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Among patients with AML with normal cytogenetics (CN-AML), the presence or absence of the NPM1 mutation (NPM1mut) and the FLT3 internal tandem duplication (FLT3-ITD) allows to define molecular subgroups, which proved to influence leukemia-free survival (LFS) both after chemotherapy and allo-SCT (Schlenk, NEJM 2008, Brunet, JCO 2012). Hence, the genotypes are currently used as “disease risk” criteria, especially to define indication for allo-SCT in CR1. The influence of these markers on overall survival (OS) after allo-SCT has not been evaluated so far.An EBMT registry-based analysis included adults fulfilling the following criteria: CN-AML, peripheral blood stem cell or bone marrow allo-SCT in CR1 between 2006 and 2011, using matched-related (MRD) or matched unrelated donor (MUD), and detailed information on the mutational status of NPM1 and FLT3-ITD being available. OS, LFS, relapse incidence (RI) and non-relapse mortality (NRM) were calculated according to molecular subgroups. Further, a multivariate Cox model for risk factors was applied, including the following, predefined variables: Age (<> median), white blood cell counts at diagnosis, time from diagnosis to CR1, donor type (MRD versus MUD), conditioning regimen (reduced versus standard) and presence or absence of NPM1mut and FLT3-ITD.366 patients (median age: 49.5 years, range 18.0–70.6; 49% males, MRD in 54%) were included. Median time from diagnosis to CR1 was 45 days (range: 7–181), and median time from CR1 to allo-SCT was 109 days (range: 11–308). Median follow-up from allo-SCT was 12 months (range: 1–61). The Kaplan-Meier estimates of 2-year OS and LFS for the entire cohort were 69±3% and 62±3%, the cumulative incidence of relapse and NRM were 23±2% and 14±2%. Presence of an NPM1mut had no influence on LFS or OS. In contrast, presence of an FLT3-ITD was strongly associated with increased RI (p=0.0004), and decreased LFS (p=0.004) and OS (p=0.0007). Results at 2 years from allo-SCT (% +/− SD) according to molecular subgroups are shown in the table below (mut, mutated, WT, wild type):In the multivariate Cox model, age above the median of 49.5 years was the only factor associated with increased NRM (HR= 3.15, 95%CI: 1.27–7.82, p=0.01), whereas FLT3-ITD was the only factor that correlated with RI (HR=2.80; 95%CI; 1.26–6.20, p=0.01). Both older age and presence of FLT3-ITD were significantly associated with inferior LFS (HR=1.73, 95%CI: 1.03–2.91, p=0.04 for age, HR=2.03, 95%CI: 1.13–3.65, p=0.02 for FLT3-ITD) and, most importantly, with decreased OS (HR=2.29; 95%CI: 1.27–4.15, p=0.006 for age, and HR=2,75; 95%CI: 1.41–5.34, p=0.003 for FLT3-ITD). The latter data allowed the development of a scoring system, identifying three prognostic groups with 2-year survival rates of 42+/−7% (patients with both older age and FLT3-ITD), 66+/−4% (older age or FLT3-ITD) and 74+/−7% (younger age and FLT3-ITDneg, p<0.0001), respectively.We conclude that older age and FLT3-ITD are major risk factors for OS after allo-SCT in CN-AML patients in CR1, independently from other factors such as donor type, intensity of the conditioning, or NPM1 mutational status.Schmid: Novartis Germany: Honoraria, Research Funding; Fresenius Germany: Honoraria, travel grants, travel grants Other; Roche Germany: Honoraria, travel grants, travel grants Other; Pfizer: Travel Grants, Travel Grants Other; MSD Pharma: Honoraria, Travel grants Other; Cellgene: travel grants, travel grants Other. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

Mohty: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

due to a risk of relapse of underlying disease in patients transplanted with progressive malignancy, the use of antithymocyte globulins (ATG), incorporated within the conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT), is still controversial. We report here on a study of 245 consecutive patients transplanted between January 1999 and December 2009 in 26 French and Belgian centers for progressive MDS, defined as stable, untreated, relapsed or refractory disease.Inclusion criteria included patients aged over 18 who received allo-SCT from either a sibling (n=153) or HLA-A, -B, -C, -DRB1 and -DQB1 allele matched unrelated donor (10/10) (n=86) for MDS or AML/RAEB-t (with 20–30% BM blasts). Data quality was ensured using computerized discrepancy errors and vigorous on-site data verification of every single file. A qualified research technicien has been appointed by the University-Hospital of Lille to assist on-site centers that couldn't meet data quality requirements. HLA matching was double-checked by the French Bone Marrow Donor Registry.The first 239 files analyzed until now are presented, including 154 males and 85 females. According to the WHO classification at diagnosis, 85 patients had RA/RARS/RCMD, 86 RAEB1, 62 REAB2 and 6 RAEB-t/AML. Sixty-six patients had progressed to a more advanced disease before allo-SCT. At diagnosis, 102 patients had an IPSS int-2 or higher. Cytogenetic IPSS was recorded as favorable (n=109), intermediate (n=61), unfavorable (n=63) and missing (n=6). Disease status at transplant was established as follows: relapsed or refractory disease (n=106) and untreated or stable disease without hematological improvement (n=133). Median age at transplantation was 53 years (range, 20–70). Patients received myeloablative conditioning (n=105) and nonmyeloablative (n=134) including busulfan-based regimens (n=127), TBI-based regimens (n=92) or other alkylating-agent-based regimens (n=20). In this series, 95 patients (40%) received ATG as part of conditioning ('ATG' group), whereas 144 did not ('no-ATG' group). The analysis reference date of April 1st 2011, median follow-up in survivors was 50 months (IQR, 33–92) with 59 patients having died of relapse and 77 of TRM. The estimated 3-year OS and EFS was respectively 42.3%, and 32.4%. The probability of relapse, overall and event-free survival at 3 years was not significantly different between the two groups. In contrast, the cumulative incidence of grade 2–4 acute GVHD was 48% in the no-ATG group and 30% ATG group (P <.001) and the cumulative incidence of grade 3–4 acute GVHD was 24% and 11% respectively (P <.001). Although the cumulative incidence of chronic GVHD was similar in the no-ATG and ATG groups (64% vs 46%, p=.15), a trend for a lower TRM was observed in the ATG group (22% vs 31%, p=.06). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of acute grade 2–4 [HR = 2.28, 95% CI: 1.39–3.74, p=.001] and grade 3–4 GVHD [HR = 2.19, 95% CI: 1.04–4.61, p=.035].the addition of ATG to the conditioning regimen resulted in a decreased incidence of acute GVHD without increasing relapse rates and compromising patient survival undergoing allo-SCT for progressive MDS.Yakoub-Agha: Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Research Funding; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Michallet:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fresinus: Honoraria, Membership on an entity's Board of Directors or advisory committees. Deconinck:Celgene: Honoraria. Mohty:Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The role of allogenic stem cell transplantation (SCT) for the treatment of relapsed/refractory Hodgkin Lymphoma (HL) remains controversial.we retrospectively analyzed 227 patients who underwent alloSCT between April 1998 and December 2008 for relapsed HL and whose data were reported in the French Society of Marrow Transplantation and Cellular Therapy registry. Thirty-six patients underwent alloSCT with Myeloabaltive Conditioning (MAC) and 191 with Reduced Intensity Conditioning (RIC). Median age was 31 years (13-63 years). Median number of previous therapy regimens was 4. Eighty-nine percent of patients had received a previous Autologous Stem Cell Transplantation (ASCT).Median follow up was 36 months (2-103 months). The 1-year cumulative incidence of non-relapse mortality (NRM) was 17%. Estimated 3 years Overall Survival (OS), Progression free Survival (PFS) and cumulative incidence of relapse (CIR) were 55%, 36%, 47%, respectively for the entire cohort. In multivariate analysis, there was no difference in outcome between patients in CR and PR at time of transplantation for OS (67% vs 68% at 3 years) and PFS (50% vs 40% at 3 years, p=ns). However, patients with chemoresistant disease (stable or progressive) at time of transplantation had a significantly shorter PFS (13% at 3 years p<0.0001) and OS (30% at 3 years p<0.0001) than patients with chemosensitive disease (CR and PR). Moreover, patients with chemoresistant disease have a higher CIR and NRM compared to patients with chemosensitive disease: 62% versus 40% (p<0.0001) and 28% versus 13% (p=0.015) at 3 years. Interestingly, in multivariate analysis for OS, previous ASCT occurring less than 3 months before allogenic stem cell transplantation was found to be associated with better outcome (HR=0.51 (0.27 to 0.99, 95% CI), p=0.046). Use of cord blood was associated with poor outcome (HR =2.74 (1.12 to 6.71, 95%CI), p=0.027). However, there was no impact of chronic Graft-versus-host disease (cGVHD) on outcome when cGVHD was studied as a time-dependent covariate.This study shows that Allogenic SCT especially following reduced intensity conditioning is a feasible option for relapsed HL. Disease status at transplantation remains the major risk factor for outcome. In addition our data suggest that allogenic SCT should be performed as early as possible after ASCT.No relevant conflicts of interest to declare.

for all prognostic analysis pf and pt TNC and CD34 were divided into 4 categories at 25th, 50th and 75th percentiles.Single UCBT: there was a highly statistical significant correlation between pf and pt TNC and CD34 (p<0.001, respectively). Median time to ANC recovery was 26 days (6-84). Cumulative incidence (CI) of ANC recovery at day 60 was 83%. In univariate analysis, the best cutoff point (associated with greater ANC recovery) of pfTNC and pfCD34 were ≥3.6 ×107/kg and ’1.6 ×105/kg and ptTNC and ptCD34 were ≥3.3 ×107/kg and ≥1.3 ×105/kg. In multivariate analysis pf or pt TNC or CD34 were independently associated with ANC recovery (pfTNC HR=1.4, p=0.005; pfCD34 HR=1.3, p=0.01; ptTNC HR=1.4, p=0.01, ptCD34 HR=1.4, p<0.0001). We have not found any association of number of HLA disparities and ANC recovery. When analyzing only adults, patients receiving <2.0 ×107/kg, CI of ANC recovery was only 70% compared to 81% for ≥2.0 ×107/kg (p=0.02). CI of aGVHD at day 100 was 36% and was not associated with TNC or CD34. Estimated 2 year (y) OS was 47%, 2 y DFS was 40%. Interestingly, in a multivariate analysis, pfTNC, pfCD34 or ptCD34 were not associated with OS or DFS, but only higher ptTNC (≥3.3 ×107/kg) was associated with OS (51%vs43%, HR: 0.78, p=0.05) but not with DFS. Double UCBT: there was a highly correlation between pf and pt TNC and CD34 (p<0.001, respectively). CI of ANC recovery at day 60 was 81% in a median time of 23 days (5-64). In univariate analysis, pfTNC, pfCD34 and ptTNC were not associated with ANC recovery. However, there was an association of ptCD34 cell dose (Figure1) and ANC recovery. Chimerism data was available for 75% of the patients (n=298) during the first 100 days: 76% were full donor, 14% were mixed and 11% of the patients had autologous recovery. Autologous recovery was also associated with lower CD34 cell dose, it was 49% in patients receiving (<0.9×105/kg), and 25% for remainders (p<0.001). In multivariate analysis, ptCD34 >0.9x ×105/kg was the only independent factor associated with ANC recovery (HR=1.6, p=0.001). CI of acute GVHD at day 100 was 42% and was not associated with TNC or CD34 cell dose. At 1 y NRM was 22% and relapse incidence 26%. Estimate 1 y DFS was 50±3%. TNC or CD34 cell dose were not associated with any of the above outcomes. Only disease status at transplant impacts outcomes (64% early phase, 49% intermediate phase and 37% for more advanced disease). In conclusion, our study confirms the impact of cell dose measured by pf and ptTNC and CD34 on neutrophil recovery after sUCBT and the minimum cell dose recommended should be pfTNC≥2.5 ×107/kg and ptTNC≥2×107/kg, however only ptTNC is associated with survival in sUCBT. This is the first time that an impact of ptCD34 cell dose on neutrophil recovery after dUCBT is demonstrated and may be used to choose the best CB units. The different associations of cell dose in sUCBT and dUCBT can be explained by biological and immunological properties of other CB cells in the graft.No relevant conflicts of interest to declare.

There is increasing information about reduced intensity conditioning regimen AlloHSCT (Allogeneic Hematopoietic Stem Cell Transplantation) in children. The safety of this approach is now well established but data regarding efficacy are limited and the role in pediatric cancer has yet to be defined.We report results of a French pediatric AlloHSCT protocol with ATG-fludarabine (180 mg/m2) - Busilvex (3.2 at 4.8 mg/kg/d for 2 days) conditioning regimen. Related, unrelated bone marrow (BM) and Peripheral blood stem cell (PBSC) donors and Cord blood units (CB) were allowed. In case of CB a TBI 2 grays, Cyclophosphamide 50 mg/kg, Fludarabine 100 mg/m2 conditioning regimen was recommended. GVH prophylaxis consists in cyclosporine alone. A rapid discontinuation of systemic immunosuppression and re-injecting donor lymphocytes to initiate graft-versus-tumor effect are based on tumor assessment and blood chimerism. Inclusion criteria are children with malignancies that can be potentially cure by allograft but a conventional conditioning regimen being impossible due to toxicity and children with solid tumor or hematological malignancy remaining unresponsive to the reference strategies according to French best practices in pediatrics.From April 2007 to April 2010, 40 RIC AlloHSCT were performed in 10 different French pediatric graft centers: 13 Hodgkin Lymphoma, 7 acute myeloblastic leukaemia, 2 acute lymphoblastic leukaemia, 6 neuroblastoma, 8 rhabdomyosarcoma, 3 desmoplastic tumor and 1 Ewing sarcoma. Median age at transplantation was 15 years and median time from diagnosis to transplant was 18 months. Before transplant, 15 patients are in complete response and 25 patients (14/18 solid tumors) have active disease (11 progressive, 14 partial response). 21 had already received a myeloablative therapy (18 autograft and 3 allograft). Graft source was PBSC in 17 cases (7 related and 10 unrelated), BM in 18 (10 related and 8 unrelated), and 5 CB. The RIC Bu-flu conditioning regimen permits rapid engraftment without major toxicity contrary to the Cy-TBI in CB. 1 patient had primary graft failure: 1 CB and 5 patients experienced secondary graft failure: 3 CB, 1 PBSC and 1 BM. Median time to reach an ANC of 0.5 109/l was 16 days. Median time to reach a platelet count of 20 × 109/l was 2 days. Platelet count did not decrease below 20 109/l in 10 allografts. At day 30 post-transplant, chimerism is mainly donor for 30 and partial for 6 children. At day 100 post transplant, 4 out of 6 with initial mixed chimerism were converted into full donor chimerism. 8 patients received DLI and 17 patients experienced acute graft versus host disease (GvH) (2 grade IV and 15 grade ≤ II). A low day 365 TRM of 5% is reported in these heavily pre-treated patients. With a median follow-up of 15 months, the estimated 2 yr overall survival (OS) was respectively 57 % (71% for hematological malignancies and 42% solid tumors) (fig 1) and event free survival (EFS) 36% (50% for hematological malignancies and 19% solid tumors). Univariate analysis of EFS and OS showed no effect of related versus unrelated stem cell sources and BM versus PBSC. Our analysis identified a group of patients, who had no measurable disease at transplant, with a 2 yr OS and EFS of 86%. In term of efficacy, we observe a graft versus lymphoma effect in patients with advanced active Hodgkin lymphoma. Concerning solid tumors, all children included had a very bad prognosis and detectable disease before transplant. Our results may suggest that an immune-mediated effect cannot be excluded in some refractory solid pediatric tumors particularly in neuroblastoma. The main cause of failure of this approach is disease progression. Immunologic approaches after transplantation may help cure more of these very-high-risk patients.Even if further follow up is needed, this prospective study suggest that RIC regimen provides promising outcome in children previously not eligible for myeloablative AlloHSCT.This study “RICE” was registered at www.clinicaltrials.gov as NCT 007 50 126No relevant conflicts of interest to declare.

CLL remains incurable with standard therapies. Myeloablative allogeneic SCT (allo-HSCT) is still associated with high TRM and few late relapses. Recently, the major focus of transplantation in CLL has been with reduced-intensity conditioning (RIC) allo-HSCT, which is applicable to the more elderly patient population and which attempts to exploit the graft-versus-leukemia (GVL) effect that was proved in CLLTo evaluate the efficacy and toxicity a RIC regimen including fludarabine and total body irradiation (TBI) with the introduction of rituximab for allo-HSCT in patients with a CLL stage B or C diagnosis.This prospective study included adult CLL patients with age < 65 years in stage B or C in response after a salvage treatment either following at least 2 treatment lines (1 including fludarabine) or after a progressive disease after auto-HSCT, having a HLA identical sibling donor and a good performance status (Karnfosky >70%). Donors were mobilized by G-CSF and in case of collection failure, bone marrow aspiration was authorized. The conditioning included: rituximab 375mg/m2 on day -5, fludarabine 30 mg/m2 from day-4 to day-2, TBI 2grays (6-7 cGrays/minute) on day 0 and rituximab 500mg/m2 on day1 and day8. GVHD prophylaxis used cyclosporine A (IV 3mg/kg/day) from day-2 and mycomofetil fenolate oral (2g/day) from day 1.Between April 2003 and December 2008, 40 patients were included, 34 (85%) males and 6 females with a median age of 54 years (35-65), 38 (95%) were in B stage at diagnosis and 2 in stage C. Among 23 explored for cytogenetics, 8 were abnormal (3 del17, 1 trisomy12, 1 t(8-11) & 1 del13). Before transplantation, 17 patients received 2 lines treatment, 10 three lines, 5 four lines, and 8>4. Only 1 patient received a previous auto-HSCT. Among 18 explored for Matutes status, 1 was in score 1, 1 in score 2, 3 in score 3, 5 in score 4 & 9 in score 5. At time of allograft, 7 (17%) patients were in complete response (CR), 29 (73%) in partial response (PR) and 4 (10%) < PR. For sex-matching, 59% were mismatched (27%of them were F>M). For ABO matching, 68% were compatible, 19% major incomp. & 13% minor incopm. The median interval diagnosis-allo-HSCT was 58 months (6-177). Median CD34+ number was 7.64 (3.1-18.7). Seven (17%) patients did not receive rituximab during conditioning because the protocol did not include it at the beginning and has been amended later.Thirty-nine (98%) patients engrafted with a median time to neutrophils recovery of 20 days (11-70), 79% of patients reached a total donor chimerism at day 90. Seventeen patients developed aGVHD grade ≥II (8 grII, 8 grIII & 1 grIV) with a cumulative incidence at 3 months of 44% (36-52). The cumulative incidence of cGVHD was, at 12 months: 29% (21-36) for limited and extensive; at 18 months: 32% (24-40) limited and 42% (34-50) extensive. After a median follow-up of 28 months (3-71), the median OS was not reached with 3 and 5-years probability of 55%(41-74). The median time of EFS was 30 months (15 - 70) with a 5-years probability of 46%(33-66). The cumulative incidence of relapse at 1 and 3 years was 17% (11-23) and 22% (15-29) respectively. The cumulative incidence TRM at 1 and 3 years was 10% (5-15) and 27% (20-35) respectively. At the last follow-up, 17 patients died, 6 due to relapse and 11 due to TRM. We noticed a high severe infection rate (56%) and 4% of deaths related only to infection. The univariate analysis showed a positive trend of rituximab on OS and relapse, and a significant protective effect on aGVHD>=2 (p=0.02). The multivariate analysis studying age, interval diagnosis-allo-HSCT, ABO and sex matching, disease status at allo-HSCT, CD34+ number, and rituximab, showed a positive significant impact of this last factor (rituximab) on OS and EFS [HR=0.1 [0-0.6] p=0.02 & HR=0.1[0-0.4] p=0.035 respectively].We showed interesting results in terms of OS, relapse and TRM in patients with advanced CLL after Fludarabine/TBI allo-HSCT. The introduction of rituximab allowed a better outcome especially a significant reduction of incidence and severity of acute GVHD. Nevertheless there was still a high incidence of cGVHD, already known following the Fludarabine/TBI conditioning, leading us to propose either to increase the number of rituximab injections after allo-HSCT, or to test Fludarabine/busilvex/ATG associated to rituximab.No relevant conflicts of interest to declare.

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.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.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<0.001) and platelets reached 50,000/mm3 sooner after BMT (day 28.3 ± 16.6) than after CBT (day 48.5 ± 20.3; p<0.001). No engraftment occurred in 3 cases (1 BMT, 2 CBT) with gradual autologous reconstitution, and one rejection was observed 3 years post-transplant. GvHA grade ≥ II occurred in 23% of patients, GvHA ≥ III in 4.4%, chronic GvH in 9.6% (extensive in 3 cases). No GvHD ≥ II or chGvHD were observed after CBT. Death occurred in 6 cases (4 were GvHD-related, 1 hemorrhagic stroke in a patient with severe cerebral vasculopathy with Moya and 1 sepsis in aplasia). No veno-occlusive disease was observed, but hemorrhagic cystitis (n=4), EBV proliferative disease requiring anti-CD20 therapy (n=1), nephrotic syndrome (n=1), and cerebral vasculopathy not SCA-related (n=1) were. Despite preventive measures such as anticonvulsant prophylaxis, strict control of hypertension, swift magnesium replacement, and an increase in the red blood cell and platelet transfusion thresholds to 9 g/dL and 50,000/mm3, respectively, seizures and posterior leukoencephalopathy, albeit reversible, remained a particularly frequent adverse effect of CSA and steroid therapy. Replacing CSA in 2002 by mycophenolate mofetil in case of GvHD requiring steroid therapy resulted in a significant reduction of the rate of these complications. With a median follow-up of 3.1 years (range 0.2–15.5), the overall survival at 3 yr was 95% (95%CI:91-99%). Considering as events the non-engraftments, rejections and deaths, the event-free survival (EFS) was 92.9% (95%CI:88.3-97.5). However, comparing the results before (n=23) and after 2000 (n=121) showed significant improvement of EFS at 3 yr: 73.9% (95%CI: 55.5–92.3) for transplants performed before 2000 vs 96.8% (95%CI:93.2-100) after 2000.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.No relevant conflicts of interest to declare.

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).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.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)No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

In order to investigate the efficacy and the safety of imatinib in children and adolescents with untreated Philadelphia-positive CML, the CML working party of the Société Française des Cancers de l'enfant (SFCE) conducted an open label, multicentric phase IV study trial (Clinical Trials.gov.NCT00845221).Patients less than 18 yrs of age with newly diagnosed CP CML were eligible. Imatinib was administered orally at a dose of 260 mg/m2 which is equivalent in terms of drug exposure to the total dose of 400 mg in adults. Forty four children (64% boys) with a median age of 11.5 yrs (range 10 months-17 yrs) have been enrolled from 15 French pediatric centres between July 2004 and December 2008. Side effects were reported prospectively using the NIH CTCv2.0 criteria.Median follow up is currently 17 months (range:1-67). The complete hematologic response rate was 86% and 98% (ITT) at 3 months and 6 months, respectively. The rate of complete cytogenetic response (CCyR) was 62% (ITT) at 12 months. The rate of major molecular response (MMR) defined as a BCR-ABL/ABL ratio ≤ 0.1% according to the International Scale was 34% (ITT) at 12 months. The median daily dose of imatinib was close to the intended doses, 250 mg/m2 (range 176-405) with a median treatment duration of 16 months (2 w to 67 mo). Three pts (7%) had a dose reduction of more than 25% of the theoretic dose. Nine pts (20%) interrupted imatinib temporarily at least once for a median duration of dose interruption of 12 days (range 2-70). Ten pts (23%) discontinued imatinib. The reasons for discontinuation were the following: allogeneic HSCT in CCyR or MMR (2 pts) according to the investigator choice, adverse event (2 pts: muscle pain 1 pt, liver enzyme elevation 1 pt), disease progression or failure (6 pts: loss of CHR [L248V mutation] 1pt, loss of CCyR [L384M mutation] 1pt, no cytogenetic response 1 pt, no molecular response 1 pt, loss of MMR 2 pts). One of them (loss of hematologic response) transformed to blastic phase shortly after coming off study and died. Grade III or IV toxicity was recorded in 14 pts (32%). GradeIII-IV hematologic toxicity was recorded in 8 pts (18%) including neutropenia in 18% and thrombocytopenia in 5%. Nine pts (21%) developed grade III or IV non-hematologic toxicity: muscle pain (2.5%), arthralgia (5%), weight gain (13%), liver enzyme (GOT/GPT) increase (6.5%). Change of body height was observed during the first year of treatment with imatinib in the 22 pts with a sufficient follow-up: a significant decrease of height standard deviation scores (SDS) was observed with a median of the difference of -0.37 (range, -1.09 to +0.14)(p<0.0001) between the start of the treatment and 12 months later.Imatinib is efficient in children and adolescent with previously untreated CML in early chronic phase. However, we report for the first time, a negative impact of imatinib on the growth in a cohort of children and adolescents treated with imatinib.No relevant conflicts of interest to declare.

Primary induction failure or relapse in AML patients maintains a very poor prognosis despite the cytogenetic stratification and the introduction of new molecules. Nevertheless, allo-HSCT can improve the overall survival of some of these patients, although new strategies are needed especially in conditioning to allow a better outcome in this high risk population of patients.The aim of this analysis was to investigate the safety and efficacy of FLAMSA sequential regimen in patients with high-risk acute leukaemia and MDS, in a multicenter retrospective French study.We analyzed 79 patients, 44 males & 35 females with a median age of 55 years (19-69), there were 50 de novo acute leukaemias, 3 secondary leukaemias and 26 MDS, who underwent allo-HSCT after FLAMSA conditioning [fludarabine (30 mg/m2), high-dose AraC(2 g/m2), and amsacrine (100 mg/m2) from day -12 to -9 + cyclophosphamide (40 mg/kg with related donors, 60 mg/kg with unrelated or mismatched donors) on days -4 and -3, ATG 2.5mg/kg on days -4, -3, and -2 + TBI 4 Gy on day -5 (n=42) or Busilvex 3.2 mg/kg on days -4 & -5(n=37)] who were reported to the Societe Francaise Greffe de Moelle et de Therapie Cellulaire (SFGM-TC) registry. Thirteen patients had undergone previous HSCT (10 allogeneic and 3 autologous). The disease status at transplantation were: 19 (24%) of the patients in primary induction failure (PIF) or refractory disease, 14 (17,7%) in second relapse, 25 (32%) in early relapse, 8 (10%) in untreated disease and 13 (16.3%) in progressive disease. Thirty-four patients were transplanted from HLA identical siblings and 45 from unrelated donors. Sixty four grafts were PBSC, 5 bone marrow and 8 cord blood cells.After HSCT, 73 patients engrafted (6 non valuable early deaths) with a median time to neutrophil recovery of 16 days (8-41). There were 31 aGVHD (grade I: n=10, grade II: n=12, grade III: n=4 and grade IV: n=5) and 18 chronic GvHD (10 limited, 5 extensive and 3 unclassified). At the last follow-up, 32 patients are alive, after a median follow-up of 4.2 months, the probability of OS for the whole population at 2 years was 22.8% with 43.8% for untreated patients, 13.8% for patient in relapse, it was 47% for progressive and 23% for PIF patients. The univariate analysis showed a better significant OS according to 4 factors: disease status (untreated patients) (p= 0.04), kind of disease (p<0.001); HLA matching (p=0.03) and HSC source (PBSC) (p=0.004) without any significant impact of age, sex-matching, CMV matching, ABO matching, conditioning regimen (TBI or Busilvex) and interval between diagnosis and transplantation. The multivariate analysis using Cox regression model showed the significant impact of 2 factors on OS: kind of disease; HR=0.284 [0.09-093] (p=0.03) and minor ABO incompatibility HR=2.55 [0.99-6.61] (p=0.05). The cumulative incidence of relapse and TRM at 6 months, 1 & 2 years were: 33%, 39.2% & 40.5% and 20.2%, 21% & 21.5% respectively without any TRM in the untreated group. The multivariate analysis showed also the significant impact of disease status on TRM (p<0.001), and minor ABO incompatibility on relapse HR=5.35 [1.81-15-81] (p=0.002). The estimated cumulative incidence of death from leukaemia at 1 and 2 years from transplant was 62,7% (95% CI, 48,4%-73,1%) and 72,2% (95% CI, 57,3%-87,8%).Our study showed a total OS of 23% at 2 years with a better survival in the untreated patients (44%) and progressive patients (47%); a worse survival for the PIF and relapsed patients group (23% & 12% respectively). When comparing to the German study, we observed similar results regarding TRM and relapse incidence, the only difference was the leukemia mortality with a higher rate in our patients which could be explained with the different relapse treatment.No relevant conflicts of interest to declare.

This analysis concerned 164 allogeneic HSCT after standard (Std) or reduced intensity conditioning (RIC) using double cord blood cells (CBC), reported to the SFGM-TC registry. There were 57 females (F) and 107 males (M) with a median age of 39.5 years (18–66). The diagnosis pretransplant were acute leukaemia: 93 (56 AML and 37 ALL), MDS: 9, MPS: 9 (CML: 4), CLL: 5, NHL: 18, HD: 7, MM: 13, AA: 7, other diseases: 3 (2 inborn errors and 1 solid tumour). The median interval between diagnosis and HSCT was 20.6 months (2.6–385.5). Among 154 evaluated patients (pts), disease status prior conditioning were 92 CR (CR1: 45, CR 2: 34, >CR2: 12 and 1 non classified), 21 PR, 21 stable diseases (SD) (SD: 6, AA: 6, inborn errors: 2, CML in CP: 3, myelofibrosis: 2 and MDS: 2), 22 progressive diseases (PD) (PD: 4, relapses: 10 and refractory diseases: 8), 8 pts were not documented. Among 158 pts documented, 49 (31%) were completely sex matched and 109 (69%) sex mismatched [72 CBC1+2 (F+F or F+M) for a M recipient and 37 CBC1+2 (M+M or M+F) for a F recipient]. Among 158 documented, 42% of recipients, 37% of CBC1 and 38% of CBC2 were CMV+; there was a complete ABO compatibility between the 2 CBC and the recipient in 38 cases, 1 or 2 minor incompatibilities in 40 cases and almost 1 major incompatibility in 80 cases. For HLA matching, we distinguished 3 groups: group1 [n=78 (HLA compatibility at least 4/6 between recipient and CBC1+2) and between CB1 and CB2 including total HLA DRB1 matching)], group 2 [n=55 (HLA compatibility at least 4/6 between recipient and CBC1+2) considering neither HLA compatibility between CBC1-CBC2 nor HLA DRB1 matching)] and group3 [n=25 (all others)]. At harvesting, the median number of total nucleated cells (TNC) (x107/kg) was 4.67(1.6–12.2), the CD34+ (x105/kg) 1.8 (0.3–10.8), the CFU-GM (x104/kg) 3.67 (0.94–25), and after thawing 3.24(0.58–12), 1.4(0.2–9.2) and 2(0.27–16.4) respectively. The TNC threshold number was set to 5x107/kg because more than 96% of pts received more than 3x107/kg. Among 135 documented, 26 (19%) received Std conditioning and 109 (81%) RIC. After transplantation, 129 pts (96%) engrafted with 86% (80–92) of neutrophil recovery at day 60 with no significant difference according to TNC (<5x107/kg: 88%, ≥ 5 x107/kg: 90%; p=0.28) and HLA matching (group1: 86.6%, group2: 89.6% and group3: 83.3%; p=0.81). Eighty-four pts developed an AGVHD: gr I: 20 and ≥ gr II: 60 (35 gr II, 16 gr III and 4 grade IV), 4 patients were not classified. At day 90, the cumulative incidence of AGVHD grI was 10.4%(5–16), gr ≥ II: 42%(33–51)[grII: 24%(16.5–32), grIII-IV: 18%(11–25)]. Moreover, we observed for AGVHD gr ≥ II according to HLA typing and TNC: group1: 41%(28–54), group2: 46%(31–60) and group3: 33%(8–58); TNC<5x107/kg: 38%(25–51) and TNC>5.107/kg: 46%(32–60). Twenty-one pts presented a chronic GVHD (9 limited and 12 extensive) and the cumulative incidence at 1 year was 13.7%(4–24) for limited and 20%(9–21) for extensive. With a median follow-up of 7.3 months, the probability of 1-year and 2-year overall survival and disease-free survival were 49.6% (40–61.5) and 38% (27–54), 43% (33.5–54.5) and 36% (25–51) respectively. The probabilities of OS, NRM and RM according to TNC, disease status pre-transplant, HLA matching and sex matching are shown in Figure 1 and Table1.The multivariate analysis showed a significant impact of 2 factors on OS: disease status PD vs CR: HR=6.16 (1.87–20.25) (p=0.002); HLA matching group2 vs group1: HR=0.29 (0.11–0.82) (p=0.01), and 3 significant factors on DFS: sex-matched HR=0.29 (0.09–0.94) (p=0.03), sex-mismatched (F recipient) HR=0.15 (0.04–0.61) (p=0.008) and HLA matching (group 2 vs group1) HR=0.32(0.11–0.88) (p=0.02).A refined chimerism analysis is ongoing and will be presented. In conclusion, this large retrospective analysis showed that the quantitative objective of double cord blood use for allogeneic HSCT is achieved (only 4% had received < 3x107/kg TNC) with no further significant impact of TNC number on OS, NRM and RM. As usual in other types of allogeneic HSCT, we demonstrated the significant impact of disease status before transplantation on transplant outcome. Finally, the most interesting point was the better results observed in group 2 but which needs more precise analysis in the future. Table 1. Probability of OS, NRM, RM according to different variables. Probability of OS Probability of NRM Probability of RM Whole population (cummulative 1 year) 49.6%(40–61.5) 49.7%(39–60) 7.5%(2–17) TNC TNC < 5 × 107/kg 50%(36.6–68.5)) 47%(32–62) 8%(0–16) TNC ≥ 5 × 107/kg 44.5%(29.6–67) 56.5%(38.5–74.5) 9.5%(0–20) Disease status pre-transplant CR 51%(38–68) PR 54%(31–92.5) SD 75%(43–100) PD relapse 35.5%(18–70) HLA compatibility Group 1: 4/6 or more for all(2/2 for DRBI) 34%(21–54) 62%(46–78) 10%(3–20) Group 2: 4/6 or more for R-CB1 and R-CB2 61%(45–81) 39%(21–57) 2%(0–6) Group 3: Others 61.6%(42–90) 42.5%(19–66) 10%(0–24.5) Sex matching M recipient with sexmismatch 35%(22–57) 63%(46–79) 8%(2–14) Sexmatch 61%(45–82) 43%(23.5–63) 4.5%(0–13.5) F recipient with sexmismatch 54%(36.5–80)) 42%(24–62) 9%(0–22) Figure 1: Probability of OS according to different HLA groups Figure 1:. Probability of OS according to different HLA groups

The results of RIC allo-SCT for MM are still under considerable debate. While EBMT data did not support the universal use of RIC for MM allografts, the Italian and spanish randomized multicenter trials suggested that in newly diagnosed myeloma, outcome in recipients of a hematopoietic stem-cell autograft followed by RIC allo-SCT from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts. The aim of this multicenter retrospective national study was to identify prognostic factors for outcome of high-risk patients with MM after allo-SCT prepared by RIC. Data from 219 patients (median age 52 years, range 27–66), who received grafts from a sibling (n=197) or unrelated donor (n=22) were analyzed. At time of transplant, only 37 patients (17%) received RIC allo-SCT in CR or VGPR, while 134 patients (61%) were transplanted in PR. 48 patients were transplanted either in stable disease (n=15) or were in refractory/ progressive disease (n=33). All patients have received at least one autologous transplant prior to RIC allo-SCT. The graft source was PBSCs in the majority of patients (n=183). 21% of the patients received the Seattle Fludarabine and low dose TBI RIC regimen, while 53% of patients received Fludarabine, Busulfan and ATG. 32 patients (15%) died of transplant-related complications. The incidences of grade 2–4 acute GVHD and extensive chronic GVHD were 37% and 20% respectively. At 3 years, overall and progression free survivals (OS, PFS) were 41% (95%CI, 34–49) and 19% (95%CI, 14–27) respectively. Disease status (CR, PR, SD vs. progressive) was significantly associated with overall survival (P=0.0002). In multivariate analysis, disease status at time of RIC allo-SCT, was the strongest parameter associated with an improved OS and PFS (P=0.005 and P=0.004 respectively). Despite its obvious caveats, the relatively low TRM observed in this series, suggest that there is still space to investigate RIC allo-SCT for MM. However, RIC allo- SCT appears to result in a durable response only if it is applied early in the disease history, especially when patients are still chemosensitive. Since the latter results are also expected to be further improved with the systematic and early use of maintenance therapies (Bortezomib and/or Lenalidomide) after RIC allo-SCT, randomized or quasirandomized prospective studies are still warranted.

Purpose:Objective was to assess indication, feasibility and efficacy of double allograft with reduced intensity conditioning.

This report updates a retrospective study from SFGM-TC registry concerning 1108 patients who underwent allogeneic hematopoeitic stem cell transplantation (HSCT) after reduced intensity conditioning (RIC) from HLA identical siblings (84%) and unrelated donors (16%) for hematological malignancies. At time of conditioning, 442 patients were in CR, 337 in PR, 107 in stable disease (SD) and 222 in progressive disease (PD). As conditioning, 255 patients received fludarabine and TBI (2 grays), 465 patients fludarabine, busulfan and ATG and 388 patients an other regimen. After transplant, 336 patients (30%) developed an acute GVHD ≥ grade II (grade II: 178, III: 80 and IV: 78). A chronic GVHD was present in 388 patients (35%) (185 limited and 203 extensive). With a median follow-up of 30 months, the 3 and 5-year probability of overall survival (OS) were 43.5% (40–47) and 32%(29–35) respectively and the 3 and 5-year probability of event-free survival (EFS) were 35%(31–39) and 28% (24.5–31) respectively. The TRM at 1 year, 2 years and 3 years was 15% (13–17), 18% (15.5–21) and 20% (17–23). A mixture model, gfcure with Splus statistical package determined the percentages of long-term survivors and its adequacy was verified graphically. The probability to be a long-survivor was 24% (17.5–32.5) (Fig.1) and to be a long event-free survivor was 23% (19–28) (Fig. 2). The multivariate analysis has tested recipient and donor age, disease status pre-transplant, number of transplants before RICT, HSC source, sex matching, HLA matching, CMV status and ABO compatibility. The only factor which had a significant impact on long-term survival after RICT was the disease status just prior conditioning: PR versus CR: HR: 3.63 [1.14–9.18] p<0.001 and PD versus CR: HR: 4.35 [2.22–8.51] p<0.0001. In conclusion, these updated data demonstrate that allogeneic HSCT after RIC was able to possibly cure 23% of patients with haematological malignancies and the most important factor to take into account remains to be in CR pre-transplant. Figure 1 Figure 1. Figure 2 Figure 2.

Goal: Compare results after allogeneic HSCT for AML in CR1 in pediatric population after myeloablative conditioning regimen either based on TBI or busulfan. Patients and Methods: Retrospective analysis from French registry including all consecutive patients under 18 years of age (n=131) from Dec’1979 and Oct’2004 transplanted for AML in CR1 with either sibling (n=104) or matched unrelated donor and given either multi-fractionated TBI 12Gy and cyclophosphamide 120mg/kg (TBI-Cy) or Busulfan 16mg/kg and Cyclophosphamide 200mg/kg (BuCy200). Results were analysed according to EBMT statistical analysis guidelines i.e. OS and EFS were analyzed by KM method and Log-rank test for comparison where TRM and relapse incidence were analyzed by cumulative incidence method and Gray test for comparison. Multivariate analyses were performed using proportional hazard model for the distribution of competitive risks defined by Fine and Gray. Results: 131 patients (female: 51.5%) were included. Median age at initial diagnosis was 11y (0.5 to 17.8). Median time from diagnosis to transplantation was 4.2 months. Eighty-three patients received BuCy200 and 48 patients were transplanted after TBI-Cy. Patient subgroups were comparable for age, gender, sex mismatch, source of graft (BMT vs PBSC), donor type (geno-identical vs 10/10 matched unrelated donor vs other), cytogenetical analysis and WBC at initial diagnosis, and for donor-recipient CMV status (−/+ vs others). Both 5 year-overall and event-free survival rates appeared significantly better in BuCy200 group than in TBI-Cy group with 73.3% vs 56.1% (p=0.02) and 67+/−7% vs 38+/−9% (p=0.002), respectively. TRM incidence at day 365 was dramatically better in BuCy200 group than in TBI-Cy group with 4,7% vs 26.1% of TRM rate (p=0.002), respectively. Even though there were no statistical significant differences for both acute and chronic GVHD cumulative incidences whatever given conditioning regimen, there was a trend for obtaining lesser GVHD in BuCy200 group: day 100 grade II-IV aGVHD cumulative incidence was 13% vs 37% and 2 year extensive cGVHD was 9 vs 19% for BuCy200 and TBI-Cy group, respectively. At 5 years, there was a trend for less relapse in BuCy200 group than in TBI-Cy 16+/−3% vs 32+/−6% (p=0.09), respectively. Conclusion: This study demonstrates the superiority of BuCy200 on TBI-Cy conditioning regimen for paediatric patients presenting with AML in CR1 and undergoing allogeneic hematopoietic stem cell transplantation from either matched related or unrelated donor. These results, obtained from a larger cohort, confirm and update those published by our group in 1994. Figure 1: Overall survival Figure 1:. Overall survival

Isolated extramedullary relapse is diagnosed in 2 to 6% of children with acute lymphoblastic leukemia (ALL). It usually occurs in the CNS or the testis. Because the prophylaxis of extramedullary leukemia has increasingly become an important part of the first line treatment, the ability to achieve a sustained second remission is now complicated by drugs toxicities and resistances. It is already known that prognosis depends on duration of first complete remission (CR1).Here, we report on the efficiency of a combination of chemotherapy and radiotherapy for the treatment of extramedullary relapses. Furthermore, we specifically searched for prognosis factors of the Event Free Survival (EFS). Between May 1997 and December 2002, 68 children and adolescents up to 20 year-old with first isolated extramedullary relapse (group G3) of B-cell (non Burkitt) ALL were included in the prospective, stratified, and multicentric trial COPRALL-97 This trial had been designed for patients pretreated with an intensive frontline therapy (EORTC or FRALLE) without cranial radiotherapy except for 5 patients. Stratification criteria was time to relapse: CR1 of less than 24 months for group G3A (n=35), relapse beyond 24 months for group G3B (n=33). Treatment consisted of risk-adapted alternating short course multiagent chemotherapy through systemic (with good CSF penetration) and intrathecal ways and conventional maintenance therapy and irradiation (18 Gy). Stem cell transplantation (SCT) was performed if an HLA identical related donor was avalaible in group G3A. Sixty four of 68 eligible patients achieved a second complete remission. There were 45 CNS relapses, 22 testis relapses and one ovary relapse. In group G3A (33 CNS, 2 testis), 20 patients received chemotherapy only and 15 had SCT (12 HLA-identical sibling donor, 2 HLA-identical unrelated donor and one autologous. In group G3B, (12 CNS, 20 testis, 1 ovary), all patients but one (SCT not indicated) were treated by chemotherapy. EFS and overall survival (OS) for all registered patients at 8 years were 40% and 53% respectively. EFS at 8 years for patients of group G3A and G3B were respectively 26% and 51% (p=0,0071) while OS at 8 years were respectively 40% and 68% (p=0,065). Our analyses highlighted two independant risks factors predictive of decreased EFS: early relapse and age at the initial diagnosis above 6 years. All other factors studied (sex, site of relapse, immunophenotype, SCT) did not predicted outcome. Most of the second relapses involved bone marrow (n=11), CNS (n=6) or were combined (n=6). There were 6 toxic deaths.We conclude that more than half of the patients who were treated with COPRALL-97 therapy had long term survival. Time of relapse and age at initial diagnosis represent important factors that should be considered when adapting treatment intensity to individuals in future trials. Furthermore, as already reported by others, early CNS relapses have a bad prognosis and new therapeutic strategies are needed.

Shwachman Diamond syndrome (SDS) is a rare multi organ genetic disease bearing a very high risk of haematological complications i.e. MDS/leukaemia and Bone Marrow Failure. The aim of this study is to explore genotype predisposition of the major complications observed in SDS's patients and to explore prognosis factors of MDS/leukaemia.

We have previously reported that the incidence of acute graft-versus-host disease (GVHD) after myeloablative peripheral blood stem cell transplantation correlates more strongly with the blood donor CD34+ cell count after G-CSF mobilization than with the dose of CD34+ cells infused to the recipient (Dhedin et al. Exp Hematol 2006). The aim of this study was to confirm this finding in non myeloablative transplantation. We studied 92 patients transplanted with HLA-identical sibling donor after a conditioning regimen associating 2GY total body irradiation and fludarabine. The median blood donor CD34+ cell count on day 5 of G-CSF administration was 70/μl (range 9–210/μl). The median infused CD34+ and CD3+ cell doses per kilogram of recipient bodyweight were respectively 6.4 × 106 (range 1.3–22.6) and 275 × 106 (range 88–839). The cumulative incidence rates of grade II–IV aGVHD and grade III–IV aGVHD were respectively 34.4% (se=0.05) and 9.9% (se=0.03) on day 100. The cumulative incidence rates of all GVHD and extensive cGVHD at 24 months were respectively 60.5% (se=0.06) and 36.2% (se=0.06). Donor and recipient characteristics, the doses of infused CD34+ and CD3+ cells, and the donor CD34+ cell count after G-CSF mobilization were analyzed as potential risk factors for GVHD. No correlation was found between these parameters and the occurrence of acute GVHD. As in several previous studies, the CD34+ cell dose tended to influence the incidence of extensive cGVHD, but the correlation was not statistically significant (p=0.14). In contrast, the blood donor mobilized CD34+ cell count, divided into quartiles, was the only factor significantly associated with extensive chronic GVHD: In univariate analysis, the incidence of extensive cGVHD was significantly higher in the quartile of patients (N=24) whose donors had the highest mobilized CD34+ cell counts (quartile n°4: >109 CD34+ cells/ml at day 5 of G-CSF mobilization), compared to the three other quartiles (cumulative incidence of extensive cGVHD in quartile n°4 was 58.9% compared to respectively 20.8, 37.5 and 25% in the third, second and first quartiles (p=0.03)). In multivariate analysis, the donor CD34+ cell count was the only variable associated with the risk of extensive cGVHD: the hazard ratio associated with the highest quartile was 2.59 (95% CI [1.30–5.18], p=0.007).In conclusion, we confirm in non myeloablative transplants, that donor response to G-CSF is a better prognosis factor of GVHD, than the dose of CD34+ cell infused. “Outstanding mobilizers” seemed to have greater alloreactive potential. These findings do not support limiting the dose of CD34+ cells infused to prevent GVHD. They have also direct implications for transplant management, and especially for the modalities of GVHD prophylaxis.

Reduced-intensity conditioning regimens (RIC) had become a classical strategy of allogeneic hematopoietic stem cell transplantation (HSCT) and many patients are now transplanted with unrelated donor. The aim of this restrospective study was to evaluate the impact of HLA mismatches between donor (D) and recipient (R) at the allelic level on survival after RIC. We analyzed 103 patients registered in France from Jan 1999 to Dec 2003 with a median age of 46 years (18–67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. Anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The main source of stem cells was PBSC (n=65). Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The results showed that 96% of patients engrafted. Acute GVHD grade II to IV and grade III/IV occurred in 46% and 19% of patients, respectively. The risk of developing cGvHD was 45% at 2 years. Overall survival (OS) was 42% at five years. Among the 47 patients alive, the median disease free survival (DFS) was 28 months. Among non-HLA parameters studied, the only factor associated with a good OS was the diagnosis of lymphoid disease (HD or NHL or CLL) (p=0.003). Recipient age <46y was only associated with less acute GvHD grade II to IV (p=0.008). Among HLA mismatches, we found that HLA-A and/or -B allelic mismatches had a negative impact on OS (p=0.006), DFS (p=0.006), acute GvHD grade II to IV (p=0.05). On the other hand, HLA-C or -DQB1 mismatches did not impact on OS, DFS, acute or chronic GvHD. We could not analyze DRB1 mismatch since there was only 2 patients reported. In conclusion, HSCT following RIC, with match or mismatch unrelated donors, is a feasible approach with best results observed for patients with lymphoid malignancies (NHL, CLL or HD). Among allelic HLA mismatches, HLA-A and/or -B seemed to be deleterious as compared to HLA-C or DQB1. These results help to identify most suitable donors and patients who are likely to benefit from RIC with unrelated donors when there is not a fully HLA match donor available.

We aimed to determine whether outcome of HSCT from an unrelated donor has improved over time for patients with severe acquired aplastic anemia (SAA) and, if so, to determine whether improvement resulted from changes in patient selection, changes in transplantation technique, or both. We thus analyzed the outcome of 89 patients (median age 17 years, range 0–52) who received such transplantations between 1989 and 2004. We compared two cohorts of patients transplanted within two successive time-periods (1989–1998 and 1999–2004) associated with probabilities (± 95% confidence interval) of 5-year survival significantly different: 29% ± 7% and 50% ± 7%, respectively (P<.01, Figure 1). Significant differences between the two cohorts concerned transplant-related, but not patient- and disease-related variables: the use of ATG and of fludarabine within conditioning and HLA matching at the allelic level for the 10 HLA-A, -B, -C, -DRB1 and -DQB1 loci (P=.0004) were more frequent in the recent 1999–2004 period. In multivariate analysis, the only 2 factors influencing survival were HLA allelic matching (P<.01) and younger age of recipient (<17 years, P<.0001). Of note, the impact of HLA matching disappeared in multivariate analysis when it was considered at the antigenic level for HLA-A, -B and -DR antigens, which underlines the importance of considering HLA matching at the allelic rather than the generic level for these transplantations. Survival reached 78% ± 11% at 5-year for the younger patients fully HLA-matched (n=14), which can be compared with survivals obtained for HLA-identical sibling transplants in similar young patients. Cumulative incidences of graft failure, grade II–IV or grade III–IV acute GVHD, and chronic GVHD were: 14% ± 4 % at 2 years, 50% ± 5 % and 24% ± 4 % at 100 days, and 28% ± 5 % at 2 years after HSCT (limited: 17% ± 4 %, extensive: 11% ± 3 %), respectively. In a competing risk analysis, allelic HLA matching - particularly incorporating HLA-C but not -DQB1 matching - but also a high cell-dose injected (> 2,6.108/kg nucleated cells, the median value of the cohort) and the use of fludarabine and/or ATG in the conditioning regimen were found as protective against graft failure and acute GVHD, respectively. Our results suggest that survival after unrelated transplantation for SAA has improved over the past 15 years, due to a better HLA matching at the allelic level for both HLA class I and class II antigens, but also to other transplant-related factors. Figure 1 Figure 1.

Despite progress in their primary therapy, nearly half of patients (PTS) with DLCL will either relapse or fail to archieve a remission. Autologous transplantation may salvage those PTS with chemosensitive disease. However, PTS with high-risk disease or relapsing after autologous transplantation have a particularly poor prognosis. AlloSCT with RIC offers the advantage of a decreased transplant-related mortality combined with a Graft-versus-Lymphoma effect explaining its increasing use in PTS who fail standard therapy. We retrospectively analyzed all PTS with DLCL reported to the SFGM-TC registry, who underwent alloSCT after RIC. 51 PTS (median age 42 years, range 22 to 64 years) were transplanted from Oct. 2002 to Oct. 2004. 23% of PTS had received > 2 lines of prior therapy and 78% had relapsed after autologous transplantation. For 22% of PTS, alloSCT was the first graft. Median time from diagnosis to alloSCT was 33 months (6–126). Disease status at time of alloSCT was: complete remission (CR) n=22, partial remission (PR) n=18, stable disease (SD) n=2, progressive disease (PD) n=7. RIC consisted of fludarabine + busulfan in 27 PTS, fludarabine + total body irradiation in 10, fludarabine + cyclophosphamide in 7 and miscellaneous combinations in 7. GVHD prophylaxis consisted of cyclosporin A (CyA) alone in 18 PTS, CyA/methotrexate in 14 PTS, CyA/mycophenolate mofetil in 14 PTS and other immunosuppressive drugs in 5 PTS. 31 PTS received antithymocyte globulin. Stem cell source was peripheral blood stem cells in 43 PTS and bone marrow in 8. 47 donors were HLA-matched siblings, 4 were unrelated (3 donors HLA-matched and 1 donor with 1 HLA antigen mismatch). Median follow-up after alloSCT was 12 months (0–72). All PTS engrafted except one who died early after transplantation. Grade II to IV acute GVHD occurred in 16 PTS and extensive chronic GVHD in 8/43 valuable PTS. Non relapse mortality was 21% (multi-organ failure : 3, acute GVHD : 1, chronic GvHD : 1, interstitial pneumonia : 1, infection : 4, neurological complication : 1, unknown origin : 1). 20 PTS progressed after a median follow-up of 4.5 months (0–29) and 10 PTS died of progressive DLCL. 23 PTS remain alive and disease-free at a median follow-up of 17 months (1–72). Overall survival is 48% at 22 months. We observe a trend for better survival without statistical significance in PTS who received alloSCT as first graft compared to >1 graft. In PTS in CR or PR prior to transplantation, Kaplan-Meier analysis demonstrates a nearly significant trend for better survival compared to non-responders (55 vs. 28%, p=0,09), but it has to be noted that 3 of 7 PTS transplanted with PD are still alive. RIC followed by alloSCT seems to be feasible even in heavily pretreated PTS and offers the perspective of long lasting remission. Further prospective studies with RIC and alloSCT earlier in the disease course or in defined high-risk PTS in first relapse as an alternative to autologous transplantation should be undertaken.

Background: In children busulfan (Bu) is often included in conditioning regimens prior to allogeneic (allo-) haematopoietic stem cell transplantation (HSCT). The IV Bu formulation represents a substantial improvement over the oral Bu form for the control of Bu-systemic drug exposure (AUCs) and for successful targeting, but the age-based dosing (3–4 years cut-off) is not likely to be the optimal strategy (L Nguyen et BMT 2004). We tested IVBu fixed dose body-weight (BW) based calculation combined with cyclophosphamide (Cy) as conditioning regimen prior to allo-HSCT. Aims: To validate and confirm the PK relevance of this new dosing strategy which allows to target AUC (900–1500 µM.min) in children, To investigate the safety especially the early non-relapse mortality (NRM), to evaluate the consequences of such IVBu administration modalities upon children clinical outcomes. Methods: Thirty-six children (21 male/15 female) with a median age and weight of 7.5 y (range 0.3 to 17.2 y) and 27 kg (range 5.0 to 62.0) were enrolled. Indications for HSCT were: AML (n = 17: 14 CR1, 2 CR2, 1 PR), CML (n = 3), ALL (n = 1), MDS (n = 1), SAA (n = 1); hemoglobinopathy (n = 8), and immunodeficiency (n = 5). IVBu (Busilvex®) was given over 2 h q6h × 16 doses at: 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts with <9 kg, 9 to <16 kg, 16–23 kg, >23–34 kg, and >34 kg BW, respectively. Cy was given at 50 mg/kg qd×4. Donors were HLA-matched related (28/36) or unrelated (5/36). Pharmacokinetics (PK) of Bu at dose 1, 9, and 13, and regimen-related toxicity (RRT) were determined. Cumulative incidence (Ci) of relapse / NRM, and Kaplan-Meier EFS/OS were estimated. Results: PK results are available in 28/36 pts. Although Bu clearance was highly variable (CV= 45%), the average AUCs after 1st and subsequent doses were similar whatever age and BW. In 75 % of pts AUC was within the target AUC. Mean AUC at dose 1 was 1205 ± 187 µM.min (range 963–1619 µM.min). All pts engrafted at 19 days (range 9–47) for neutrophils = 0.5 ×109/L, and 30 days (range 16–111) for platelets = 50 ×109/L. Donor cells (DC) were documented in all recipients: 31/36 achieved complete chimerism (> 99% DC), and 5/36 were mixed chimeras (> 85% DC). IVBu was well tolerated: one grade (G) IV toxicity (pulmonary), G III (mainly stomatitis) occurred in 14 pts. VOD occurred in 8% (95% CI: 1.8–22.5%) but none was severe. Grades II–IV a-GVHD rate was 42%. There was one death (3%) at day+100, and Ci of NRM was 6% ±8% (hemorrhage =1, c-GVHD =1). After a median follow-up of 36.7 months (range 3.9–49.1) the Ci of relapse, EFS and OS rates were: 12% ±11%, 82% ±13%, and 85% ±12%, respectively. For pts with malignancies (mainly AML) the results are excellent: neither VOD nor NRM, and EFS and OS rates were 82% ±16%, and 86% ±14%, respectively. Conclusions: The new IVBu dosing optimises Bu treatment, confirming that IVBuCy is an efficacious, reduced-toxicity, myeloablative conditioning regimen for children undergoing standard HSCT.

Rational: HSCT is widely used as treatment of poor-risk pediatric hematological malignancies from 80’s. Many different TBI or busulfan based conditioning regimen have been developed. Although many studies have compared TBI vs busulfan, few studies were available for evaluating different TBI based regimen. Methods: In order to compare efficacy, safety and toxicity of these different TBI based regimen, we realized retrospective study regarding HSCT in pts under 18 years of age from French HSCT registry from 1985 to 2004. P value under 0.05 was considered as statistically significant. Results: A total of 702 pts were transplanted during this period using 26 different TBI based conditioning regimen but just 4 of them included more than 30 patients: TBI+Cyclophosphamide (R1, n=305), TBI+Cytarabine+Melphalan (R2, n=249), TBI+VP16 (R3, n=35) or TBI+Cyclophosphamide+VP16 (R4, n=30). We exposed here the results of 554 pts given either R1 or R2. Main characteristics and results are summarized in table. Engraftment rates were similar in R1 and R2. Ten years OS was significantly better for R1 vs R2 (57.8+/−4.1% vs 48.8+/−4%, P=0.0008). There were no significant differences for both conditioning regimen regarding the risk of relapse (R1: 35.8+/−3.9% vs R2: 27.6+/−3.9%), the risk of grade III and IV aGVHD (R1: 16.7+/−2.2% vs R2: 20.01+/−2.6%) and the risk of cGVHD (R1: 26.9+/−3.2% vs R2: 32.4+/−5.2%). TRM at 10 years was significantly worse for R2 vs R1 (33+/−3.3% vs 22.8+/−2.8%, P=0.004). The results obtained with TBI+VP16 were similar than those with TBI+Cy where the results from TBI+VP16+Cy were closed to those from TBI+Arac+Melphalan (data not shown). Discussion and Conclusion: Too many different TBI based conditioning regimen were used. In order to standardize procedures among transplant centers, we would like identify a gold standard. In our study, TBI + Cy appears safer than TBI+Cytarabine+Melphalan as conditioning regimen for pediatric hematological malignancies since OS and TRM were better although same relapse and GVHD rates were obtained. Main characteristics TBI + Cy (n=305) TBI+Arac+MEL (n=249) TBI: total body irradiation; Cy: cyclophosphamide; Arac: cytarabine; MEL: melphalan % of male 56 62 Median age at diagnosis (years) 11 (0–17.7) 5 (0.8–17.1) Median age at graft (years) 12.5 (0.4–18) 8.5 (1.9–17.8) Median time from diagnosis to graft (months) 8 (2–173.3) 24 (3–151) Diagnosis ALL low risk/high risk 139(46%)/17(6%) 191(77%)/30 (12%) AML low risk/high risk 46(15%)/43(14%) 3(1.2%)/7(2.8%) MDS 12 (4%) 4 (1.6%) CML chronic phase/other (%) 28(9%)/5(1.6%) 2(0.8%)/1(0.4%) Source of Stem Cells Bone marrow 222 (73%) 221 (89%) Peripheral blood 22 (7.3%) 5 (2%) Cord blood 60 (20%) 19 (7.6%) Sibling 145 (47%) 125 (50%) Unrelated 156 (51%) 102 (41%) Matched/Mismatched 69/31% 75/24% Median follow-up (months) 19.8 (0.7–229.5) 13 (0.2–210.9)

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.

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 followed by allogeneic SCT have demonstrated to induce complete donor chimerism and long-term survival with decreased transplant-related mortality in adults with poor-risk hematological malignancies. Pediatric experience of RIC regimens is mostly reported in children with non malignant diseases in whom late long-term complications should be reduced. There are only limited data in children with malignancies, ineligible for conventional SCT. We conducted a retrospective survey of 28 children who underwent a RIC regimen for a malignant hematological disease (18 AL, 2 RAEBt, 1 CML, 3 NHL, 2 HD) or a solid tumor (1 Ewing sarcoma, 1 rhabdomyosarcoma) from 1998 to 2004 in 11 participating hospitals. All children had contraindications against myeloablative regimen. Median age was 14 years. Fourteen patients (pts) had an advanced disease (> CR2, refractory or progressive).Ten pts had already undergone at least one transplantation. Most RIC were fludarabine-based (n= 26). Nineteen children received additional anti-thymocyte globulin and 4 were transplanted with a T-depleted graft. Source of hematopoietic stem cell was marrow (n= 17), peripheral blood (n= 9) or cord blood (n= 2). Donor was matched related (n= 12) or unrelated (n= 8), mismatched related (n= 2) or unrelated (n= 6). Median follow-up after SCT is 142 days (range: 22–2345). Engraftment was observed in all 25 valuable pts. Day-90 chimerism analysis was performed in 18 pts and showed complete donor cells in 12 and autologous reconstitution in 3 pts. Grade II–IV aGVHD and cGVHD developed in 8/25 and 3/16 valuable pts, respectively. The day-100 transplant-related mortality rate was 18%. Disease progression or relapse occurred in 13 pts. Nineteen pts died: 11 from initial disease, 2 from infection, 2 from GVHD, 4 from other toxic complication. Four pts underwent a second transplantation for relapse or autologous reconstitution (3 myeloablative, 1RIC SCT). Five pts are alive in CR 145, 336, 782, 993, 2345 days after a first transplantation, 2 pts 272 and 1062 days after a second transplantation. Only 1 child among the 14 with an advanced disease is alive versus 6 among those with a lower-risk disease. In conclusion, allogeneic SCT with RIC is feasible in heavily pre-treated children. In order to reduce the high incidence of relapse, further prospective studies are needed to determine best pts selection criteria (initial diagnosis, treatment prior to transplant, chemosensitivity of the disease) and the best transplantation strategy (timing, type of the RIC, post-transplant additional treatment).

Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

Metoclopramide has been shown to be a potential new therapeutic approach for Diamond-Blackfan anemia (DBA) affected individuals and has been hypothetized to stimulate erythropoiesisis through the induction of prolactin release. Among 15 transfusion-dependent patients enrolled in a previous pilot study, 9 completed 16 weeks of treatment, 3 of whom reaching a complete and sustained response (Abkowitz et al, Blood 2002). In order to further assess the drug efficacy we performed a prospective study in patients included in the French DBA registry. Patients over 2 years of age and dependent on regular transfusions were randomized at inclusion either to be treated immediately after a transfusion (Arm B), or 6 weeks later (Arm A), the comparison of these 2 groups aiming to provide a more accurate determination in the delay of response. All patients were prescribed metoclopramide for 16 or 22 weeks: 10 mg x 3/d in adults and 0.2 mg/kg x 3/d in children (weight < 50 kg). Packed Red Blood Cell transfusions were prescribed for hemoglobin values < 80g/L. The definition of response relied on Hb levels, reticulocyte counts, and the intervals between transfusions. Prolactin as well as other hormones levels were assessed. The study was initiated in October 2003. 7 adults and 22 children have been included so far (13F, 16M): 17 in A and 16 in B arms, respectively; 4 additional pts are planned to be included within a month. The treatment had to be prematurely discontinued in 2 pts because of severe side effects: nervous breakdown (8w of treatment) and anaphylaxis (14w of treatment). Other side effects were mild. Most patients complained of asthenia and drowsiness which both decreased after the 1st weeks of treatment; amenorrhoea (2 pts) and bulimia (3 pts) were also observed. No increase in transfusion need occurred. An update of the trial was performed on August 1st: at that time 21 pts had completed at least 16w of treatment. None of them experienced a complete response, as defined by a transfusion independence. In two a partial response, as defined by an increase in the transfusion interval was obtained: In one patient it evolved from 3–4 to 8 w, and in the other from 6–8 to 10–11w. Both are still on treatment. Lastly, it has to be emphasized that the 2 French responder patients previously included in the pilot study are still transfusion independent more than 5 yr after the initiation of metoclopramide treatment. CONCLUSION: metoclopramide may be of interest in some DBA affected individuals, even though we only obtained a low rate of partial responses in the present ongoing trial. We believe that this non toxic, and low cost treatment warrants to be tested in all patients with regular transfusion need or requiring high dose steroids. The duration of response and long term tolerance remain to be determined. Acknowledgments: Maria Daniela Arturi Foundation, DBA foundation and Assistance Publique-Hôpitaux de Paris (DRRC)

Antifungal therapy is appropriate in neutropenic patients who have unexplained persistent fever, despite receipt of few days of antibacterial therapy. Conventional or liposomal amphotericin B are the preferred agents in this situation for allografted patients but toxicity or interaction with other drugs could limit their prescription. Caspofungin, the first inhibitor of fungal cell wall glucan synthesis, is the only echinocandin approved by the FDA for treatment of candidiasis. In case of suspected or documented aspergillosis infection, caspofungin is generally reserved to patients who failed to respond to amphotericin B or voriconazole. Recently, Walsh et al (ICAAC 2003) demonstrated in a randomised trial that caspofungin was comparable to liposomal amphotericine B in overall success as empirical antifungal therapy of persistently febrile neutropenic patients and was better tolerated. Here, we report our experience of caspofungin as preventive and empirical anti-fungal treatment, between November 2002 and May 2003, in 19 allografted patients with neutropenia (< 500/mm3 neutrophils) ± persistent fever despite at least 4 days of appropriate antibacterial therapy (n=12). There were 15 adult and 4 children, 11 male and 8 female. Median age was 33 years (range: 3–57). There were 6 ALL, 5 AML, 1 Myelodysplasia, 1 CML, 1 Hodgkin disease, 1 NHL, 1 myeloma, 1 aplastic anemia, 1 carcinoma and 1 Ewing sarcoma. A myeloablative conditioning regimen was used in 14 patients consisting of total body irradiation (TBI) plus high-dose chemotherapy in 9 patients and busulfan plus cyclophosphamide in 5 patients. A non myeloablative conditioning regimen was used in 5 patients. For graft-versus-host disease prophylaxis, the regimen was cyclosporin plus methotrexate in 13 patients or ATG in 6 patients. Nine patients received a bone marrow graft, 9 received granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem-cells and 1 received an unrelated cord blood transplant. Twelve/19 patients have received prophylaxis with fluconazole from day 0 of the graft. Patients received caspofungin at an initial dose of 70 mg then 50 mg per day. Caspofungin was initiated within a median of 10 days after allograft (range: 0–174) including 7 patients receiving preventive caspofungin treatment at the date of aplasia. The mean duration of caspofungin therapy was 16 days (range: 3–72). Caspofungin was well tolerated and not stopped because of toxicity: WHO grade 1 and 2 hepatotoxicity occurred in 5 patients including 3 with previous hepatic abnormalities, WHO grade 1 and 2 nephrotoxicity occurred in 6 patients. No infusion reaction was observed. Only one patient developed a probable invasive bronchopulmonary aspergillosis on day 30 while receiving caspofungin. Seventeen/19 (89%) patients remain alive at least 7 days after the end of caspofungin administration without documented or suspected fungal, bacterial, or viral infection. Resolution of fever occurred in 11/12 febrile neutropenic patients in a median of 2 days (range:2–13) after starting caspofungin. We conclude that caspofungin is safe and effective as preventive and empirical antifungal treatment of neutropenic allografted patients.

Diamond-Blackfan anemia (DBA) is a constitutional disease characterized by a specific maturation defect in cells of erythroid lineage. We have assembled a registry of 229 DBA patients, which includes 151 patients from France, 70 from Germany, and eight from other countries. Presence of malformations was significantly and independently associated with familial history of DBA, short stature at presentation (before any steroid therapy), and absence of hypotrophy at birth. Two hundred twenty-two patients were available for long-term follow-up analysis (median, 111.5 mo). Of these individuals, 62.6% initially responded to steroid therapy. Initial steroid responsiveness was found significantly and independently associated with older age at presentation, familial history of DBA, and a normal platelet count at the time of diagnosis. Severe evolution of the disease (transfusion dependence or death) was significantly and independently associated with a younger age at presentation and with a history of premature birth. In contrast, patients with a familial history of the disease experienced a better outcome. Outcome analysis revealed the benefit of reassessing steroid responsiveness during the course of the disease for initially nonresponsive patients. Bone marrow transplantation was successful in 11/13 cases; HLA typing of probands and siblings should be performed early if patients are transfusion dependent, and cord blood should be preserved. Incidence of DBA (assessed for France over a 13-y period) is 7.3 cases per million live births without effect of seasonality on incidence of the disease or on malformative status. Similarly, no parental imprinting effect or anticipation phenomenon could be documented in families with dominant inheritance.

Long-term effects of BMT during childhood are still to be defined according to the type of BMT (ALLO BMT versus AUTO BMT), the type of preparation regimens (Total Body Irradiation: TBI. Total Lymphoid Irradiation:TLI) and the possible Graft vs Host Disease (GVH). 32 patients (21 B, 11 G) have been followed up for at least one year after transplantation (Leukaemia:21, Lymphoma:3, Tumors:3, Aplastic aneamia:2, Metabolic:3). 11 have been previously given cerebral irradiation (CR). Age at the BMT was 6.7 y (0.4-13.5 y). 20 received ALLO BMT and 12 AUTO BMT. Auxological evaluation was performed at 1 year for all, at 2 in 21 and at 3 in 8. Results are summarized in the table (in SOS according to SEMPE)*181 given in 6 or more fractions in 21Height loss was quite similar among patients given TBI, even in the absence of CR. The only regimen leading to normal growth was AUTO BMT without TBI. Our data support a deleterious effect of TBI, even if fractionated, in association with ALLO BMT. The reduction in velocity was not correlated with GH secretion (pharmacological and nocturnal) or thyroid abnormalities. A direct effect of either TBI or GVH on cartilage is likely to explain these results.