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Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.

Efforts to implement family cord blood banking have been developed in the past decades for siblings requiring stem cell transplantation for conditions such as sickle cell disease. However, public banks are faced with challenging decisions about the units to be stored, discarded, or used for other endeavors. We report here 20 years of experience in family cord blood banking for sickle cell disease in two dedicated public banks. Participants were pregnant women who had a previous child diagnosed with homozygous sickle cell disease. Participation was voluntary and free of charge. All mothers underwent mandatory serological screening. Cord blood units were collected in different hospitals, but processed and stored in two public banks. A total of 338 units were stored for 302 families. Median recipient age was six years (11 months-15 years). Median collected volume and total nucleated cell count were 91 mL (range 23–230) and 8.6×108 (range 0.7–75×108), respectively. Microbial contamination was observed in 3.5% (n=12), positive hepatitis B serology in 25% (n=84), and homozygous sickle cell disease in 11% (n=37) of the collections. Forty-four units were HLA-identical to the intended recipient, and 28 units were released for transplantation either alone (n=23) or in combination with the bone marrow from the same donor (n=5), reflecting a utilization rate of 8%. Engraftment rate was 96% with 100% survival. Family cord blood banking yields good quality units for sibling transplantation. More comprehensive banking based on close collaboration among banks, clinical and transplant teams is recommended to optimize the use of these units.

Summary Background Enteroviruses are the most frequent cause of acute meningitis and are seen increasingly in sepsis-like disease and fever without source in the paediatric population. Detection of enterovirus in cerebrospinal fluid (CSF) specimens by PCR is the gold standard diagnostic test. Our aim was to assess a method of detecting enterovirus in blood specimens by PCR. Methods We did a prospective, multicentre, observational study at 35 French paediatric and emergency departments in 16 hospitals. We recruited newborn babies (aged ≤28 days) and infants (aged >28 days to ≤2 years) with fever without source, sepsis-like disease, or suspected meningitis, and children (aged >2 years to ≤16 years) with suspected meningitis, who were admitted to a participating hospital. We used a standardised form to obtain demographic, clinical, and laboratory data, which were anonymised. Enterovirus PCR testing was done in blood and CSF specimens. Findings Between June 1, 2015, and Oct 31, 2015, and between June 1, 2016, and Oct 31, 2016, we enrolled 822 patients, of whom 672 had enterovirus PCR testing done in blood and CSF specimens. Enterovirus was detected in 317 (47%) patients in either blood or CSF, or both (71 newborn babies, 83 infants, and 163 children). Detection of enterovirus was more frequent in blood samples than in CSF specimens of newborn babies (70 [99%] of 71 vs 62 [87%] of 71; p=0·011) and infants (76 [92%] of 83 vs 62 [75%] of 83; p=0·008), and was less frequent in blood samples than in CSF specimens of children (90 [55%] of 163 vs 148 [91%] of 163; p

Patients with sickle cell anemia (SCA) have increased susceptibility to infections partially explained by functional splenic and alternative complement pathway defects. Cord blood transplants (CBT) and high doses anti-thymoglobulin (ATG) are suspected to be responsible for viral complications and EBV lymphoma but most of the reports concerned unrelated SCT. The aim of the present study was to compare the immune reconstitution after CBT vs BMT from HLA-identical sibling, in patients prepared with the same myeloablative conditioning regimen (MAC). This retrospective analysis concerns SCA-children all followed in the same CHI-Créteil referral center and transplanted from a HLA-identical sibling with MAC consisting of busulfan, cyclophosphamide and rabbit ATG (Genzyme at 20mg/kg). Pre- and post-transplant clinical and biological data were prospectively recorded in the local database. Lymphocyte subpopulations (CD3+, CD4+, CD8+), IgG, IgA, IgM were recorded each month during the first year post-transplant. Jolly bodies (classified as 0=absent, 1=rare, 2=a few, 3=numerous) and HBs, DTPolio vaccinal serologies were assessed at transplant time (T0), 1 (T1) and 2 years (T2) post-transplant. Revaccination with DTPolio was performed at 1y post-transplant One-hundred-seven SCA-patients (41F,56M) with severe disease were transplanted (1992-2012) with BM (n=83), CB (n=21), CB+BM (=3) at median (range) age: 9.7y (3.4-22.2) for BMT and 6.1y (3.2-12.9) for CBT (p=0.002). Four patients had splenectomy and 5 others partial splenectomy. Rate of rejection was higher after CBT (p=0.002) with 2 non-engraftments and no late rejection whatever the source. TRM was not different despite the occurrence of 3 deaths only after BMT (obliterant bronchiolitis at 1.1year, hemorrhagic stroke at day36, adenoviral encephalitis at month5). Acute GVHD ≥II was observed in 18 patients (16 BMT, 2 CBT) and mild and extensive chronic-GVHD in 5 and 2 patients respectively after BMT and 1 mild after CB+BMT. At 5-year DFS was 95.3% (CI:91.3-99.3%). No significant difference in GVHD and DFS rates was observed according to the source. Neutrophils reached 500/mm3 at mean day32 vs day21 (p Paired analysis comparing results at T0 vs T1 and T2 showed a significant decrease of the mean (SD) Jolly bodies score from 1.38 (0.85) at T0 to 0.50 (0.81) at T1 and 0.28 at T2 (p We confirm the improvement of splenic function after SCT and conclude that contrary to unrelated CBT and SCT using high dose ATG, CBT from HLA-identical sibling do not expose significantly to more frequent viral infections or reactivations and have satisfactory vaccinal response Figure Disclosures Bernaudin: BlueBirdBio: Consultancy; AddMedica: Honoraria, Other: Help for travel; GBT: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy.

Hematopoietic stem cell transplant (HSCT) from an HLA identical sibling is a well-established curative therapy for sickle cell disease (SCD). HSCT from an unrelated donor is a treatment option, but the likelihood of finding a donor varies according to ethnicity and results are still limited. HLA haploidentical relatives can be alternatively used but, to date, only small series of patients have been described. We report outcomes of patients (pts) transplanted with related haploidentical (Haplo) or unrelated (UD) donors grafts and reported to EBMT/EUROCORD databases. Sixty four pts transplanted in 22 EBMT centers between 1991 and 2017 were retrospectively analyzed. Pts were described according to the donor type: haploidentical (n=40) and unrelated (n=24) [adult UD n=19; cord blood (CB) n=5]. The objective of the study was to describe alternative donor transplants for SCD in Europe without performing comparison analyses due to the size and heterogeneity of the groups. Primary endpoint was 3-year overall survival (OS). Median follow-up (FU) was 28 months (range: 1.6-156) [29.5 months (range: 2.1 - 133.5) for Haplo and 24.6 (range: 1.6 - 156) for UD]. Median age at HSCT was 14.2 years (range: 3-31.7) in Haplo and 11.8 (range: 2.1-42.8) in UD, with a predominance of children ( In both groups, vaso-occlusive crisis and cerebral vasculopathy were the most frequent SCD complications and the main indications for HSCT. Other complications were acute chest syndrome (44%), liver disease (31%) and infection (23%). In Haplo, median year of transplant was 2014 (range: 1991-2017) and in UD 2011 (range: 2004-2015). In Haplo, two major protocols were used: (1) post -transplant cyclophosphamide (PTCY) with G-CSF primed bone marrow (BM) and a fludarabine+ cyclophosphamide+thiotepa+2Gy TBI conditioning regimen [16 pts and 2 centers performing most (n=13) of the transplants]; (2) a protocol (performed in 2 centers) consisting in the use of G-CSF mobilized peripheral blood stem cells (PBSC) with ex-vivo B and T cell depletion (BT depleted) (15 pts) and a fludarabine+thiotepa+ treosulfan conditioning regimen (14/15 pts). Haplo donors were most frequently the parents [mother (50%), father (29%), brother (14%) and cousin (7%)]. ATG was used in 95% of transplants and the most frequent combination for graft versus host disease (GvHD) prophylaxis was mycophenolate mofetil (MMF)+sirolimus in PTCY and MMF+ cyclosporine A (CSA) in BT depleted. In UD, graft source distribution was 14 BM, 5 PBSC and 5 CB. Conditioning regimens were mainly myeloablative (83%) with fludarabine+thiotepa+ treosulfan in 54% of HSCT. ATG was used in 87% and campath in 9% of transplants; GvHD prophylaxis was CSA and methotrexate in 50%. Neutrophil engraftment at 60 days was 95±4% in Haplo and 84±8% in adult UD, after a median engraftment time of 18 and 22 days, respectively. In Haplo, 7 pts experienced graft failure (3 primary and 4 late), of those 3 had a second allogeneic transplant and were alive at last FU, at 16, 16 and 63 months respectively; 1 patient died after rescue with autologous transplant and 3 were alive after autologous reconstitution. In adult UD, 3 pts had a primary and 1 a late graft failure, none of them had a second transplant and were all alive at last FU, at 2, 13, 28, 118 months respectively. Grade II-IV acute GvHD at 100 days was 25±7% in Haplo and 21±9% in adult UD; acute GvHD grade III-IV was observed in 3 pts in Haplo (none in BT depleted) and 2 pts in adult UD. Chronic GvHD was observed in 10 pts in Haplo (5 extensive, 3 of these in PTCY) and 3 pts in adult UD (2 extensive). OS at 3 years was 88±4%; being 89±5% in Haplo (88±8% for PTCY, 92±8% for BT depleted) and 94±5% in adult UD. 3-year event free survival was 58±7%; in detail, 60±9% in Haplo (56±12% for PTCY, 68±13% for BT depleted) and 60±12% in adult UD. Overall, 8 pts died (5 Haplo and 3 UD) due to infections or GVHD. Among the 5 pts receiving CB transplant 3 are alive (1 of which after graft failure and a second allogeneic transplant). Conclusion: This preliminary analysis shows that, despite an acceptable OS, rejection and chronic GvHD are still of concern; therefore alternative donor transplants for SCD should be performed in experienced centers with prospective clinical trials. Disclosures Pondarré: Blue Bird Bio: Honoraria; Novartis: Honoraria; Addmedica: Membership on an entity's Board of Directors or advisory committees. Zecca:Chimerix: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy. Bader:Medac: Patents & Royalties, Research Funding; Riemser: Research Funding; Neovii: Research Funding; Cellgene: Consultancy; Novartis: Consultancy, Speakers Bureau. Bernaudin:AddMedica: Honoraria; Pierre fabre: Research Funding; BlueBirdBio: Consultancy; Cordons de Vie: Research Funding.

BACKGROUND: Empirical antifungal therapy is the standard of care for neutropenic patients with hematological malignancies who remain febrile despite broad-spectrum antibacterial treatment. Recent diagnostic improvements may ensure the early diagnosis of potentially invasive fungal disease. Reserving antifungals for this stage may achieve similar survival rates and reduce treatment toxicity and costs. METHODS: In this multicenter, open-label, randomized noninferiority trial, we compared an empirical antifungal strategy with a preemptive one. Empirical treatment was defined as antibacterial treatment of patients who have persistent or recurrent fever. Preemptive treatment was defined as treatment of patients who have clinical, imaging, or galactomannan-antigen-assay evidence suggesting fungal disease. First-line antifungal treatment was amphotericin B deoxycholate (1 mg/kg/day) or liposomal amphotericin (3 mg/kg/day), depending on daily renal function. The primary efficacy outcome was the proportion of patients alive at 14 days after recovery from neutropenia. RESULTS: The median duration of neutropenia (neutrophil count

BACKGROUND: There is, until now, no prognostic grading system for infections occurring in allogeneic stem cell transplant (SCT) recipients. The aim of this study was to determine the prognostic value of a grading system of infectious complications in predicting death. METHODS: For the purposes of a prospective allogeneic SCT trial, we classified severity of infections in 3 grades according to expected rates of mortality (>or= 60% for grade 3). We prospectively recorded the type and time of occurrence of 440 infectious events in 190 consecutive patients until 6 months after transplant. We used multivariate Cox models with time-dependent covariates to analyze the relationship between the grade of severity of each infectious episode and mortality due or not due to infection, adjusting for possible confounders. RESULTS: Only patients with grade 3 infections had a significantly increased risk of death (P

Background. The authors have previously shown that mononuclear cells derived from patients with resistant chronic graft-versus-host-disease (GVHD) express high calcineurin (CN) activity, suggesting that in vitro assessment of CN activity may be a useful index to estimate the degree of immunosuppression afforded by cyclosporine A (CsA). The goal of this study was to assess CN activity during the first 2 months after allogeneic stem-cell transplantation (SCT) and to correlate its evolution with the occurrence of acute GVHD. Methods. Thirty-one allogeneic SCT recipients were enrolled during a 21-month period. All received GVHD prophylaxis with CsA (2 mg/kg/day) and methotrexate (on days 1, 3, and 6). CN activity was measured before transplant, and then once weekly, for at least 2 months. Results. Eighteen patients developed acute grade II or higher GVHD at a median time of 22.5 days and were treated with steroids. CN activity was significantly increased in these 18 patients when compared with 13 patients who did not develop GVHD. Analysis involving the receiver operating characteristic curve demonstrated that acute grade II or higher GVHD can be predicted with a sensitivity of 89% and a specificity of 54% with the use of a cutoff value of 28 pmol RII/mg proteins/min of CN activity. Conclusions. CN activity appears to be a promising therapeutic test to predict acute GVHD after allogeneic SCT. This functional assessment of the in vivo efficacy of CsA opens new insights for CsA dose adjustment—in particular, the administration of its most efficient dose instead of its maximal tolerated dose, as is currently performed.

This study has been partially presented as a poster at the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 27–30 September 2002 (Abstract M 894); International audience; Although the efficacy and safety of voriconazole to treat invasive fungal infections have been demonstrated in prospective trials, its use for secondary prophylaxis to prevent reactivation of these infections remains unknown. Delaying the scheduled treatment of leukemia until complete resolution of fungal infection may have major implications for prognosis. We report 11 leukemic patients with previous aspergillus (n = 10) and candida ( n = 1) infection who received voriconazole 400 mg/day intravenously or orally for between 44 and 245 days. Nine patients were scheduled for allogeneic stem cell transplant, and two for consolidation therapy for acute leukemia. None of the patients had a relapse of fungal infection, and scheduled treatment was delayed only once. Voriconazole was well tolerated, except in one patient who had abnormal liver tests secondary to hepatic graft-versus-host disease, and one who had visual disturbances. This small but homogeneous series indicates that voriconazole may be useful to prevent fungal relapse during at-risk periods in leukemic patients. Prospective trials are warranted to confirm these encouraging results.

In this retrospective multicentre study, we analysed the results of 82 consecutive second early allogeneic transplants for primary (n = 28) or secondary (n = 54) graft failures performed between 1985 and 1997 in patients with acute leukaemia (n = 33), aplastic anaemia (n = 29) or chronic myeloid leukaemia (n = 20). HLA-matched siblings were used in 64 cases. The same donors were used for both transplants in 56 cases and the first transplant was T-cell depleted in 30 cases. The median age at transplant was 25 years and the median intertransplant time interval was 2 months. Estimates of the 3-year overall survival and day 100 transplant-related mortality were 30% and 53% respectively. A recipient age

Early recommendations on prophylactic transfusion of thrombocytopenic patients involved a standard platelet dose of about 0.5 × 1011/10 kg body weight. Given the lack of data supporting this dose, we prospectively studied the dose response to platelet transfusions in adults and children with hematologic malignancies. Each patient received, in similar clinical conditions, a medium, high, and very high dose of fresh (< 24 hours old) ABO-compatible platelets, in the form of apheresis platelet concentrates (APC). For the adults, the medium dose was defined as APC containing between 4 and 6 × 1011 platelets, the high dose between 6 and 8 × 1011, and the very high dose > 8 × 1011; for the children, the three doses corresponded to 2 to 4, 4 to 6, and > 6 × 1011 platelets. The end points were the platelet increment, platelet recovery, and the transfusion interval, and the results were compared with a paired t-test. Sixty-nine adults and 13 children could be assessed. Recoveries in the adults were similar with the three doses (from 28% to 30%), but the high and very high doses led to a significantly better platelet increment (52 and 61 × 109/L, respectively) than the medium dose (33 × 109/L, P < .01). The main difference was in the transfusion interval, which increased with the dose of platelets transfused, from 2.6 days with the medium dose to 3.3 and 4.1 days with the high and very high doses, respectively (P< .01). The positive effect of the high dose was observed regardless of pretransfusional clinical status, but was more marked in patients with no clinical factors known to impair platelet recovery. In these patients, a platelet dose of 0.07 × 1011 per kg of body weight led to a transfusion interval of more than 2 days in 95% of cases. In patients with clinical factors favoring platelet consumption, the proportion of transfusions yielding an optimal platelet increment and transfusion interval increased with the dose of platelets.The platelet dose-effect was also significant in the children, in whom the high and very high doses led to 1.5-fold to twofold higher posttransfusion platelet counts and transfusion intervals. We conclude that transfusion of high platelet doses can reduce the number of platelet concentrates required by thrombocytopenic patients and significantly reduce donor exposure. © 1998 by The American Society of Hematology.

Introduction: Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD), though rarely used due to inadequate donor availability, associated regimen-related toxicities, and high mortality rate in adults. A reduced intensity, haploidentical bone marrow transplantation (Haplo-BMT) regimen with post-transplant cyclophosphamide (PTCy), reported by the Johns Hopkins Group (JHG) in adults with SCD, resulted in successful engraftment, minimal toxicity, abrogation of sickle cell related symptoms, but was associated with a high graft failure rate of 43% (Blood. 2012;120(22):4285-4291). A multi-institution learning collaborative was developed in 2013 with main objective of reducing the graft failure rate in individuals with SCD who undergo a haplo-BMT with PTCy from first-degree relatives. Material and methods : The collaborative included 3 sites, similar eligibility criteria, monthly phone conferences for sharing of group learning experiences, and independent IRB approvals at each site, allowing for aggregate data sharing. A common conditioning regimen was used based on the JHG haplo-HSCT protocol - fludarabine 150 mg/m2, Cy 29 mg/kg, Thymoglobulin 4.5 mg/kg, and TBI 2Gy), and graft versus host disease (GVHD) prevention with PTCy 100 mg/kg, mycophenolate mofetil and sirolimus. However two additional modifications were systematically added which were believed to improve engraftment rates with two different strategies. In strategy 1, a Data Safety Monitoring Committee (DSMC) planned an interim analysis after enrollment of the first 5 participants using the JHG haplo-HSCT protocol, with modifications for > 20% mortality rate, graft rejection, or severe GVHD. In strategy 2, the participants in this group had preconditioning with 2 drugs for 3 months (azathioprine 3mg/kg/d, hydroxyurea 30 mg/kg/d) and hypertransfusion, plus thiotepa (10 mg/kg/day) on D-7. No DSMC was established. All donors were mobilized with filgrastim (5-10 μg/kg/d x5 days). Primary graft failure was defined as day +42 in patients with prior documentation of > 5% donor cells by day +42. Results: All potential patients that sought haplo-BMT had a HLA haplodonor (n=34). Median total nucleated and CD34+ cell doses were 8.40 x 108 /kg and 3.63 x 106/kg respectively; median follow-up was 20.3 months (1.4-37.5). In strategy 1 (n=5), median age was 26.4yr (12-50), and 3 out of 5 had graft failure, (2 primary; 1 secondary), triggering the stopping rule. Subsequently, thiotepa alone (10 mg/kg/day; D-7) was added; for 7 patients transplanted in this cohort, median age was 18.1yr (7-26), 100% engrafted, median time to neutrophil engraftment was 25 days; 33.1 and 36.9 days for platelets >20 x 109/L and >50 x 109/L, respectively, with an EFS and OS of 100%, respectively. Main complications were 2 independent viral reactivation events (CMV and EBV), 2 patients had > grade 2 acute GVHD (gut) but no significant chronic GVHD developed in any participant. One patient with graft failure using the non-thiotepa approach, was re-transplanted >1 yr after initial haplo-BMT with the thiotepa alone containing regimen with successful engraftment. In strategy 2 (n=22), median age was 10yrs (3-18), 100% engrafted, median time to neutrophil engraftment was 17days; 36.5 and 38.5 days for platelets >20 x 109/L and >50 x 109/L, respectively. Mortality was 13.6% (3/22) mainly from infectious complications and macrophage activation syndrome; 2 patients had secondary graft failure (9.1%). The cumulative incidence of acute and chronic GVHD was 18.2%, respectively, all resolved; EFS and OS was 81.8% and 86.4% respectively. All patients were off immunosuppressive therapy > I year posttransplant. Conclusion: We have provided preliminary evidence that haplo-BMT with PTCy plus thiotepa alone when compared to no thiotepa, improves donor engraftment without increasing morbidity or mortality. Preliminary evidence also indicates that there is no benefit for the 2 drug preconditioning regimen with azathioprine, hydroxyurea plus thiotepa when compared to addition of thiotepa alone. An NIH sponsored BMTCTN phase II trial, of haplo-BMT with PTCy plus thiotepa is underway to determine if this regimen maximizes donor engraftment, with reduced morbidity and mortality. Disclosures Brodsky: Achillion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees.

Allogeneic marrow transplantation can cure sickle cell disease; however, HLA-matched donors are difficult to find, and the toxicities of myeloablative conditioning are prohibitive for most adults with this disease. We developed a nonmyeloablative bone marrow transplantation platform using related, including HLA-haploidentical, donors for patients with sickle cell disease. The regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and total body irradiation, and graft-versus-host disease prophylaxis with posttransplantation high-dose cyclophosphamide, mycophenolate mofetil, and tacrolimus or sirolimus. After screening 19 patients, we transplanted 17, 14 from HLA-haploidentical and 3 from HLA-matched related donors. Eleven patients engrafted durably. With a median follow-up of 711 days (minimal follow up 224 days), 10 patients are asymptomatic, and 6 patients are off immunosupression. Only 1 patient developed skin-only acute graft-versus-host disease that resolved without any therapy; no mortality was seen. Nonmyeloablative conditioning with posttransplantation high-dose cyclophosphamide expands the donor pool, making marrow transplantation feasible for most patients with sickle cell disease, and is associated with a low risk of complications, even with haploidentical related donors. Graft failure, 43% in haploidentical pairs, remains a major obstacle but may be acceptable in a fraction of patients if the majority can be cured without serious toxicities.

Serum antibodies to hepatitis C virus (HCV) were tested for inpatients undergoing allogeneic BMT to determine the risk of acquiring HCV infection and the role of HCV in posttransplant liver complications. The HCV seroconversion rate was evaluated according to the date of BMT and blood donor screening at the time. Anti-HCV antibodies (anti-HCV) were detected with a second-generation ELISA and confirmed with a second-generation radioimmunoblot assay. All patients received leukocyte-depleted blood products and most received apheresis platelet concentrates. One hundred twenty of 181 consecutive patients transplanted from January 1987 to December 1991 were anti-HCV-negative before BMT, had at least 6 months of follow-up, and were thus evaluated for the seroconversion rate. Before screening for non-A, non-B hepatitis, 14% of the patients seroconverted to HCV (0.44% per unit transfused). After introduction of screening for alanine aminotransferase and antibodies to hepatitis B core antigen the risk of seroconversion was 4% per patient (0.26% per unit). When, in addition, blood was screened for anti-HCV the risk fell to 1.6% (0.03% per unit). Positive anti-HCV status before and after BMT was not predictive of veno-occlusive disease, liver graft-versus-host disease (GVHD), or death due to liver dysfunction. In contrast, the risk of chronic hepatitis was significantly increased.

Background The impact of cytogenetic abnormalities in multiple myeloma after allogeneic stem cell transplantation has not been clearly defined. This study examines whether allogeneic stem cell transplantation could be of benefit for myeloma patients with high-risk cytogenetic abnormalities.Design and Methods This is a retrospective multicenter analysis of the registry of the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire, including 143 myeloma patients transplanted between 1999 and 2008.Results The incidences of cytogenetic abnormalities were 59% for del(13q), 25% for t(4;14), 25% for del(17p) and 4% for t(14;16). When comparing the population carrying an abnormality to that without the same abnormality, no significant difference was found in progression-free survival, overall survival or progression rate. Patients were grouped according to the presence of any of the poor prognosis cytogenetic abnormalities t(4;14), del(17p) or t(14;16) (n=53) or their absence (n=32). No difference in outcomes was observed between these two groups: the 3-year progression-free survival, overall survival and progression rates were 30% versus 17% (P=0.9), 45% versus 39% (P=0.8) and 53% versus 75% (P=0.9), respectively.Conclusions These data indicate that allogeneic stem cell transplantation could potentially be of benefit to high-risk myeloma patients.

Resume L'efficacite transfusionnelle des plaquettes conservees a ete evaluee chez 136 patients thrombocytopeniques en fonction de leur statut clinique. L'efficacite clinique a ete appreciee sur l'augmentation de la numeration plaquettaire apres transfusion (rendement) et la survie, evaluee par le delai au-dela duquel une nouvelle transfusion etait necessaire (D). Des plaquettes fraiches ont ete utilisees a titre de controle dans une etude par paire. Chez 48 patients cliniquement stables, le rendement des plaquettes fraiches et conservees etait identique (47 % et 41 % respectivement), de meme que la survie (J4/J3). Par opposition, chez 27 patients porteurs d'une infection bacterienne, les rendements ainsi que la survie etaient significativement differents (24/5 %) et (J3/J1) pour les plaquettes fraiches et conservees respectivement. De la meme maniere, chez 16 patients qui recevaient de facon concomitante de l'amphotericine B, 18 patients presentant une maladie du greffon contre l'hote (GVH), 5 une splenomegalie et 3 une maladie veino-occlusive (MVO), une meilleure efficacite a ete observee avec les plaquettes fraiches qu'avec les plaquettes conservees, avec des rendements de respectivement 27 %/ 18 %, 29 %/ 5 %, 15 %/ 1 %, 22 %/ 3 %. De plus, la necessite d'une retransfusion dans un delai inferieur a 24 heures a ete significativement plus importante avec les plaquettes conservees. Par contre, chez 19 patients porteurs d'anticorps anti-HLA, qui ont recu des plaquettes HLA compatibles, fraiches et conservees, l'efficacite a ete similaire avec un rendement de 38 %/ 34 % et une survie a J4/J3. Cette etude met en evidence que dans certaines conditions cliniques, la conservation est responsable d'une alteration majeure de l'efficacite des plaquettes transfusees.

In 1992, we reported the results of the first randomized trial comparing the combination of cyclophosphamide (CY) (120 mg/kg) and total body irradiation (TBI) (CYTBI) versus CY and busulfan (BU) (BUCY) as preparation for an allogeneic bone marrow transplantation (BMT) for adult patients with acute

Transcranial Doppler (TCD) is used to detect children with sickle cell anemia (SCA) who are at risk for stroke, and transfusion programs significantly reduce stroke risk in patients with abnormal TCD. We describe the predictive factors and outcomes of cerebral vasculopathy in the Créteil newborn SCA cohort (n = 217 SS/Sβ0), who were early and yearly screened with TCD since 1992. Magnetic resonance imaging/magnetic resonance angiography was performed every 2 years after age 5 (or earlier in case of abnormal TCD). A transfusion program was recommended to patients with abnormal TCD and/or stenoses, hydroxyurea to symptomatic patients in absence of macrovasculopathy, and stem cell transplantation to those with human leukocyte antigen-genoidentical donor. Mean follow-up was 7.7 years (1609 patient-years). The cumulative risks by age 18 years were 1.9% (95% confidence interval [95% CI] 0.6%-5.9%) for overt stroke, 29.6% (95% CI 22.8%-38%) for abnormal TCD, which reached a plateau at age 9, whereas they were 22.6% (95% CI 15.0%-33.2%) for stenosis and 37.1% (95% CI 26.3%-50.7%) for silent stroke by age 14. Cumulating all events (stroke, abnormal TCD, stenoses, silent strokes), the cerebral risk by age 14 was 49.9% (95% CI 40.5%-59.3%); the independent predictive factors for cerebral risk were baseline reticulocytes count (hazard ratio 1.003/L × 109/L increase, 95% CI 1.000-1.006; P = .04) and lactate dehydrogenase level (hazard ratio 2.78/1 IU/mL increase, 95% CI1.33-5.81; P = .007). Thus, early TCD screening and intensification therapy allowed the reduction of stroke-risk by age 18 from the previously reported 11% to 1.9%. In contrast, the 50% cumulative cerebral risk suggests the need for more preventive intervention.

Background Patients with poor-risk Waldenstrom’s macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients. Design and Methods We examined the long-term outcome of allogeneic stem cell transplantation in Waldenstrom’s macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg. Results Median age at the time of transplant was 48 years (range, 24–64). The patients had previously received a median of 3 lines of therapy (range, 1–6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11–149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46–81) and 58% (95% CI: 38–75). The 5-year estimated risk of progression was 25% (95% CI: 10–36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant. Conclusions Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenstrom’s macroglobulinemia.

The toxicity of autologous bone marrow transplantation (ABMT) is correlated to neutropenia. Although recombinant human granulocyte- macrophage colony-stimulating factor (rhu GM-CSF) seems to hold promise in accelerating neutrophil recovery, few analyses from randomized studies are presently available. Ninety-one patients with non-Hodgkin's lymphoma receiving high-dose ablative chemotherapy followed by ABMT with unpurged or purged marrow were included in a randomized, double- blind, placebo-controlled trial. Forty-four patients received 250 micrograms rhu GM-CSF (Escherichia coli)/m2 and 47 patients received placebo. Treatment was administered daily as continuous infusion from day of ABMT until the absolute neutrophil count (ANC) reached 0.5 x 10(9)/L for 7 days or until day 30, whichever was first. With rhu GM- CSF, 50% of the patients reached an ANC count greater than 0.5 x 10(9)/L at day 14 as opposed to day 21 with placebo (P less than .0001). Patients transplanted with marrow purged by mafosfamide also recovered earlier when treated with rhu GM-CSF (16 v 20.5 days, P = .013). The hospitalization duration was shorter in the rhu GM-CSF group (median, 23 v 28 days, P less than .05). No difference was observed in fever, number of infections, and antibiotic administration between the two groups. The major adverse event ascribed to rhu GM-CSF was a capillary leak syndrome in three patients graded as severe in two patients, moderate in one, and reversible in all three patients. In addition, one patient in the rhu GM-CSF group died suddenly with no explanation. In long term follow-up, the relapse rate was identical in both groups and there was no significant difference in the number of deaths at 1 year (12 with rhu GM-CSF v 9 with placebo), although deaths seemed to occur slightly earlier in the rhu GM-CSF group. We conclude that after ABMT with purged or unpurged marrow, rhu GM-CSF (E coli) significantly reduces neutropenia duration and hospitalization stay. A positive causative relation between the study drug and/or its mode of application with an increased toxicity as compared with GM-CSF from other sources and/or other modes of application cannot be deduced from the experiences in this study. Additional randomized trials would be necessary for an appropriate answer.

Background: Sclerodermatous chronic graft-versus-host disease is a disabling complication after allogeneic bone marrow transplantation from HLA-identical sibling donors. Only a few series of patients have been reported and the dermatologic features have never been extensively described. Objective: The purpose of the study was to describe clinical and biologic features of chronic selerodermatous graft-versus-host disease and to compare them with scleroderma. Methods: We reviewed 196 patients grafted between April 1973 and July 1987 with survival times sufficient to be at risk of chronic graft-versus-host disease. Seven had the Sclerodermatous form. Results: Most patients had disseminated sclerosis of the trunk and the proximal portions of the limbs. In two cases, atrophy of the skin was predominant, corresponding with a severe clinical evolution. Periorbital pigmentation was observed as an initial manifestation in three cases. Visceral manifestations resembled those observed in scleroderma but histologic and immunologic studies demonstrated clear differences. Response to therapy was variable. Conclusion: Chronic Sclerodermatous graft-versus-host disease may realize two different patterns. Major atrophy is associated with a more severe progression.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD); nevertheless, its use has been limited by the risk of transplantation-related mortality (TRM). Between November 1988 and December 2004, 87 consecutive patients with severe SCD ranging from 2 to 22 years of age received transplants in France. Cerebral vasculopathy was the principal indication for transplantation (55 patients). All the patients received grafts from a sibling donor after a myeloablative conditioning regimen (CR). The only change in the CR during the study period was the introduction of antithymocyte globulin (ATG) in March 1992. The rejection rate was 22.6% before the use of ATG but 3% thereafter. With a median follow-up of 6 years (range, 2.0 to 17.9 years), the overall and event-free survival (EFS) rates were 93.1% and 86.1%, respectively. Graft versus host disease (GVHD) was the main cause of TRM. Importantly, cord blood transplant recipients did not develop GVHD. No new ischemic lesions were detected after engraftment, and cerebral velocities were significantly reduced. The outcome improved significantly with time: the EFS rate among the 44 patients receiving transplants after January 2000 was 95.3%. These results indicate that HLA-identical sibling HSCT after myeloablative conditioning with ATG should be considered as a standard of care for SCD children who are at high risk for stroke.

International audience; BACKGROUND AND OBJECTIVES: High-dose chemotherapy with allogeneic stem cell transplantation (SCT) has proven to be a successful treatment for low-grade lymphoma (LGL), but is associated with considerable transplant-related mortality (TRM). In an effort to reduce toxic mortality while maintaining the graft-versus-leukemia effect, allogeneic SCT has been combined with a reduced-intensity conditioning (RIC) regimen. The aim of this study was to determine the outcome of patients with LGL treated with RIC allogeneic SCT. DESIGN AND METHODS: This retrospective multicenter study included 73 patients with relapsed or refractory LGL allografted after a RIC regimen between 1998 and 2005 whose data were recorded in a French registry. RESULTS: Patients received a median of three lines of therapy prior to RIC allogeneic SCT. The most widely used conditioning regimens were fludarabine + busulfan + antithymocyte globulin (n=43) and fludarabine + total body irradiation (n=21). Prior to allografting, patients were in complete response (CR; n=21), partial response (PR; n=33) or had chemoresistant disease (n=19). The median follow-up was 37 months (range, 16 to 77 months). In patients in CR, PR and chemoresistant disease, the 3-year overall survival rates were 66%, 64% and 32%, respectively, while the 3-year event-free survival rates were 66%, 52% and 32%, respectively. The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. INTERPRETATION AND CONCLUSIONS: Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival.

Purpose To investigate the influence of donor type (human leukocyte antigen [HLA] -identical sibling donor versus HLA-A–, HLA-B–, HLA-Cw–, HLA-DRB1–, and HLA-DQB1–identical unrelated donors, or so-called 10/10) on the outcome of patients who underwent allogeneic stem-cell transplantation (alloSCT), adjusting for other prognostic factors, in patients with standard-risk hematologic malignancy. Patients and Methods Between March 2000 and January 2003, we prospectively investigated the outcome of 236 consecutive patients with standard-risk malignancy from 12 French centers. Fifty-five patients underwent alloSCT from an unrelated HLA-identical donor at the allelic level, whereas 181 patients received an alloSCT from an HLA-identical sibling. Diagnoses included acute leukemia (n = 175), chronic myeloid leukemia (n = 43), and myelodysplastic syndrome (MDS; n = 18). All patients received unmodified marrow graft following myeloablative conditioning with cyclophosphamide and total-body irradiation. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and short-course methotrexate in all patients. Results In multivariable analysis, overall survival and transplantation-related mortality were adversely influenced by recipient cytomegalovirus (CMV) -positive serology, age of donor older than 37 years, and the occurrence of acute grade ≥ II GVHD. Event-free survival rates were lower for patients with recipient CMV-positive serology. Acute grades II to IV GVHD rates were higher for patients with chronic myeloid leukemia (CML). No factor was found to influence either relapse or acute grades III to IV GVHD. The effect of donor type was nonsignificant for all criteria. Conclusion In patients with standard-risk malignancy, transplantation from unrelated HLA-allellically matched donors led to outcomes similar to those from HLA-identical sibling donors.

To the editor: We have read with great interest the comprehensive and detailed review on hematopoietic stem cell transplantation (HSCT) for sickle cell disease (SCD) published by Hsieh et al in a recent issue of the journal.[1][1] As emphasized by the authors, allogeneic HSCT is currently the only

PURPOSE: To compare hematologic recovery in patients receiving allogeneic blood cell transplantation (BCT) with those receiving allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: One hundred eleven patients with leukemia in the early stages and with HLA-matched sibling donors were randomized in this study. One hundred one underwent transplantation. Standard procedures for collection and transplantation were used. Patients did not receive prophylactic granulocyte colony-stimulating factor after undergoing transplantation. In addition to clinical end points being established, a prospective and comparative economic evaluation of the first 6 months after transplantation was performed. RESULTS: Groups were balanced for patient, donor, and transplant characteristics. Blood cell collection led to the collection of a higher number of CD34+ and CD3+ cells than did bone marrow collection (P < 10−6) without reported side effects for the donor. Patients in the BCT group reached platelet counts of 25 and 50 × 109 platelets/L 8 and 11 days earlier than did the BMT group (P < 10−4 and P < 10−5), respectively. This resulted in fewer platelet transfusions during the first 180 days after transplantation (P = .002) for the former group. The time to reach neutrophil counts of 0.5 and 1 × 109 neutrophils/L was 6 and 7 days shorter, respectively, in the BCT group than in the BMT group (P < 10−5). This quicker hematologic recovery was associated with a shorter length of hospitalization and a decrease in total cost of procedure during the first 6 months. CONCLUSION: This study establishes that allogeneic BCT results in quicker hematologic recovery but is associated with a higher occurrence of chronic graft-versus-host disease.

One hundred and seventy patients were analysed for interstitial pneumonitis and 151 for venocclusive disease of the liver after bone marrow transplantation. We present our results with emphasis on the role of the parameters of single fraction total body irradiation.

Background Reverse seroconversion to hepatitis B virus (HBV), i.e., HBV reactivation in patients with pretransplant antibodies to hepatitis B surface antigen (anti-HBs) and to hepatitis B core antigen (anti-HBc), is rarely re-ported after allogeneic bone marrow transplantation. Methods To determine this risk, we studied clinical outcome and serological changes in 37 patients with pretransplant anti-HBs and anti-HBc. Results In 33 cases, no change in HBV markers was observed in the posttransplant period. In four cases, anti-HBs and anti-HBc were lost, and hepatitis B surface antigen, hepatitis B e antigen, and HBV DNA emerged together with acute hepatitis, after cessation of immunosuppression. The actuarial risk of reactivation in the 37 patients was 20.5% (median follow-up 20 months). No reactivation occurred in patients with anti-HBs-positive donors. Conclusion Although few cases of postallogeneic bone marrow transplantation reverse seroconversion to HBV have been reported, this study demonstrates that the actuarial risk is relatively high and suggests that donor vaccination might be proposed prophylactically or that HBs-specific immunoglobulin infusions might be warranted.

BACKGROUND Acute graft-versus-host disease (aGVHD) is still one of the main causes of morbidity and mortality after allogeneic bone marrow transplantation. Attempts to avoid GVHD are associated with an increased risk of relapse, probably because the graft-versus-leukemia effect is also abrogated. It was recently suggested that a high frequency of host-specific donor helper T cell precursors (HTLp) might be predictive of significant aGVHD (grade > or = II). METHODS We retrospectively studied the frequency of HTLp by means of simplified limiting-dilution analysis to determine its predictive value for aGVHD and relapse. Pre-bone marrow transplantation, host-specific donor HLTp frequencies were analyzed in 32 patients who had received marrow from HLA-identical siblings for hematological malignancies, in terms of aGVHD and relapse. RESULTS HTLp frequencies were significantly higher in patients who had aGVHD > or = grade II (n=14) than in those without aGVHD (n=18) (P=0.007). Patients who relapsed (n=13) had significantly lower HTLp frequencies than those who did not relapse (n=19) (P

A case of primary cutaneous aspergillosis occurring in an allogeneic bone marrow transplant recipient in a laminar airflow room is reported. The patient developed grade III graft-versus-host-disease and epidermolysis. Although the patient had remained in his laminar airflow room from the graft onward, he subsequently developed primary cutaneous aspergillosis. The aspergillosis became invasive and the patient died. The patient was probably contaminated by air containing conidia when he left the sterile room for endoscopy, and the fluidized bed used may have contributed to the local development of the disease. This nosocomial aspergillosis stresses the necessity of performing invasive procedures under laminar airflow protection to prevent Aspergillus contamination in immunocompromised hosts at risk for aspergillosis.

Background Sickle Cell Anemia (SCA) remains a disease with high risk of morbidity and early death. HSCT is currently the only curative treatment for SCA, but its use has been limited by the risks of transplant-related mortality (TRM) and GVHD. We have previously demonstrated that antithymocyte globulin (ATG) efficiently decreases the rejection rate in HSCT for SCA; however, its optimal dose has not been defined, prompting us to retrospectively analyse outcomes in patients from the SFGM-TC cohort receiving different ATG doses. Patients and Methods The cohort includes 236 SCA-patients (109F, 127M), (229 SS, 5 Sb0, 2 SDPunjab) transplanted in France (1988-2012) with geno-identical donors after homogeneous myeloablative conditioning regimen (CR; BU-CY), and rabbit ATG (n=215) at 5-15 mg/kg (n=35), 20 mg/kg (n=160) or no ATG (n=20). Cell sources were bone marrow (BM, n=197), cord blood (CB, n=30), CB+BM (n=8), and peripheral blood cells (PBC, n=1). Chimerism was assessed by quantitative real-time PCR from PBC at Day-30, 60, 90, Month-6, 12 and every year post-transplant, and defined as total donor chimerism (TDC): >95% donor (D); low (5-50%D) or high (50-95%D) mixed chimerism (MC),; or rejection (< 5%D). Disease-free survival (DFS) was defined as the absence of HSCT-related death and rejection. GVHD prophylaxis consisted of CSA-short MTX for BMT and CSA alone for CBT. Results Mean age at transplant was 9.7yr (range: 2.2-28.9), with 33 patients older than 15. With a mean follow-up of 5.6yr (range 0.5-22.5), TRM was not different with or without ATG (3.4%; 0.8-6%) whereas DFS was higher (p=0.004) with ATG (95.4%; 92-4-98.4) than without (72.7%; 51.7-93.7), due to differences in rejection rates (p15 (OR=7.9, 95%CI: 2.5-25.6,p Conclusion This study confirms that myeloablative CR with ATG offers 95% DFS to SCA-patients and that stable MC in absence of SCA-symptoms does not require intervention such as DLI. It reports for the first time in HSCT for SCA that donor’s age significantly increases GVHD risk, suggesting to choose the youngest sibling when possible, and that high ATG dose (20 mg/kg), which significantly reduces cGVHD risk without enhancing viral risk, should be recommended. Disclosures: Bernaudin: Novartis: Research Funding. Bertrand:ERYTECH Pharma: Principal Investigator Other. Gluckman:Cord use: Honoraria; gamida: Honoraria.

We report on 71 consecutive patients with de novo myelodysplastic syndromes referred to physicians belonging to the Societe francaise de greffe de moelle from 1982 through 1991 and transplanted with marrow from HLA-identical siblings. There were 16 cases of refractory anemia, 27 of refractory anemia with excess of blast cells, and 28 of refractory anemia with excess of blast cells in transformation. Seventeen patients had received cytoreductive chemotherapy before the graft. The disease progressed in 17 patients between diagnosis and grafting. Twenty-three patients are alive with a median follow-up of 6 years, whereas 24 died from relapse and 24 from transplant-related complications. Kaplan-Meier estimates of event-free survival, relapse and transplant-related mortality at 7 years were 32%, 48%, and 39%, respectively. The log-rank test and Cox's model revealed better outcome among young patients, patients in an early stage of the French-American- British (FAB) classification or with a low percentage of marrow blasts before transplantation, patients who did not undergo cytoreductive chemotherapy before transplantation, and patients conditioned with total body irradiation and cyclophosphamide. The high rate of relapse in advanced FAB stages has led us to graft patients earlier in the course of the disease, and we are currently conducting a multicenter, randomized study to determine the value of intensive chemotherapy before grafting in patients with an excess of marrow blasts.

We report a case of mild, clinically asymptomatic, immune thrombocytopenia after allogenic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML) caused by the presence of a recipient- origin Br(a) antibody that recognized the donor platelets. Although the antibody titer decreased, it remained detectable more than 3 years after BMT. Chimerism studies were performed combining cytogenetics, blood cell phenotype studies, and genomic amplification of hypervariable sequences. Cytogenetic studies and molecular analysis of peripheral blood cells, purified B- and T-lymphocyte subpopulations, and bone marrow colonies showed the hematopoiesis to be of donor origin, but absorption-elution experiments with peripheral RBCs showed a small amount of recipient RBCs. The CML chimeric transcript was also detected by means of polymerase chain reaction on samples collected until day +867 post-BMT. This case shows that recipient-origin platelet alloantibodies can cause thrombocytopenia after BMT and that the persistence of small numbers of recipient cells (even leukemic) is not necessarily associated with hematologic relapse.

Abstract 3516 Allogeneic Bone Marrow Transplantation (ABMT) is currently the only curative treatment for sickle cell disease (SCD). However, in adult patients, myeloablative conditioning is usually considered as excessively toxic and non-myeloablative procedures have resulted in high rejection rates or frequent mixed chimerism. In these mixed chimeras, erythropoiesis is usually of donor origin, but the long-term stability of this chimerism remains unknown. In this context, we report the French experience of myeloablative ABMT in young adults, using a preparative regimen previously successful in children (Bernaudin et al. Blood 2007). Patients and Methods: Twelve SCD patients,8 males and 4 females, 16 to 28 years old (mean 20,6) were transplanted with an HLA identical sibling between 1999 and 2009 in five french centers. These patients were listed in the French BMT registry (SFGM-TC). All patients received the same BU-CY +ATG (varying dosage) preparative regimen and Cyclosporine and Methotrexate for GVHD prophylaxis. Reason for transplant included a stroke history in 4 patients, asymptomatic pulmonary hypertension (TRV: 2.9m/s) in 1 patient, and frequent vasoocclusive crisis and/or acute chest syndrome in all the others. Before transplant, 10 patients had received numerous transfusions (>20 units) and none had received Hydroxyurea. Erythrocyte immunisation was present in 1 patient. The donors were AA in 7 cases and AS in 5. Eight donors were seropositive for CMV and 4 had a major ABO incompatibility with the recipient. The median follow-up of surviving patients is currently 36 months (range 9–120). Results: All patients engrafted (mean time for PMN > 0.5×109/L: 23days) and no rejection was observed. A patient who had successful engraftment but previous severe CNS vasculopathy and moya-moya, had a massive intracerebral haemorrhage at day 32 after transplant and died. Early toxicity included also a sub-dural haemorrhage successfully evacuated in a patient without any previous cerebral vasculopathy. Other early complications included seizures, viral pericarditis, bacteriemia and CMV reactivations, but no veno occlusive disease was observed. Four patients had acute GVHD grade II that responded to Prednisone treatment. Two patients had limited chronic GVHD, one with severe peripheral thrombocytopenia; however, both episodes resolved and the patients do not currently receive any immunosuppression. Only one death was observed, resulting in an overall survival and disease-free survival of 92% at 3 years. All survivors have the Hb electrophoretic profile of their donor and a normal Hb level. DNA-chimerism was characterized as full-donor. All patients have a normal quality of life, except for the sequelae of previous CNS disease in two patients and residual migraine after hematoma evacuation in one patient. Conclusion: This experience demonstrates that myeloablative allogenic BMT is feasible in selected young adults with SCD: The overall results are similar to those obtained in younger children. Early regimen-related toxicity does not appear to be increased as compared to BU-CY regimen used for other disease,but the early transplantation course has been more complicated in these patients than in younger children. Patients with severe CNS disease require special care. Of note, only one patient with significant renal involvement was included in this study. Acute and chronic GVHD have been moderate and easy to manage in these patients younger than 30 with an HLA identical sibling. A stable long-term full chimerism and cure has been achieved in all survivors. These results should encourage physicians to perform HLA typing in all young adults with SCD and their family in order to identify as early as possible potential candidates for transplantation. Although this experience is limited, it suggests that SCT could be proposed to young adults who had non-severe disease during childhood but developed severe criteria during adulthood such as a tricuspid regurgitant jet velocity at least 2.5 m/second. Count actuel 3359 (3800 autorisés) Disclosures: No relevant conflicts of interest to declare.

Abstract 3518 Background: Despite progress made in sickle cell anemia (SCA) management, such as the prevention of pneumococcal infections, introduction of hydroxyurea therapy and early cerebral vasculopathy detection with transcranial Doppler, SCA remains a disease with high risk of morbidity and early death. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA; nevertheless, its use has been limited by the risk of transplant-related mortality (TRM). Our first experience, reported in Blood 2007, included 87 consecutive severe SCA- patients transplanted in France between 1988 and Dec-2004. We showed that the introduction of rabbit anti-thymocyte globulin (ATG) in the conditioning regimen in 2000 allowed a significant reduction of the rejection rate from 22.6% to 3% and that the outcome improved significantly with time as the DFS rate among the 44 patients transplanted after January 2000 was 95.3%. These data have justified continuing to transplant symptomatic young sickle cell patients having a geno-identical donor with the same conditioning regimen (CR) consisting of intravenous Busulfan (BU), Cyclophosphamide (CY) and rabbit ATG. Patients and Methods: In France, from 1992 to 2010, 144 SCA-patients (84M, 60F) have now been transplanted with a geno-identical donor using BU-CY-ATG as CR at the median age of 9.0 years (range:3.2-27.5). Transplants were performed in 16 different centers but 60 were performed in Hopital St-Louis and 21 in Hopital Debré in Paris. All recipients were SS or Sb0 and 76% of them were CMV+. All had been transfused and 47% had received more than 20 units. The source of cells was the bone marrow (BM) (n=121), cord blood (CB) alone (n=21), CSP (n=1) or BM+CB (n=1). GvHD prophylaxis consisted of the association of cyclosporine (CSA)-short MTX for BMT and CSA alone for CBT. Results: Engraftment was successful in 141/144; the time to absolute neutrophil count > 500/mm3 was significantly shorter after BMT compared to CBT (mean ± SD; 21.3 ± 6.7 vs 32.1 ± 9.8, respectively; p Conclusion: These results with 121 patients transplanted since 2000 confirm that it is possible to offer more than 95% chances of cure to SCA-children, indicating that HLA-geno-identical HSCT after myeloablative conditioning with ATG should be considered as standard of care for SCA children, not only for those at high risk of stroke but also for children experiencing crises or other complications requiring intensive therapy such as transfusion program or hydroxyurea. Sibling cord-blood cryopreservation should be systematically offered and pre-implantation genetic diagnosis coupled with HLA selection discussed with the parents. Disclosures: No relevant conflicts of interest to declare.

Purpose: Objective was to assess indication, feasibility and efficacy of double allograft with reduced intensity conditioning. Patients and Methods: All double allogeneic hematopoietic stem cell transplantation (AHSCT) after reduced intensity regimen reported to Promise database were retrospectively studied. Because of the initial lack of clinical and biological data in the Registry, all centers were contacted to improve the database. Results: 66 double mini-allografts were realized in 25 french transplant centers. At this time, 35 mini-allografts presented complete informations corresponding to 14 transplant centers. Diagnosis was LAM (n=15), aplasic anemia (n=5), MDS and/or MPS (n=5), LAL (n=2), Myeloma (n=2), ovarian cancer (n=1), LNH (n=2), LLC (n=1), LMC (n=1) and Hodgkin lymphoma (n=1). Median age at first transplantation was 49.3 years [12.75–64.9] with a median time from diagnosis to first transplant of 22.9 months [3.6–163.7]. Disease status before transplant was progression (n=5), partial response (n=3), complete response (n=18), induction failure (n=2) and chronic phase (n=2). The 5 aplasic anemias were not evaluable for this status. Most patients received fludarabine (n=31), SAL (n=22), busulfan (n=15) based regimen. Graft source was PBSC in 74% of grafts. Median age of donor was 42 years [4–68]. HLA relation of donor with patient was identical sibling (n=22), match unrelated (n=10) or mismatch unrelated (n=3). Second allograft indication was relapse (n=22), lost of graft (n=7), no engraftment (n=5) or residual disease (n=1). Eihgty percents of patients underwent a different conditioning. It was similar for only 7 patients (same n=1, increase SAL dose n=1, SAL addition n=2, dose reduction n=1). Median time between the two allografts was of 7.6 month [1.1–61.0]. Source of stem cells and donor were changed in 13.6% and 37% of allograft respectively. The median time to reach an absolute neutrophil count of 0.5 × 109/l and platelet count of 50 × 109/l was shorter after second allograft (21.4 days [12.4–759.5] versus 16.8 days [6.2–105.4] and 16.3 days [9.3– 71.3] versus 14.26 [3.1–83.7]) with no significant difference. Overall incidence of acute GvH was similar after the two allografts (34% versus 43%). However, acute GvH grade III–IV proportion seems to be higher after second allograft (8% versus 40%). Similarly, proportion of chronic GvH was 23% versus 27% with an increase of extensive GvH after second allograft (50% versus 66%). Response was improved by second allograft in five patients (15%) and allowed to engraftment in 3 patients (7%). To date, 8 patients are still alive. 14 patients died from progression and 11 of TRM (3 multiple organ failure, 5 respiratory failure, 2 fungal infection and 1 rejection) giving a TRM proportion of 31%. With a median follow-up of 57.1 months [21.9–128.8], the median overall survival (OS) was of 24 months [2–71]. Delay greater than 7.7 months and same source of stem cell between two mini-allografts improved OS (50 months versus 9 months, p = 0.0085 and 28 months versus 14 months, p=0.11). Conclusions: Our preliminary results suggests response improvement after double AHSCT with reduced conditioning. However, TRM proportion was high.

Background: In acute leukemia (AL) patients, mortality rates of the most common IFI (i.e., aspergillosis and candidiasis) are well illustrated in the literature from the IFI diagnosis, as well as the rate of fungal relapse during subsequent periods at risk, such as neutropenic phases, or transplant. However, few data are available about the impact of IFI on the subsequent chemotherapy schedule and the indirect impact of IFI on the relapse-free and overall survival. Clinicians are usually reluctant to give the full chemotherapy doses on time, due to the risk of life-threatening fungal relapse during the subsequent courses. Even with secondary prophylaxis, they often delay or decrease the doses of chemotherapy. This may impact on the leukemia outcome. The aim of this case-control study was to assess the potential impact of proven or probable IFI onset on the application of the chemotherapy schedule in AL patients, and its consequences on the leukemia outcome, by comparing patients with and without IFI in a single institution. Delays and changes in chemotherapy doses and drug choices were evaluated and compared to the planned schedule in the protocol. Methods: All consecutive AL patients with a first episode of proven or probable IFI according to the EORTC-MSG criteria between 2000–2006 were reviewed. All patients have been treated in, or according to, clinical research protocols where timing and doses of chemotherapy were predefined. Patients who were planned for allogeneic transplant were excluded as those who were at their last consolidation course when they got IFI or in a palliative phase of the leukemia. Any delay, dose decrease, or dose change were defined as any difference compared to the planned schedule. We planned to include 3 control patients for each case, selected among AL patients without IFI, and matched for age, sex, type of AL, chemotherapy protocol, and year of treatment. 27 case and 76 control patients were finally included. The event-free survival (EFS) was defined as survival without evidence of relapse or progression, or death of any cause. Results: The mean age of the 27 case patients (26 myeloid and 1 lymphoblastic AL) was 52 y (± 13), the M/F ratio was 14/13 IFI (7 candidiasis, 19 aspergillosis, 1 zygomycosis) was proven for 10 patients (37%), and probable for 17 (63%). Twenty (71%) of these IFI occurred during the first induction phase. All patients were treated for their IFI with ≥ 1 antifungal, and 4 of them had a surgical resection of the main fungal lesion(s). These 27 patients were compared to 76 controls (73 myeloid and 3 lymphoblastic AL) without IFI. A delay of the next course of chemotherapy according to the planned protocol was significantly more frequent in the IFI group (16/27, 59%) than in the control group (16/76, 21%) (p=.001). Similarly, the dose or choice of the drugs was modified more frequently in the IFI group (7/27, 26%) than in the control group (6/76, 8%) (p=.037). Only 9 (33%) patients got their next chemotherapy course without any modification in time, dose, or choice of drug, vs. 19/76 (75%) in the control group (p Conclusion: In this single-institution case-control study, the occurrence of IFI significantly modified the application of chemotherapy courses, both on timing of the courses, and dose and choice of the drugs when compared to patients without IFI. Although the difference was not significant, there was a tendency for a lower EFS in the IFI group when compared to the control group.−

Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality among neutropenic patients with hematological malignancies. Prevention and early antifungal treatment include prophylaxis where antifungal agent is started along with neutropenia; empirical therapy where antifungal agent is initiated in persistently febrile patients at least four days after neutropenia onset; preemptive therapy where antifungal agent is initiated later for a suspected IFI based on clinical symptoms, lung imaging, or biological markers. Without data from clinical trials comparing antifungal strategies, determining an optimal antifungal strategy for these patients is challenging. Objective: To determine the cost-effectiveness of all possible antifungal strategies. Target Population: Adult patients with hematological malignancies in induction chemotherapy at high risk for IFIs. Interventions: Prophylaxis with either fluconazole or posaconazole, empirical strategy, and preemptive strategy with fist-line antifungal therapy being amphotericin B, liposomal amphotericin B or caspofungin (Table). Design: Cost-effectiveness decision model. The study cohort encountered seven successive chance nodes during hospital stay: having fever; in those having fever, IFI incidence; Aspergillus or Candida species among IFI; admission in intensive care unit; dying from IFI or underlying hematological malignancy; in patients alive, having severe nephrotoxicity as defined by a twofold increase in baseline serum creatinin; dying from severe nephrotoxicity. Antifungal strategies modified the probabilities of IFI and severe nephrotoxicity that depended on both the duration and the type of antifungal drugs administered. Data Sources: PREVERT trial1, effectiveness data published to December 2007, probabilities of ICU admission and in-hospital mortality according to the occurrence of IFI in the French DRG database, life expectancy of French patients with acute myeloid leukemia, and actual French hospitalization costs (2007 euros). Time Horizon: Lifetime. Perspective: Societal. Outcome Measures: Incremental cost (euros) per discounted life-year saved averaged from 100 samples of 1000 patients (second-order probabilistic Monte Carlo simulations). Results (Table): Fluconazole prophylaxis followed by ampho-B treatment was the cheapest antifungal strategy. Posaconazole prophylaxis followed by ampho-B was nearly cost-effective (59,610 € per discounted year of life gained). Other strategies were either dominated or beyond usual societal thresholds of what may be worth it. Similar results were found in sensitivity analyses among plausible ranges. Conclusions: As compared to previous studies showing that new antifungal drugs were cost-effective within a single strategy, empirical and preemptive antifungal strategies were dominated by prophylaxis strategies. Table: Incremental cost-effectiveness ratio of antifungal strategies in high-risk neutropenic patients Total cost (2007 euros) Years of life gained ICER IFI (%) Aspergillus (%) Nephro-toxicity (%) Antifungals’ cost (2007 euros) Fluconazole then amphoB 35606 2.3448 -- 3.81% 2.61% 4.22% 909 Fluconazole then L-amphoB 36025 2.3457 (extended dominance) 3.81% 2.61% 3.67% 1430 Empirical amphoB 36033 2.3433 (dominated) 3.38% 2.3% 5.98% 1914 Posaconazole then amphoB 36065 2.3525 59,610 € 1.2% 0.81% 3.67% 2646 Preemptif amphoB 36160 2.3449 (dominated) 3.89% 2.67% 4.42% 1247 Posaconazole then L-amphoB 36389 2.3532 462,857 € 1.2% 0.81% 3.21% 3055 Fluconazole then Caspo 36557 2.3459 (dominated) 3.81% 2.61% 3.53% 1985 Preemptif L-amphoB 36616 2.3455 (dominated) 3.89% 2.67% 3.84% 1809 Posaconazole then Caspo 36828 2.3533 4,390,000 € 1.2% 0.81% 3.13% 3509 Empirical L-amphoB 37308 2.3462 (dominated) 3.38% 2.3% 4.39% 3239 Preemptif Caspo 37346 2.3458 (dominated) 3.89% 2.67% 3.55% 2597 Empirical Caspo 39123 2.3473 (dominated) 3.38% 2.3% 3.47% 5080

To the editor: The lymphopenic environment can induce T-cell expansion/activation, a phenomenon referred to as lymphopenia-induced proliferation that can be distinguished from (allogeneic) antigen-induced proliferation.[1][1] Dudley et al showed that a cyclophosphamide (Cy) and fludarabine (Flu)

We thank Dr Fitzhugh and colleagues for their careful reading of our paper. We agree with the authors that the 95% chance of cure reported for stem cell transplantation (SCT) in the most recent patient cohorts will elicit its recommendation to more patients and families. Therefore, documented data

Invasive fungal infection (IFI) occurs in 2–12% of acute leukemia patients, with different prevalences according to centers, and phases of treatment. The mortality rates of the main IFI (i.e., aspergillosis and candidiasis) are well illustrated in the literature, as well as the risk of fungal relapse during subsequent periods at risk, such as a new neutropenic phase, or transplant. However, few data are available about the impact of IFI on the subsequent chemotherapy schedule. Clinicians are usually reluctant to give the full chemotherapy doses on time, due to the risk of life-threatening fungal relapse during the subsequent courses. Even with secondary prophylaxis which is now widely given, they usually delay or decrease the doses of chemotherapy. This may impact on the leukemia outcome. Objective: The aim of this single-institution retrospective study was to look at the impact of proven or probable IFI onset on the application of the chemotherapy schedule as planned in the initial strategy in patients with acute leukemia. Delays, and changes in chemotherapy doses and drug choices were evaluated and compared to the planned schedule in the protocole. Methods: All consecutive acute leukemia patients with a first episode of proven or probable IFI according to the EORTC-MSG criteria between 2000–2006 were reviewed. All patients have been treated in, or according to, clinical research protocols where timing and doses of chemotherapy were predefined. Patients who were planned for allogeneic transplant were excluded as those who were at their last consolidation course when they got IFI. Any delay, dose decrease or dose change were defined as any difference compared to the planned schedule. Results: 28 patients (7 candidiasis, 20 aspergillosis, 1 zygomycosis) were included (M/F: 15/13; mean age: 54y), including 27 acute myeloid leukemia and one acute lymphoblastic leukemia. Eleven (39%) were proven, 17 (61%) were probable. Twenty (71%) of these IFI occurred during the first induction phase. All patients were treated for their IFI with ≥ 1 antifungal, and 4 of them had a surgical resection of the main fungal lesion (s). Seventeen of 28 (60%) had their next course delayed (median delay: 14 days) when compared to the planned protocole. The doses of the antineoplastic drug(s) were modified in 7 (25%) patients. Only 9 (32%) patients got their next chemotherapy course without any modification in time, dose, or choice of drug. Although the number of patients in our study does not allow definite conclusions, these changes should have an impact on leukemia-free and overall survivals. Conclusion: Due to the risk of fungal relapse during a subsequent period at risk, IFI has a practical impact on the dates, doses, and choices of chemotherapy in acute leukemia in more than two thirds of the patients, due to subjective decisions of the clinicians. Effective antifungal strategies are needed to avoid the onset of IFI in acute leukemia patients.

We have previously shown [1] that a calcineurin activity (CA) < 28 pmol RII/mg proteins/min was significantly associated with the absence of acute GVHD after allogeneic stem cell transplant (SCT). The CA is poorly correlated with cyclosporine (CsA) trough level which is not a good marker of CsA efficacy. Therefore, the in vitro assessment of CA could help in adapting the cyclosporine doses for GVHD prophylaxis, better than blood CsA levels. Objective: The aim of this prospective study was to evaluate the feasibility of adapting the CsA doses to the values of in vitro CA either until GVHD occurs, or until day 100, whichever occurs first. Methods: CA assessment methods in PBMC of transplant patients and monoclonal CsA level measurement methods were previously reported [1]. CA and CsA levels were measured once a week from d0–d15, twice a week from d16–d35, then once a week up to d100. The CsA doses were adapted in order to maintain a CA < 28 from transplant by 20% progressive changes of the CsA daily dose. Adaptation was stopped in case of clinical CsA blood levels ≥ 600 ng/ml, creatinine clearance < 40 ml/mn, serum bilirubin > 40 m/L, or severe clinical toxicity. Patients: 39 adult patients with malignant hemotologic diseases (acute leukemia: 28; chronic leukemia: 4; others: 4) or aplastic anemia (3), and undergoing myeloablative SCT were included (HLA-id donor: 20; unrelated donor: 19). GVHD prophylaxis consisted in short course Methotrexate and CsA (initial dose: 3 mg/kg IV). Results: Out of 39 patients, 2 were adapted until d100 and did not develop GVHD; 27 were adapted without CsA toxicity until they developed GVHD (grade I: n=2; grade II: n=18; grade III–IV: n=7). In 10 (26%) patients, adaptation was stopped before d100, due to neurologic (n=1), renal (n=2) or liver (n=2) toxicity, severe nausea (n=1), investigator decision (n=1) or protocol violation (no CsA increase despite high CA and no CsA toxicity: n=3). Conclusion: Our study shows that CsA dose adaptation is feasible on the basis of CA regular assessment within the safety limits defined in our protocole. This adaptation is, however, limited by CsA toxicity, due to the need to significantly increase the CsA dose to get a CA < 28 pmol in 26% of the patients. A prospective controlled study is needed to compare the routine use of CA to the use of CsA blood levels for managing CsA doses in GVHD prophylaxis.

Empirical (E) antifungal therapy (ATF) is a standard of care in neutropenic patients with persistent or recurrent fever. However, the safety and cost-effectiveness of the E strategy are challenged by the development of better diagnostic methods and more effective therapies for invasive fungal infection (IFI). An economic analysis was conducted alongside a multicenter open-label randomized non-inferiority trial showing that a pre-emptive (PE) strategy based on clinical symptoms and GM Ag did not reduce the overall survival of prolonged neutropenic patients when compared to a E strategy (details provided in abstract 551005). Objective: The objective of the study was to compare hospital costs between the PE strategy and E strategy. Patients: 293 adult patients with hematologic malignancies and an expected neutropenia ( Methods: The economic analysis was conducted from the hospital perspective (€2005). Total medication costs were computed from individual records during hospital stay. Results: Overall, mean medication costs did not differ significantly between the PE and E groups (see Table). In patients in induction phase (n=151), mean medication costs were higher in the PE group than the E group (+921€, [95%CI, −1602 to +3444]) as explained by the significantly higher proportion of IFI in the PE group (16.4% vs. 3.9%, p Conclusion: Cost comparison between E and PE strategy showed opposite results in induction or consolidation/ASCT phases. This finding is mainly explained by different risks of developing IFI according to the therapeutic phase. (Grants: PRC 2002 AOR02028). Table: Comparison of mean(std) medication costs, antifungal therapy costs, and proportion of IFI between PE and E groups (€2005) PE strategy E strategy p Overall (n=293) Medication costs 3595 (7444), n=143 3745 (4768), n=150 ns Antifungal therapy costs 2218 (6969), n=143 2337(4093), n=150 ns Proportion of IFI 9.1% (13/143) 2.7% (4/150)

Between 1998 and 2004, 2141 allogeneic hematopoietic stem cell transplantations with unrelated donor (excluding cord blood) have been recorded on the SFGM-TC data base. The lack of unique behavior in regard of Anti Lymphocyte Globulin (ALG) use in unrelated donor transplants allowed us to perform a retrospective study to assess the influence of ALG in such grafts. To avoid biaises we excluded T cell depletion or monoclonal antibody use, reduced intensity conditioning and focused only on patients (pts) with acute leukemia (AL) and myelodysplasia (MDS). So we defined a study population of 553 pts. In addition, in order to analyze the actual impact of ALG on wellknown targets (engraftment, acute GvHD, relapse, survival) we choose to keep only the cases in which was available the allelic HLA typing (4 digits) for the recipient and the donor, i.e. 250 pts. There were 106 females and 144 males, allografted in 29 centers. The median age was 23 years (1–62) and there were 77 children under 15. There were 223 AL - myeloid n=120, lymphoid n=103 - and 27 MDS. The source of cells was bone marrow for 190 pts and peripheral mobilized stem cells for 60. One hundred and ninety-three pts received a conditioning regimen including Total Body Irradiation. Ninety-five pts received ALG (mainly Thymoglobulin Mérieux-Genzyme Lyon France at various doses) for a median of 3 days (group 1) and 155 did not (group 2). There were 189 donor/recipient pairs strictly HLA-matched 10/10, 49 with one allelic difference (HLA A n=13; HLA B n=8; HLA C n=13; HLA DRB1 n= 5; HLA DQB1 n=10 ), 11 with 2 allelic differences and 1 with 3 allelic differences. 238 pts have sustained engraftment at a median time of 20 days (9–41) without any influence of ALG use (97% vs 94% NS). Overall survival at 3 years was 45% in group 1 and 52% in group 2 (NS). The incidence of acute GvHD (grade II to IV) was similar in the two groups (59% vs 54%), but the incidence of acute GvHD (grade III to IV) was lower in group 1 (21% vs 32% p=0.03). Use of ALG did not affect rate relapse (18% vs 20% NS). In a multivariable analysis including HLA disparities, patient age, use of ALG, two factors appear as predictive for grade III–IV GvHD: HLA-identity (p=0.05) and use of ALG (p=0.02). These factors are not significant for survival in the same multivariable analysis but in this allelic matched population, the influence of ALG should be analyzed in regard of exact dose of ALG.

In hematology patients, HAI are a complex mixture of infections due to therapy, especially to transplant procedures, conditioning regimen, immunosuppressive drugs, and invasive procedures. These HAI may occur within the hospital and be related to the hospital environment (i.e., NI), or not. These different kinds of infections require very different preventive measures. The objective of our study was to assess the incidence, overlap, and causes of HAI and NI in our hematology ward over a 6 month period. Methods and Definitions: Infections were considered to be HAI, irrespectively of their site of occurrence (hospital or not) when they were directly related to the therapeutic procedures and subsequent immune deficiency. This included: febrile neutropenia (FN) subsequent to chemotherapy, catheter-related infections, herpes virus reactivations in patients previously sero+ to the virus, primary CMV infection in CMV− patients transplanted with a CMV + donor, toxoplasmosis reactivation, invasive fungal infections, and any infection occurring within 6 months of transplant, or later in case of immunosuppressive treatment after this date. Infections were considered to be NI when they occurred ≥ 48 h after hospitalization without any symptom of infection at hospitalization. Aspergillosis was considered to be NI when there was a delay of 7 days between hospitalization and first symptoms.We retrospectively assessed 223 consecutive infectious episodes occurring between 7–12/2000 in 137 patients, including 59 stem cell transplant recipients (allogeneic: 23; autologous: 36). Results : 204/223 infectious episodes (91,4%) were HAI while 94/223 (42%) were NI. 7/223 (3,6%) were causes of death. Among the 42 bacterial documented infections, 20 (47.6%) were due to potentially hospital-acquired strains: 16/23 (69.5%) of HAI-NIs, and 4/19 (21%) of the non NI-HAIs. Conclusion: In a preventive infection program, the assessment of NI clearly underestimates half of the HAI in hematology patients. Although hospital environment control is of paramount importance in transplant programs, we suggest that HAI should be a better quality indicator for hematology programs than NI.

Hematopoietic cell transplantation (HCT) is the only potentially curative treatment for sickle cell disease (SCD). The probability of event-free survival is currently between 85 and 90% after matched sibling-donor HCT. This intensive treatment conducts to a major change for patients and families. The purpose of the present study was to determine the psychological impact on individuals and their families of this recovery process after HCT. The hypothesis was that the recovery is a process with different aspects (medical, psychological, individual, familial and cultural) which could be discordant. This study was supported by the Etablissement Français des Greffes (EFG) and conducted by child and adolescent psychiatrists, psychologists and a medical anthropologist. The assessment consisted in two semi-structured interviews adressed to the patients and their families for studying their illness narratives and questionnaires for quality of life, post-traumatic stress disorder (PTSD), depression and anxiety. 28 patients (17 males, 11 females) with SCD treated in France by HCT (22 by bone marrow and 6 by cord blood transplantation) and their families were evaluated at least one year (median 5 years, range, 1–14 years) after HCT at the median age of 14 years (range, 4–24 years). Among these 28 patients, 7 had prior history of severe vasculopathy and 6 of stroke before the HCT. At evaluation, 27 patients were free from SCD symptoms (but 3 had moderate chronic GVHD), 1 had graft rejection. 9 patients (4 males, 5 females) (median age 16 years, range 7–23 years) presented psychiatric symptoms as inhibition, depression, hypomaniac symptoms, anxiety, stutter. A psychiatric care was indicated for these 9 subjects. No diagnosis of current PTSD was found. Psychological distress was reported by parents. 21 patients considered themselves as cured, 4 of them in an incomplete way (none with stroke before the HCT, 3 with moderate chronic GVHD), and 3 not cured at all (none with stroke before the HCT, 1 with graft rejection). The study of the narratives illustrated the major individual, familial and cultural changes after the HCT. The recovery needed complex adjustments. Patients had to cope with new potentialities and requirements: school and relationships with peers, identity issues (disease transmission, infertility) and family changes. This study underlies the importance of psychological interventions for improving the outcome of patients with SCD treated by HCT and their families.

RIC regimens are mainly used for patients who cannot benefit from the myelo-ablative (MA) approach, due to age, previous SCT, or comorbidities, based on an expected early toxicity of MA regimen. Some centers may also choose the RIC strategy in young patients because they have no facilities for the management of prolonged neutropenia. The development of RIC has been so encouraging that programs now compare MA and RIC in patients who could tolerate both approaches. However, RIC may fail, and MA SCT be secondary considered. Objective: The goal of this retrospective survey was to assess the toxicity and outcome of MA after RIC SCT. Patients: 17 patients (14–63 y; 6 CML, 4 AML, 2 CLL, 2 myeloma, 1 NHL, 1 CMML, 1 myelodysplastic syndrome) received a MA SCT after RIC, for relapse (n=12), graft rejection (n=4), or in a planned program (n=1), from an HLA-id sibling (n=12), a familial mismatched donor (n=1), an unrelated donor (n=3) or a cord blood (n=1). The reason for initial RIC approach was age in 4, a research program in 6, comorbidities in 3, and previous autologous SCT in 4 patients. RIC included Fludarabin (Flu)-Busulfan (BU) in 8, Flu-2Gy irradiation in 4, Cyclophosphamide (CPM)-antithymocyte globulin (ATG) in 1, and various Flu- regimens in 4. One patient had 2 consecutive RIC SCTs before MA SCT. The median delay between RIC and MA SCT was 9 months (range: 2.5–36 months). The same donor was used for the 1st and 2nd SCT in 12/17 cases. The MA transplant was conditioned with BU-CY (±VP16) in 9, Cyclo-TBI in 4, and other regimens in 4 patients. The median follow-up after MA SCT was 9 months Results: After the MA transplant, 1 patient developed veno-occlusive disease, 2 developed interstitial pneumonia. Five patients died from relapse between 8 and 21 mo after the MA SCT. Seven (41%) died from transplant-related causes at a median of 8 months (GVHD:3; infection:1; multi-organ failure:1; thrombotic microangiopathy:1; EBV proliferative disease:1). 5/17 (29.5%) patients are alive and well 4.5 to 26 months after MA transplant. Three of them have extensive chronic GVHD while they did not develop any GVHD after RIC. The delay between the 2 transplants did not influence the outcome. Conclusion: This survey shows that MA after RIC SCT is feasible, and considering that most of these patients have been initially eligible for RIC because of their age or comorbidities, MA SCT had an acceptable toxicity. It may be considered for patients who relapsed or rejected after RIC transplant.

DLI are an efficient treatment for CML in relapse after allogeneic stem cell transplantation, with 60 to 70% of complete response. However, major side effects such has graft-versus-host disease (GVHD) or pancytopenia are frequently observed after this treatment. Imatinib mesylate has also been shown to be effective in a such situation (Blood 2002, 100 (5): 1590–95). In the present study, we report the French experience, with a 3 years median follow-up of 26 patients in relapse of CML after allograft (21 sibling, 4 unrelated, 1 cord blood transplantations). At time of treatment with IM, twenty patients were in chronic phase and 5 only were in molecular relapse, while 4 patients were in blastic phase. Median time from graft to relapse was 36 months (3–132 months) and the median time from relapse to Imatinib was 15 months ( 1–96 months). Ten patients had already received DLI, 14 patients Interferon. Only 6 patients had no treatment prior to IM. With a median follow-up of 32 months (16–44 months), 19 patients are alive and 5 died. The majority of patients in chronic (19/20) phase are alive. At time of last follow-up : Three (11%) patients fail to respond to IM, 2 (8%) have a partial response, 12 (46%) are in CCR with 9/12 in molecular remission, and 4 (15%) patients present relapse (1 blastic phase, 3 molecular relapse). Eleven patients are evaluable for VNTR chimerism, 8(72%) achieved full donor chimerism at last follow-up. IM was well tolerated, and 2 GVHD reactivations were observed but 8 (42%) patients experienced cytopenias requiring drug modulation or withdrawal, and two grade IV toxicities (muscle cramps, cardiomyopathy). Six patients stopped IM (2 toxicities, 4 long term molecular remissions). Four of these patients experienced molecular relapse (3 after 12 months, 1 at 3 months). One patient achieved molecular remission after a new challenge with IM. In conclusion, Imatinib mesylate is efficient and safe treatment for CML in relapse after allogeneic HSCT without reactivating GVHD, and is able to restore full donor chimerism in a majority of responsive patients. A complete and sustained molecular response is obtained in about one third of patients, however molecular relapse is frequent after IM withdrawal. The place of IM and/or DLI for CML in relapse after allogeneic HSCT needs to be addressed prospectively and requires a randomized trail.