Postremission Consolidation by Autologous Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia in First Complete Remission (CR) and Negative Implications for Subsequent Allogeneic HCT in Second CR: A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n = 417) or without (n = 2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P = .01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P = .03 and 1.18 (1.03 to 1.35), P = .02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P = .1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

Cord blood transplantation is associated with good outcomes in secondary Acute Myeloid Leukaemia in first remission.

BACKGROUND: We conducted a retrospective survey within the European Society for Blood and Marrow Transplantation (EBMT) registry to assess the outcomes of cord blood transplantation (CBT) in secondary acute myeloid leukaemia (sAML). METHODS: Inclusion criteria consisted of ≥18 years of age, sAML, first CBT between 2002 and 2016, and either first complete remission (CR) or active disease at CBT. RESULTS: One hundred forty-six patients met the study inclusion criteria. Status at transplantation was first CR (n = 97), primary refractory sAML (n = 30) or relapsed (n = 19) sAML. Neutrophil engraftment was achieved in 118 patients while the remaining 25 patients (17%) failed to engraft. This includes 13% of patients transplanted in first CR versus 30% of those transplanted with active disease (P = 0.008). Two-year incidences of relapse were 25% in first CR patients versus 36% in those with advanced disease (P = 0.06) while 2-year incidences of nonrelapse mortality were 35% and 49% (P = 0.03), respectively. At 2-year overall survival, leukaemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were 42% vs. 19% (P < 0.001), 40% vs. 16% (P < 0.001), and 26% vs. 12% (P = 0.002) in first CR patients versus those with advanced disease, respectively. CONCLUSIONS: We report here the first study of CBT in a large cohort of sAML patients. Main observation was that CBT rescued approximately 40% of patients with sAML in first CR.

Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukaemia: an ALWP/EBMT analysis.

BACKGROUND: Outcomes for patients with acute myeloid leukaemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) have significantly improved in recent years. OBJECTIVES: To assess the incremental improvement of transplanted AML patients in the last two decades. METHODS: Patients included in this analysis were adult AML patients who underwent allo-SCT from an HLA-matched sibling donor (MSD) or HLA-matched unrelated donor (MUD) in first remission. Patient outcomes were assessed between three cohorts according to the year of transplant (1993-2002, 2003-2007 and 2008-2012). RESULTS: The analysis comprised a total of 20 187 patients of whom 4763 were transplanted between 1993 and 2002, 5835 in 2003 and 2007, and 9589 in 2008 and 2012. In multivariate analysis, leukaemia-free survival (LFS) rates were significantly improved in more recently transplanted patients compared to patients transplanted in 1993-2002 [Hazard ratio (HR) = 0.84, confidence interval (CI) 95%, 0.77-0.92; P = 0.003], a benefit which also extended to improved overall survival (OS; HR = 0.8, CI 95%, 0.73-0.89; P < 0.0001), and decreased nonrelapse mortality (NRM) rates (HR = 0.65, CI 95%, 0.56-0.75; P < 0.0001). Subset analysis revealed that in MSD, the rates of LFS, NRM and OS significantly improved in patients in the more recent cohort with similar results also seen in MUD. Finally, the incidence of acute graft-versus-host disease (GVHD) was significantly reduced leading to improved GVHD-free/relapse-free survival (GRFS) rates in more recently transplanted patients. CONCLUSION: Outcome of allo-SCT for AML patients has markedly improved in the last two decades owing to decreased nonrelapse mortality and improved rates of leukaemia-free survival resulting in significantly longer survival.

What is the outcome in patients with acute leukaemia who survive severe acute graft-versus-host disease?

BACKGROUND: Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (HSCT). With new promising therapies, survival may improve for severe aGVHD. OBJECTIVES: We wanted to analyze the long-term outcome in patients who survive severe aGVHD. METHODS: This study was a landmark analysis of 23 567 patients with acute Leukaemia who survived for more than 6 months after HSCT, 2002-2014. Patients alive after severe aGVHD (n = 1738) were compared to controls. RESULTS: Patients with severe aGVHD had higher non-relapse mortality (NRM) and higher rate of extensive chronic GVHD (cGVHD) than the controls (P < 10-5 ). The probability of relapse was significantly lower in the severe aGVHD group, but Leukaemia-free survival (LFS) and overall survival were significantly lower than for the controls (P < 10-5 ). Five-year LFS in patients with severe aGVHD was 49%, as opposed to 61% in controls with no or mild GVHD and 59% in patients with moderate GVHD. CONCLUSIONS: HSCT patients who survive severe aGVHD have higher risk of developing extensive cGVHD, a higher NRM, a lower relapse probability, and lower LFS than other HSCT patients. This study is a platform for outcome analysis in patients treated with novel therapies for acute GVHD.

Occurrence of graft-versus-host disease increases mortality after umbilical cord blood transplantation for acute myeloid leukaemia: a report from Eurocord and the ALWP of the EBMT.

BACKGROUND: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune-mediated graft-versus-leukaemia effects. Previous studies have suggested a strong association between graft-versus-host disease (GVHD) occurrence and graft-versus-leukaemia effects after allogeneic hematopoietic cell transplantation. METHODS: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient-year within sequential 90-day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time-dependent covariate. RESULTS: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II-IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II-IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT. CONCLUSIONS: The occurrence of grade II-IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft-versus-leukemia effect of GVHD.

Distinct factors determine the kinetics of disease relapse in adults transplanted for acute myeloid leukaemia.

BACKGROUND: Disease recurrence remains the major cause of death in adults with acute myeloid leukaemia (AML) treated using either intensive chemotherapy (IC) or allogenic stem cell transplantation (allo-SCT). AIMS: The timely delivery of maintenance drug or cellular therapies represent emerging strategies with the potential to reduce relapse after both treatment modalities, but whilst the determinants of overall relapse risk have been extensively characterized the factors determining the timing of disease recurrence have not been characterized. MATERIALS AND METHODS: We have therefore examined, using a series of sequential landmark analyses, relapse kinetics in a cohort of 2028 patients who received an allo-SCT for AML in CR1 and separately 570 patients treated with IC alone. RESULTS: In the first 3 months after allo-SCT, the factors associated with an increased risk of relapse included the presence of the FLT3-ITD (P < 0.001), patient age (P = 0.012), time interval from CR1 to transplant (P < 0.001) and donor type (P = 0.03). Relapse from 3 to 6 months was associated with a higher white cell count at diagnosis (P = 0.001), adverse-risk cytogenetics (P < 0.001), presence of FLT3-ITD mutation (P < 0.001) and time interval to achieve first complete remission (P = 0.013). Later relapse was associated with adverse cytogenetics, mutated NPM1, absence of chronic graft-versus-host disease (GVHD) and the use of in vivo T-cell depletion. In patients treated with IC alone, the factors associated with relapse in the first 3 months were adverse-risk cytogenetics (P < 0.001) and FLT3-ITD status (P = 0.001). The factors predicting later relapse were the time interval from diagnosis to CR1 (P = 0.22) and time interval from CR1 to IC (P = 0.012). DISCUSSION AND CONCLUSION: Taken together, these data provide novel insights into the biology of disease recurrence after both allo-SCT and IC and have the potential to inform the design of novel maintenance strategies in both clinical settings.

Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: Fludarabine/busulfan-based conditioning regimens are widely used to perform allogeneic stem-cell transplantation (allo-SCT) in high-risk non-Hodgkin lymphoma (NHL) patients. The impact of the dose intensity of busulfan on outcomes has not been reported yet. PATIENTS AND METHODS: This was a retrospective with the aim to compare the outcomes of NHL patients who received before allo-SCT a fludarabine/busulfan conditioning regimen, either of reduced intensity (FB2, 2 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 277) or at a myeloablative reduced-toxicity dose (FB3/FB4, 3 or 4 days of busulfan at 4 mg/kg/day oral or 3.2 mg/kg/day i.v.) (n = 101). RESULTS: In univariate analysis, the 2-year overall survival (FB2 66.5% versus 60.3%, P = 0.33), lymphoma-free survival (FB2 57.9% versus 49.8%, P = 0.26), and non-relapse mortality (FB2 19% versus 21.1%, P = 0.91) were similar between both groups. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) (FB2 11.2% versus 18%, P = 0.08), extensive chronic GVHD (FB2: 17.3% versus 10.7%, P = 0.18) and 2-year GVHD free-relapse free survival (FB2: 44.4% versus 42.8%, P = 0.38) were also comparable. In multivariate analysis there was a trend for a worse outcome using FB3/FB4 regimens (overall survival: HR 1.47, 95% CI: 0.96-2.24, P = 0.08; lymphoma-free survival: HR: 1.43, 95% CI: 0.99-2.06, P = 0.05; relapse incidence: HR 1.54; 95% CI: 0.96-2.48, P = 0.07). These results were confirmed using a propensity score-matching strategy. CONCLUSION: We conclude that reduced toxicity myeloablative conditioning with fludarabine/busulfan does not improve the outcomes compared with reduced-intensity conditioning in adults receiving allo-SCT for NHL.

Allogeneic hematopoietic stem cell transplantation in solid organ transplant recipients: a retrospective, multicenter study of the EBMT.

We conducted a questionnaire survey of the 565 European Society for Blood and Marrow Transplantation centers to analyze the outcome of allogeneic hematopoietic stem cell transplantation (alloSCT) in recipients of solid organ transplantation (SOT). We investigated 28 patients with malignant (N = 22) or nonmalignant diseases (N = 6), who underwent 31 alloSCT procedures: 12 after kidney, 13 after liver and 3 after heart transplantation. The incidence of solid organ graft failure at 60 months after first alloSCT was 33% (95% confidence interval [CI], 16-51%) for all patients, 15% (95% CI, 2-40%) for liver recipients and 50% (95% CI, 19-75%) for kidney recipients (p = 0.06). The relapse rate after alloSCT (22%) was low following transplantation for malignant disorders, despite advanced stages of malignancy. Overall survival at 60 months after first alloSCT was 40% (95% CI, 19-60%) for all patients, 51% (95% CI, 16-86%) for liver recipients and 42% (95% CI, 14-70%) for kidney recipients (p = 0.39). In summary, we show that selected SOT recipients suffering from hematologic disorders may benefit from alloSCT and experience enhanced long-term survival without loss of organ function.

Incidence and risk factors for hemorrhagic cystitis in unmanipulated haploidentical transplant recipients.

BACKGROUND: Hemorrhagic cystitis (HC) is a common complication after hematopoietic allogeneic stem cell transplantation (HSCT) associated with intensity of the conditioning regimen, cyclophosphamide (Cy) therapy, and BK polyomavirus (BKPyV) infection. METHODS: We analyzed 33 consecutive haploidentical (haplo) HSCT recipients transplanted for hematologic diseases. Eleven patients had a previous transplant. Median follow-up was 11 months. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine + mycophenolate mofetil and post-HSCT Cy. RESULTS: Thirty-two of 33 patients achieved neutrophil recovery. Cumulative incidence (CI) of platelet recovery was 65%. CI grade II-IV acute GVHD was 44%. Twenty patients developed HC in a median time of 38 days. CI of HC at day 180 was 62%. BKPyV was positive in blood and urine of 91% of patients at HC onset. HC resolved in 18/20 patients. Factors associated with HC were previous transplant (P = 0.01) and occurrence of cytomegalovirus reactivation before HC (P = 0.05). Grade II-IV acute GVHD was not associated with HC (P = 0.62). CI of day 180 viral infections was 73%. Two-year overall survival (OS) was 50%; HC did not impact OS (P = 0.29). CONCLUSION: The incidence of HC after haplo with post-HSCT Cy is high and is associated with morbidity, especially in high-risk patients such as those with a previous transplant history and with impaired immune reconstitution.

Allogeneic hematopoietic cell transplantation is equally effective in secondary acute lymphoblastic leukemia (ALL) compared to de-novo ALL-a report from the EBMT registry.

Secondary acute lymphoblastic leukemia (s-ALL) comprises up to 10% of ALL patients. However, data regarding s-ALL outcomes is limited. To answer what is the role of allogeneic hematopoietic cell transplantation (HCT) in s-ALL, a matched-pair analysis in a 1:2 ratio was conducted to compare outcomes between s-ALL and de novo ALL (dn-ALL) patients reported between 2000-2021 to the European Society for Blood and Marrow Transplantation registry. Among 9720 ALL patients, 351 (3.6%) were s-ALL, of which 80 were in first complete remission (CR1) with a known precedent primary diagnosis 58.8% solid tumor (ST), 41.2% hematological diseases (HD). The estimated 2-year relapse incidence (RI) was 19.1% (95%CI: 11-28.9), leukemia-free survival (LFS) 52.1% (95%CI: 39.6-63.2), non-relapse mortality (NRM) 28.8% (95%CI: 18.4-40), GvHD-free, relapse-free survival (GRFS) 39.4% (95%CI: 27.8-50.7), and overall survival (OS) 60.8% (95%CI: 47.9-71.4), and did not differ between ST and HD patients. In a matched-pair analysis, there was no difference in RI, GRFS, NRM, LFS, or OS between s-ALL and dn-ALL except for a higher incidence of chronic GvHD (51.9% vs. 31.4%) in s-ALL. To conclude, patients with s-ALL who received HCT in CR1 have comparable outcomes to patients with dn-ALL.

Autologous haematopoietic stem cell transplantation for systemic lupus erythematosus: data from the European Group for Blood and Marrow Transplantation registry.

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) refractory to conventional immunosuppression suffer substantial morbidity and mortality due to active disease and treatment toxicity. Immunoablation followed by autologous stem cell transplantation (ASCT) is a novel therapeutic strategy that potentially offers new hope to these patients. METHODS: This retrospective survey reviews the efficacy and safety of ASCT in 28 SLE patients from eight centres reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 2001 and 2008. RESULTS: Median disease duration before ASCT was 52 (nine to 396) months, 25/28 SLE patients (89%) were female, age 29 (16-48) years. At the time of ASCT, eight (one to 11) American College of Rheumatology (ACR) diagnostic criteria for SLE were present and 17 (60%) patients had nephritis. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte-colony stimulating factor in 93% of patients, and ex vivo CD34 stem cell selection was performed in 36%. Conditioning regimens were employed with either low (n = 10) or intermediate (18) intensities. With a median follow-up of 38 (one to 110) months after ASCT, the five-year overall survival was 81 ± 8%, disease-free survival was 29 ± 9%, relapse incidence (RI) was 56 ± 11% and non-relapse mortality was 15 ± 7%. Graft manipulation by CD34+ selection was associated with a lower RI (p = 0.001) on univariate analysis. There were five deaths within two years after ASCT: three caused by infection, one by secondary autoimmune disease and one by progressive SLE. CONCLUSIONS: Our data further support the concept of immunoablation and ASCT to re-induce long-term clinical and serologic remissions in refractory SLE patients even in the absence of maintenance therapy. This study also suggests a beneficial effect of ex vivo graft manipulation on prevention of relapses post-transplantation in SLE.

Bone marrow or peripheral blood stem cell transplantation from unrelated donors in adult patients with acute myeloid leukaemia, an Acute Leukaemia Working Party analysis in 2262 patients.

BACKGROUND: No survival benefit of using blood stem cells instead of bone marrow (BM) has been shown in matched unrelated donor (MUD) transplantation. DESIGN AND METHODS: In a retrospective registry analysis, we compared the use of blood stem cells (n = 1502) and BM (n = 760) from unrelated donors in patients aged 18-60 years with acute myeloid leukaemia (AML) undergoing myeloablative conditioning between 1997 and 2008. The blood stem cell recipients were older (P < 0.01), had more advanced disease (P < 0.0001) and received less total body irradiation (P < 0.0001) and more antithymocyte globulin (P = 0.01). RESULTS: Recovery of neutrophils and platelets was faster with blood stem cells (P < 0.0001). The incidence of acute graft-versus-host disease (GVHD) was similar, but there was more chronic GVHD in the blood stem cell group [hazard ratio (HR) = 1.29, P = 0.02]. There were no significant differences in nonrelapse mortality (NRM), relapse incidence and leukaemia-free survival (LFS) between the two groups amongst patients with AML in remission. In patients with advanced leukaemia, NRM was lower (HR = 0.61, P = 0.02) and LFS was prolonged (HR = 0.67, P = 0.002) when blood stem cells were used. At 3 years, LFS for all patients, regardless of remission status, was 41% for both treatment groups. The outcome was not affected after multivariable analysis adjusted for confounders. CONCLUSION: Blood stem cells compared with BM in MUD transplantation for patients with AML in remission resulted in the same rates of LFS. In patients with advanced leukaemia, the blood stem cell group had reduced NRM and improved LFS.

Impact of patient: donor HLA disparity on reduced-intensity-conditioned allogeneic stem cell transplants from HLA mismatched unrelated donors for AML: from the ALWP of the EBMT.

Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A, -B, -C, -DRB1, -DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A, -B, -C or -DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.

Metabolic syndrome and cardiovascular disease after haematopoietic cell transplantation (HCT) in adults: an EBMT cross-sectional non-interventional study.

Metabolic syndrome (MetS) is associated with cardiovascular disease in the general population and is also a potential cardiovascular risk factor in survivors of haematopoietic cell transplantation (HCT). We report an EBMT cross-sectional, multi-centre, non-interventional study of 453 adult HCT patients surviving a minimum of 2 years post-transplant attending routine follow-up HCT and/or late effects clinics in 9 centres. The overall prevalence of MetS was 37.5% rising to 53% in patients >50 years of age at follow-up. There were no differences in rates of MetS between autologous and allogeneic HCT survivors, nor any association with graft-versus-host disease (GvHD) or current immunosuppressant therapy. Notably, there was a significantly higher occurrence of cardiovascular events (CVE, defined as cerebrovascular accident, coronary heart disease or peripheral vascular disease) in those with MetS than in those without MetS (26.7% versus 9%, p < 0.001, OR 3.69, 95% CI 2.09-6.54, p < 0.001), and, as expected, MetS and CVE were age-related. Unexpectedly, CVE were associated with occurrence of second malignancy. Screening for and management of MetS should be integrated within routine HCT long-term follow-up care for both allogeneic and autologous HCT survivors. Further research is warranted, including randomised controlled trials of interventional strategies and mechanistic studies of cardiovascular risk in HCT survivors.

Hematopoietic cell transplant nurse coordinators' perceptions of related donor care: a European survey from the EBMT Nurses Group.

Allogeneic haematopoietic cell transplantation (HCT) is a curative procedure for patients with haematological malignancies and immune deficiencies. A human leukocyte antigen (HLA) identical sibling is only available for 25-35% of patients in need. The improvement in haplo-identical transplantation has led to a marked increase in cell donation from relatives. Despite international recommendations, discrepancies in related-donors (RD) care exist between centres, particularly regarding medical suitability criteria, consenting procedures and donor follow-up. This European survey aimed to explore hematopoietic cell transplantation coordinators nurses' (HCT-CNs) perceptions of RD care, in particular the association with the presence or not of an independent unit (IU). Ninety-three HCT-CNs from seventy-six EBMT centres responded, representing 19 countries (response rate: 27%). Our results did not show a significant association between IU and HCT-CNs perceptions of related-donors care. The practices for RD care vary among centres regarding presence or not of an IU (48%), person caring for RD (haematologist in 54%, HCT physician in 17%, HCT-CNs in 20%), person to whom the results of HLA typing are communicated, use of a booklet for RD, follow-up or not and periodicity of follow-up. Qualitative data highlight the related-donation ethical issues and the need for improvement in RD care. HCT-CNs' main concerns were: the necessary confidentiality to insure the voluntary status of RD, the perceived conflict of interest felt by professionals when managing both patients and RD, plus the psychosocial aspects of related-donation. Even if there is a variety of a practice among centres, the presence of an IU is not significantly associated with an improvement in RD care.

Haematopoietic stem cell transplantation in children in eastern European countries 1985-2004: development, recent activity and role of the EBMT/ESH Outreach Programme.

The paediatric population of 19 eastern European countries amounts to approximately 80 million children. Between 1985 and 2004, the number of centres performing haematopoietic stem cell transplantation (HSCT) in children increased from 1 in 1985 to 24 in 2004 and the yearly number of paediatric HSCTs rose from 1 in 1985 to 291 in 2004. Altogether, 2342 transplants were reported to the EBMT Registry during this time (Poland 953, Czech Republic 501, Hungary 269, Russia 217, Croatia 129, Slovakia 71, Bulgaria 45, Serbia and Montenegro 36, Slovenia 35, Belarus 33, Estonia 26, Lithuania 19 and Romania 8). Out of the 2342 transplants, 1487 (63.5%) transplants were performed in paediatric centres, 453 (19.3%) in centres for adults and 402 (17.2%) in combined centres. The number of children who underwent autologous HSCT (auto-HSCT) was 1053 (45%), whereas 1289 (55%) underwent allogeneic HSCT (allo-HSCT). Peripheral blood (PB) was the source of HSC in 751 (71.3%) out of 1053 auto-transplants, BM in 246 (23.4%) and PB+BM in 52 (4.9%) (missing data in 4, that is, 0.4%). Among the 1289 allo-transplants, BM was the source of HSC in 827 (64.3%), PB in 416 (32.3%), CB in 23 (1.8%) and BM+PB in 14 (1.1%) (missing data in 9, that is, 0.7%). Among them, 728 (57.4%) obtained HSC from MSD, 322 (25.4%) from UD, 195 (15.4%) from MMFD, 14 (1.1%) from CB family donor and 9 (0.7%) from CB unrelated donor (missing data in 21, that is, 1.6%). The number of children who underwent allo-HSCT for malignant diseases was 945 (73.4%), including ALL 376 (29.2%), AML 234 (18.2%), CML 177 (13.8%), MDS 97 (7.5%), NHL 35 (2.7%) and other malignancy 31 (2.4%), while 339 (26.9%) for non-malignant disorders, including SAA 202 (15.7%), immunodeficiencies 61 (4.7%), inborn errors of metabolism 40 (3.1%), Fanconi anaemia 19 (1.5%) and others 17 (1.3%). Out of 1053 recipients of auto-HSCT, 168 (16%) were transplanted for neuroblastoma, 129 (12.2%) for NHL, 124 (11.7%) for AML, 114 (10.8%) for ALL, 109 (10.4%) for Hodgkin's disease, 62 (5.9%) for Ewing's sarcoma, 16 (1.5%) for CNS tumour, 15 (1.4%) for Wilms tumour and 316 (30%) for other tumours. In 2001, the EBMT in collaboration with the European School of Haematology (ESH) developed the Outreach Programme, that is a programme supporting emerging HSCT projects and transplant centres in countries with limited resources and/or experience.

HLA-identical sibling allogeneic peripheral blood stem cell transplantation with reduced intensity conditioning compared to autologous peripheral blood stem cell transplantation for elderly patients with de novo acute myeloid leukemia.

We conducted a retrospective registry-based analysis to compare the outcome of 361 allogeneic human leukocyte antigen (HLA)-identical peripheral blood stem cell transplants (PBSCT) with reduced intensity conditioning (RIC) to that of 1369 autologous (auto) PBSCT in patients aged 50 years or older with de novo acute myeloid leukemia (AML), performed from 1997 until 2003 and reported to the European Group for Blood and Marrow Transplantation. Median age was 58 and 57 years in the RIC and auto groups, respectively. RIC patients had more advanced disease at the time of transplant. At a median follow-up of 24 months for RIC and 16 months for auto, multivariate analysis showed a lower risk for relapse (RR 0.77, P=0.013) without increased non-relapse mortality (NRM) in RIC patients (RR 1.26, P=0.28). Moreover, leukemia-free survival (RR 1.22, P=0.02) and overall survival (OS) (RR 1.32, P=0.005) were superior in the RIC group. In patients in 1st (CR), fewer relapses were counterbalanced by significantly increased NRM. Therefore, there was no survival advantage in this subgroup. In patients in 2nd or subsequent CR, LFS and OS were superior in the RIC group. RIC transplants show encouraging results in this older patient population with de novo AML.

Investigating covariate-by-centre interaction in survival data.

In survival analysis, assessing the existence of potential centre effects on the baseline hazard or on the effect of fixed covariates on the baseline hazard, such as treatment-by-centre interaction, is a frequent clinical concern in multicentre studies. Survival models with random effects on the baseline hazard and/or on the effect of the covariates of interest have been largely applied, for instance, to investigate potential centre effects. We aimed to develop a procedure to routinely test for multiple random effects in survival analyses. We propose a statistic and a permutation approach to test whether all or a subset of components of the variance-covariance matrix of random effects are non-zero in a mixed-effects Cox model framework. Performances of the proposed permutation tests are examined under different null hypotheses corresponding to the different components of the variance-covariance matrix, i.e ., to the different random effects considered on the baseline hazard and/or on the covariates effects. Several alternative hypotheses are evaluated using simulations. The results indicate that the permutation tests have valid type I error rates under the null and achieve satisfactory power under all alternatives. The procedure is applied to two European cohorts of haematological stem cell transplants in acute leukaemia to investigate the heterogeneity across centres in leukaemia-free survival and the potential heterogeneity in prognostic factors effects across centres.

Risk factors for fatal infectious complications developing late after allogeneic stem cell transplantation.

Infectious complications remain a major problem contributing to significant mortality after hematopoietic allogeneic stem cell transplantation (HSCT). Few studies have previously analyzed mortality due to late infections. Forty-four patients dying from an infectious complication were identified from a cohort of 688 consecutive patients surviving more than 6 months without relapse. A control group of 162 patients was selected using the year of HSCT as the matching criterion. Out of 44 patients, 30 (68%) died from pneumonia, 7/44 (16%) from sepsis, 5/44 (11%) from central nervous system infection and 2/44 (4.5%) from disseminated varicella. The cumulative incidences of different types of infection were 1.6% for viral, 1.5% for bacterial and 1.3% for fungal infections and 0.15% for Pneumocystis jirovecii pneumonia. The majority (66%) of the lethal infections occurred within 18 months after HSCT. Acute GVHD (relative risk (RR): 7.19, P<0.0001), chronic GVHD (RR: 6.49, P<0.001), CMV infection (RR: 4.69, P=0.001), mismatched or unrelated donor (RR: 3.86, P=0.004) and TBI (RR: 2.65, P=0.047) were independent risk factors of dying from a late infection. In conclusion, infections occurring later than 6 months after HSCT are important contributors to late non-relapse mortality after HSCT. CMV infection or acute GVHD markedly increase the risk.

Long-term outcomes after allogeneic stem cell transplantation for children with hematological malignancies.

We analyzed long-term outcomes and psycho-social aspects in 112 children with malignancies surviving 1 year after hematopoietic stem cell transplantation. At 10 years, overall survival was 75+/-5%, TRM 18+/-4% and relapse 14+/-3%; 10-year cumulative incidence of infections was 31+/-4%, cataract 44+/-4%, pulmonary dysfunction 20+/-4%, bone and joint complications 29+/-5%, hypothyroidism 36+/-4%, cardiac complications 11+/-3% and secondary malignancies 7+/-3%. Total body irradiation (TBI) was the most significant risk factor associated with cataract, pulmonary impairment, osteoarticular complications and hypothyroidism. Chronic graft-versus-host disease was associated with higher incidence of pulmonary dysfunction. The number of complications per patient increased with time. Half of the patients had psychological disturbance, 13 signs of depression and 16 a history of eating behavior disorders; 54% of patients with one or more long-term complications had psychological problems. Sixty-nine patients had learning difficulties and 36 achieved normal scholarship. With increased follow-up, development of late effects and of psycho-social disturbance are of major concern. While the use of single-dose TBI has now been abandoned, other risk factors are still of concern in the early 2000s.