detect peripheral neuropathy early.

Hepatitis C virus (HCV) genotypes were investigated in 57 HCV-infected patients undergoing allogeneic BMT at four European BMT units where death resulting from liver failure (LF) in HCV-infected patients varied from1% to80%. The aim of the study was to determine whether differing HCV genotypes could account for the different severity of post-transplant liver disease (LD). Sera from patients with pre (n = 22) or post-BMT (n = 35) HCV infection were collected from Italy (Genova, Monza), Sweden (Huddinge) and Germany (Ulm). Patients were grouped as follows: LF: 19/57; acute hepatitis (AH): 10/57 or chronic hepatitis (CH): 22/57; no liver disease (LD): 6/57. HCV genotypes were identified by hybridisation of the 5'UTR amplified products with type-specific oligonucleotides probes according to Simmonds (Hepatology 1994; 19: 1321-1324). Genotype HCV 1 was identified in 34 patients (60%), HCV 2 in 15 (26%), HCV 3 in three (5%), mixed infection in three (5%) and undefined in two (3.5%). In the LF group HCV 1 was identified in 10/19 and other genotypes in 9/19. Median timing of LF was earlier in patients infected with HCV 1 compared to other genotypes (45 and 68 days, respectively), largely due to the cause of LF; death from veno-occlusive disease (VOD) and hepatitis occurred at 30 and 68 days post-BMT, respectively. Genotype 1 was also identified in cases with no LD. These data indicate that there was no evident correlation between HCV genotype and type or severity of post-transplant liver disease.

The aim of this study was to ascertain prevalence and natural history of hepatitis C virus (HCV) infection in a large cohort of patients cured of childhood leukemia who had been followed prospectively for liver disease for at least 10 years since chemotherapy withdrawal: 114 consecutive patients entered the study. Liver function tests and ultrasonography were used to assess presence of liver disease. Patients were tested for antibody to HCV and for serum HCV-RNA at the end of chemotherapy and at the end of follow-up. At chemotherapy withdrawal, 56 patients (49%) were HCV-RNA positive, often without detectable anti-HCV, and in these cases, transaminase levels were more elevated during (P = .08) and after (P = .04) chemotherapy compared with HCV-RNA negative cases. Patients were then followed-up 13 to 27 years (mean, 17) after chemotherapy withdrawal. During this period, 38 initially anti-HCV negative patients seroconverted to anti-HCV and 17 initially anti-HCV positive cases lost reactivity. Forty patients were persistently HCV-RNA positive in serum, while 16 initially viremic patients became HCV-RNA negative during follow-up. At the end of the observation period, a persistent transaminase elevation was detected only in four HCV-RNA positive and anti-HCV positive cases, while no patient developed signs or symptoms of decompensated liver disease. Thus, hepatitis C was a frequent finding in long-term survivors after chemotherapy. It was associated with an atypical serologic profile and did not cause severe liver impairment over a period of 13 to 27 years.

Background Unrelated donor (UD) transplants for patients with acquired severe aplastic anemia (SAA) have been known to yield inferior results when compared to transplants from HLA identical siblings (SIB). With the significant improvement of UD transplants over the past decade, on may ask whether this is still true. Aim of the study To compare the outcome of UD with SIB transplants in recent cohort of patients reported to the European Group for Blood and Marrow Transplantation (EBMT) Aplastic Anemia Registry. Patients We have analyzed 1500 patients with acquired aplastic anemia (SAA), who received a first bone marrow (BM) or peripheral blood (PB),. HLA matched transplant between 2005 and 2009, from identical siblings (n=975) or unrelated donors (n=525). Excluded were cord blood grafts. Clinical characteristics of the two groups were different: although SIB vs UD grafts had comparable age (20 vs 21 years median age , p=0.1), SIB grafts were performed earlier (152 vs 607 median days from diagnosis, p Results The cumulative incidence (CI) of engraftment was 91% for both SIB and UD transplants; and the CI of acute GvHD grade II-IV was11% in SIB and 25% in UD grafts (p In multivariate COX analysis the strongest negative predictors of survival was the use of PB as a stem cell source (RR 2, p20 years (RR 2.0, p180 days (RR 1.3, p=0.006) and no anti-thymocyte globulin (ATG) in the conditioning (RR 1.6, p=0.002). The use of an UD as compared to a SIB was not statistically significant (RR 1.2, p=0.4). When stratified for negative predictors, the actuarial 5 year survival of SIB and UD transplants was 91% vs 81% in low risk patients (n=541, 0-1 negative predictors, p=0.052), 74% vs 72% for the largest group of intermediate risk patients (n=829, 2-3 negative predictors, p=0.4) and 53% vs 50% for a small group of high risk patients (n=130, 4 negative predictors, p=0.8). Conclusions This study suggests that the outcome of UD and SIB transplant for SAA is currently comparable, if one corrects for confounding variables, and especially time to transplant. This information warrants the activation of an unrelated donor search for all patients lacking an HLA matched sibling, up to the age of 60, and this may be relevant for treatment strategies. Disclosures: No relevant conflicts of interest to declare.

The growth of 66 long-term survivors, transplanted in two centres (Genoa S. Martino and Monza) is reported. Patients were all under age 15 at the time of bone marrow transplantation (mean 9.8 +/- 3.4 years; range 1.07-15 years) with a minimum follow-up of at least 12 months. They were divided into four groups. Group 1: eight patients with severe aplastic anemia (SAA): conditioning included cyclophosphamide (CY) 200 mg/kg only. Group 2: 32 patients with acute lymphoblastic leukemia (ALL), and acute myeloid leukemia (AML): conditioning included CY 120 mg/kg and 10-12 Gy fractionated total body irradiation (fTBI). Group 3: 20 patients with ALL, who had previously received cranial irradiation; conditioning included CY 120 mg/kg and fTBI with an additional testicular irradiation (4 Gy). Group 4: six patients with chronic myeloid leukemia (CML) and AML; conditioning included CY 200 mg/kg and busulfan (BU) 16 mg/kg. Group was impaired in all four groups, including the unirradiated groups (-0.2 +/- 0.7 and -0.5 +/- 0.6 delta-SDS in groups I and 4, respectively). Growth impairment-SDS was statistically significant in the two irradiated groups (-0.7 +/- 1.0 and -0.9 +/- 1.0 delta-SDS in groups 2 and 3, respectively), more marked in patients who had had previous cranial irradiation. Chronic graft-versus-host disease and its treatment were not found to have a major effect on growth.

Increased numbers of recipients of BMTs and autologous BMTs are becoming long-term survivors. Existing data support that loss of protective immunity to agents such as tetanus and poliovirus is common in patients who received BMTs and autologous BMTs. Thus, a reimmunisation programme is needed to ensure immunity. A questionnaire concerning immunisation practices was sent to EBMT member centres. The immunisation practices varied extensively in the 59 responding BMT and 48 responding autologous BMT centres. Sixty five per cent of responding centres routinely immunise patients who received allogeneic BMTs whereas 37% were routinely immunising recipients of autologous BMTs. Tetanus toxoid and inactivated poliovirus vaccine were the most frequently used vaccines in both BMT and autologous BMT centres. Immunisations of recipients of both BMTs and autologous BMTs with tetanus toxoid, diphtheria toxoid, inactivated poliovirus vaccine and influenza vaccine are recommended. Other vaccines, and in particular live attenuated vaccines, may be considered on an individual basis.

Immunity to tetanus toxoid and polioviruses was studied in 34 (27 allografted, 7 autografted) children who underwent bone marrow transplantation (BMT). At a median time of 3 years after BMT, only one recipient was seronegative for tetanus toxoid. On the contrary 73% of children were seronegative for at least one of the three poliovirus types and 30% for all virus types. Undetectable antibody titers were more frequently found against type 3 than the other two types. We recommend that reimmunizations of children after BMT be based on serologic tests for antibody titers.