Antithymocyte globulins and chronic graft-vs-host disease after myeloablative allogeneic stem cell transplantation from HLA-matched unrelated donors: a report from the Sociéte Française de Greffe de Moelle et de Thérapie Cellulaire.

This retrospective report assessed the impact of rabbit antithymocyte globulins (ATG), incorporated within a standard myeloablative conditioning regimen prior to allogeneic stem cell transplantation (allo-SCT) using human leukocyte antigen-matched unrelated donors (HLA-MUD), on the incidence of acute and chronic graft-vs-host disease (GVHD). In this series of leukemia patients, 120 patients (70%) did not receive ATG ('no-ATG' group), whereas 51 patients received ATG ('ATG' group). With a median follow-up of 30.3 months, the cumulative incidence of grade 3-4 acute GVHD was 36% in the no-ATG group and 20% in the ATG group (P = 0.11). The cumulative incidence of extensive chronic GVHD was significantly lower in the ATG group as compared to the no-ATG group (4 vs 32%, respectively; P = 0.0017). In multivariate analysis, the absence of use of ATG was the strongest parameter associated with an increased risk of extensive chronic GVHD (relative risk) = 7.14, 95% CI: 1.7-33.3, P = 0.008). At 2 years, the probability of nonrelapse mortality, relapse, overall and leukemia-free survivals was not significantly different between the no-ATG and ATG groups. We conclude that the addition of ATG to GVHD prophylaxis resulted in decreased incidence of extensive chronic GVHD without an increase in relapse or nonrelapse mortality, and without compromising survival after myeloablative allo-SCT from HLA-MUD.

Bone markers after total body irradiation in childhood.

Total body irradiation (TBI) can cause short stature because of decreased growth hormone (GH) and skeletal abnormalities. To evaluate the plasma concentrations of markers of bone formation (osteocalcin and procollagen type 1 amino-terminal propeptide, P1NP) and resorption (carboxy-terminal telopeptide, CTX), in patients (n=65) who had been given TBI at 6.6+/-0.4 years were evaluated at 9.8+/-0.4 years. Patients given single 10 Gy or fractionated 12 Gy TBI had similar characteristics, except that plasma insulin-like growth factor (IGF-1) was lower in those given a single 10 Gy. Seven had lower osteocalcin and two had higher CTX than controls. Bone markers (as zs) were positively correlated (osteocalcin with P1NP, rho=0.42, P=0.0007; osteocalcin with CTX, rho=0.3, P<0.02), but not P1NP with CTX. Plasma osteocalcin and CTX were also positively correlated with plasma IGF-1, but not with growth rate during the first year on GH (n=28). Adult height was -2.5+/-0.2 s.d.s. (n=49). Those irradiated when young (P=0.0002) or given single TBI lost more height between TBI and adult height. Most TBI patients had normal bone formation and resorption markers. Thus, impaired bone turnover is probably not the cause of their short stature and poor response to GH.

Prospective validation of a novel IV busulfan fixed dosing for paediatric patients to improve therapeutic AUC targeting without drug monitoring.

INTRODUCTION: Oral busulfan clearance is age-dependent and children experience a wide variability in plasma exposure. BSA- or age-based dosing is used with therapeutic drug monitoring (TDM) to reduce this variability. PURPOSE: A new intravenous (IV) dosing of busulfan (Bu) based on body weight, designed to improve AUC targeting without TDM and dose-adjustment, was prospectively evaluated. METHOD: Bu was administered as a 2 h IV infusion every 6 h over 4 days (16 administrations). Five dose levels were defined on body weight as follows: 1.0 mg/kg for <9 kg; 1.2 mg/kg for 9 to <16 kg; 1.1 mg/kg for 16-23 kg; 0.95 mg/kg for >23-34 kg; 0.80 mg/kg for >34 kg. Bu treatment was followed by Cyclophosphamide or Melphalan prior to allogeneic or autologous transplantation in 55 children aged 0.3-17.2 years (median 5.6 years). RESULTS: No difference in AUC values was observed between weight strata (mean +/- SD 1248 +/- 205 micromol.min), whereas a significant difference in Bu clearance was demonstrated. This new dosing enabled to achieve a mean exposure comparable to that in adults. At dose 1, 91% of patients achieved the targeted AUC range (900-1500 micromol.min) while no patients were underexposed. At doses 9 and 13, over 75% of patients remained within that target whilst most of the others were slightly above. Successful engraftment was achieved in all patients. In conclusion, from infants to adults this new dosing enabled, without TDM and dose adjustment, to successfully target a therapeutic AUC window.

[Corneal graft activity in France (1990-2005): decreasing the gap between supply and demand]. / Activité de greffe de cornée en France (1990-2005): vers une stabilisation de la demande et de l'offre.

OBJECTIVE: To evaluate changes in the balance between supply and demand for corneal grafts over the last 15 years in France in the light of the measures implemented and the 2005 national and regional audit. MATERIALS AND METHODS: Corneal transplantation activities were estimated, mainly from a national prospective survey of ophthalmologists (1991-1994), annual surveys of ophthalmologists (1995-2000), tissue banks (1996-2005), and the national waiting list for surgery (since 2000). RESULTS: In 2005, the main indicators available were consistent with a stabilization in the number of candidates added to the waiting list every year (4606 in 2005), accompanied by a large increase in the number of grafts procured (9264 in 2005). There was also a substantial increase in quality testing of these grafts, leading to a high rate of rejection (49.5% of the procured grafts). In addition, the number of grafts exported decreased to a very low level (213 in 2005). The percentage of malades registered on the waiting list who received grafts in the same year also increased (68.5% in 2005). Once the waiting list had been updated, 3016 malades remained on the list at the beginning of July 2006. The gap between supply and demand for corneal transplantation has therefore narrowed. Two actions made particularly large contributions to these changes: the creation in 2000 of 120 full-time staff positions in hospital coordination teams, which has had a major impact on procurement rates; and the organization of the tissue bank sector, making it possible to guarantee the quality and distribution of grafts. CONCLUSION: Corneal procurement and transplantation activities seem to have reached equilibrium in France. A reliable estimation of demand, particularly at the regional level, has led the French agency in charge of tissue transplantation to modify the functioning of the national corneal transplant waiting list, with tissue banks now allowed access to declare transfers and the temporary registration of malades on the list to limit stagnation.

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

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

Combined inhaled steroids and bronchodilatators in obstructive airway disease after allogeneic stem cell transplantation.

Bronchiolitis obliterans (BO) is a potentially life-threatening complication following allogeneic stem cell transplantation (SCT) and usually carries a poor prognosis. Immunosuppressive medications are the main treatment, but are rarely effective, especially when the disease is severe. Thus, both early detection and alternative therapeutic approaches of post SCT BO are needed. We report our experience with Budesonide/Formoterol, an inhaled steroid and long-acting bronchodilatator combination, in a group of patients with mild to moderately severe BO after SCT whose systemic immunosuppressive treatment had not been modified. Thirteen patients were treated. The diagnosis of BO was based on the presence of respiratory symptoms and air-trapping on expiratory lung high-resolution computed tomography in all patients, associated with irreversible airflow obstruction in seven cases. The median follow-up was 12.8 months (range: 5-29 months). All patients improved clinically, and both forced expiratory volume in 1 (FEV(1)) and mean expiratory flow values increased significantly during follow-up (534+/-268 ml in absolute values and 36+/-27% compared to pretreatment values for FEV(1); P<0.02). These encouraging results provide new insights in the therapeutic approach of BO after SCT and require confirmation in a larger group of patients with a longer follow-up.

Final height and gonad function after total body irradiation during childhood.

Short stature and gonad failure can be a side effect of total body irradiation (TBI). The purpose of the study was to evaluate the factors influencing final height and gonad function after TBI. Fifty young adults given TBI during childhood were included. Twenty-seven had been treated with growth hormone (GH). Those given single 10 Grays (Gy) or fractionated 12 Gy TBI had similar characteristics, GH peaks, final heights and gonad function. After the end of GH treatment, 11/20 patients evaluated had GH peak >10 microg/l. Final height was <-2s.d. in 29 (58%). The height loss between TBI and final height (2.4+/-1.1 s.d.) was greater in those who were younger when irradiated (P<0.0001). When the GH-treated and -untreated patients were analyzed separately, this loss was correlated with the age at TBI at 4-8 years for the GH-treated and at 6-8 years for the untreated. Boys showed negative correlations between testicular volume and plasma follicle-stimulating hormone (FSH, P=0.0008) and between plasma FSH and inhibin B (P=0.005) concentrations. We concluded that the indications for GH treatment should be mainly based on the age at irradiation, taking into account the GH peak. The plasma FSH and inhibin B concentrations may predict sperm function.

[Ethics of stem cell donation in Europe]. / L'éthique du don de cellules souches hématopoïétiques en Europe.

Hematopoietic stem cell donation is currently carried out with peripheral stem cell after mobilisation. This donation is made according to European laws and regulations. These ones are linked to the ethical principles in order to respect the donor commitment. Ethical principles are based on the free willingness, the gratuity and the anonymity for the unrelated donors.

Treatment of chronic hepatitis C virus in allogeneic bone marrow transplant recipients.

We recently reported an increased incidence of cirrhosis in hepatitis C virus (HCV)-infected stem cell transplant (SCT) recipients. Here, we describe our experience in the treatment of these patients, which has been, to date, poorly reported in the literature. Among 99 HCV-infected HCT recipients, 36 had HCV-related liver lesions on biopsy requiring therapy. Owing to HCV treatment contraindications, only 61% of patients (22/36) could be treated. In all, 12 patients received more than one course of anti-HCV treatment if they had HCV RNA still detectable after the first course of treatment and no treatment contraindications. Combined therapy (pegylated interferon (IFN): n=9, or standard IFN: n=9, in combination with ribavirin) led to sustained virological response in 4/18 (20%) patients as compared to 2/20 (10%) in patients who received IFN alone. Hematological toxicity was more frequent with combined therapy. While anemia responded to erythropoietin and/or dose modification, thrombocytopenia usually led to treatment interruption (n=3). This study thus highlights the efficacy of combined therapy and emphasizes the fact that the undue safety concerns are not a problem when treating this particular population.

A 10-year median follow-up study after allogeneic stem cell transplantation for chronic myeloid leukemia in chronic phase from HLA-identical sibling donors.

We report long-term outcome in 102 patients with cCML transplanted from an HLA-identical sibling donor from 1982 to 1998. The conditioning regimen was based on cyclophosphamide associated with either total body irradiation (TBI) (37 patients) or with busulfan (63 patients). Graft-versus-host disease (GvHD) prophylaxis consisted of cyclosporin and methotrexate in the majority of the patients. Fifteen year overall survival was estimated at 53% (95% confidence interval (CI), 44-65) with a plateau after 2.5 years. Long-term survival was adversely affected by: longer time from chronic myeloid leukemia (CML) diagnosis to transplantation, older age at time of transplantation and GvHD (acute grade III-IV or chronic extensive). The main cause of death was infection, related to GvHD in 69% of patients. Splenectomy also significantly increased the risk of bacterial infection. 15-year relapse was estimated at 8% (95% CI, 0.1-14). Late malignancies occurred in seven patients, four of whom had an invasive cancer. Other frequent late complications included cataracts, psychological depression, osteonecrosis and hypothyroidism. These complications were more frequent following splenectomy, TBI and in patients with chronic extensive GvHD. We conclude that allogeneic transplantation with a related donor can cure more than half of CML patients in chronic phase, although physicians should be alert to long-term complications.

Do minitransplants have minicosts? A cost comparison between myeloablative and nonmyeloablative allogeneic stem cell transplant in patients with acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (SCT) is a widely used, cost-intensive procedure. Although pretransplant nonmyeloablative (NMA) or reduced-intensity conditioning regimens appear very promising, prospective studies comparing this approach with the conventional myeloablative (MA) approach in specific hematologic diseases are necessary, especially in patients in whom the conventional approach is not contraindicated. Cost may be an important factor in the decision-making process. We compared the costs of MA and NMA transplants in patients with acute myeloid leukemia (AML). We estimated 1-year resource utilization in 12 consecutive MA patients (median age: 39 years) and in 11 consecutive NMA patients (median age: 58 years) who underwent HLA-identical sibling SCT for AML. Resources care expenses were valued using the average daily rate for personnel costs, supplies, and room costs. Other data were directly collected from the patients' charts. Despite a trend for lower costs in NMA patients during the first 6 months, costs during the 6-12-month period were significantly higher after NMA due to late complications and readmissions (P=0.03). Finally, mean 1-year costs were not different in MA and NMA patients (P=0.75). Prospective studies comparing conventional and NMA approaches in homogeneous populations should include economic items.

Imaging of diffuse metastatic and dystrophic pulmonary calcification in children after haematopoietic stem cell transplantation.

The authors describe three cases of diffuse pulmonary calcification; two metastatic in children with acute transitory renal failure and the other dystrophic in a child with leukaemia. All three patients underwent haematopoietic stem cell transplantation (HSCT). Chest radiographs disclosed diffuse calcification within the lungs. The distribution of this calcification was bilateral but asymmetric. Diagnosis was made in two cases by high resolution computed tomography (HRCT) and in one case by HRCT and bone scan. Radiological characteristics, scintigraphic features, pathological mechanism and clinical outcome of such pulmonary calcification are discussed.

Granulocyte colony-stimulating factor for poor graft function after allogeneic stem cell transplantation: 3 days of G-CSF identifies long-term responders.

Poor graft function (PGF) is a frequent cause of morbidity after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To study the value of granulocyte colony-stimulating factor (G-CSF) in PGF, we retrospectively analyzed 81 episodes of PGF in 66 patients transplanted from 01/94 to 01/99 from an HLA-identical sibling (n = 45) or an unrelated (n = 21) donor. Median age was 29 years, 55 patients had malignancies. A total of 11 patients received a CD34+ selected graft. Viral infections (25%), myelotoxic drug (33%), fungal/bacterial infections (14%), and GVHD (31%) were present before PGF diagnosis. Median time from allo-HSCT to PGF was 75 (25-474) days. All patients were treated with G-CSF. In 77/81 episodes, there was a response that was sustained in 57. A total of 27 patients presented an increase of white cell count (WBC) >0.1 x 10(9)/l after 3 days of G-CSF. The 5-year survival was 37% and was significantly better in patients with increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (65 vs 18%, P < 0.0001). In multivariate analysis, increased WBC > 0.1 x 10(9)/l after 3 days of G-CSF (P = 0.002) was associated with better survival, while BuCy-based conditioning (P = 0.02) and GVHD (P = 0.005) were associated with higher risk of death. In conclusion, hematological response after 3 days with G-CSF predicted a better survival for patients with PGF after allo-SCT.

Allogeneic bone marrow transplantation for chronic myeloid leukemia in childhood: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

To determine the results of allogeneic hematopoietic stem cell (HSC) transplantation for chronic myelogenous leukemia (CML) at various stages of the disease in children, a retrospective analysis was carried out on the outcome of transplants performed on 76 children and teenagers with CML between 1982 and 1998. In all, 60 patients were transplanted from a matched sibling donor (MSD) and 16 from a matched unrelated donor (MUD). There was a higher incidence of acute graft-versus-host disease after MUD transplantation (P<10(-3)). The main cause of death was transplant-related toxicity in both groups. In MSD recipients, the probability of relapse at 5 years for patients transplanted in the first chronic phase was lower than in patients transplanted in the advanced phase (relative risk (rr)=5.90; 95% confidence interval (CI), 1.85-18.82, P<0.01). The estimated 5-year event-free survival (EFS) rate was higher after MSD vs MUD transplantation (61% (95% CI, 48-73%) vs 27% (95% CI, 4-49%), rr=0.25, P<10(-3)). In children transplanted from MSD, the 5-year EFS was higher when transplantation was performed in the first chronic phase vs the advanced phases (73% (95% CI, 59-87%) vs 32% (95% CI, 10-54%), P<10(-3)). Disease status at transplantation was the unique factor influencing survival in patients undergoing transplantation from MSD with a better outcome for those transplanted in the first chronic phase. Allogeneic HSC offers a possibility of curing childhood CML with a significant advantage for patients transplanted in chronic phase using a human leukocyte antigen-identical sibling donor.

Allogeneic bone marrow transplantation for acute myeloblastic leukaemia in remission: risk factors for long-term morbidity and mortality.

In this single-centre retrospective study, we analysed risk factors for nonrelapse long-term morbidity and mortality in patients with acute myeloblastic leukaemia (AML) who had undergone allogeneic transplantation. A total of 112 patients with de novo AML in first complete remission (CR1), n=90 or second complete remission (CR2, n=22) who received un-manipulated bone marrow grafts from human leukocyte antigen identical siblings between January 1985 and August 2000 were included. Of these, 97 patients alive and disease-free for at least 100 days after transplant were selected for the purpose of this long-term analysis. The use of an intensified conditioning regimen, Gram-negative bacteriaemia before transplantation, year of transplantation and number of pretransplant chemotherapy courses for patients in CR1 significantly affected the 7-year event-free survival which was 57%. 7-year transplant-related mortality TRM was 22%. Significant predictors for TRM were: bacterial infections before transplantation, major ABO blood group incompatibility, late severe bacterial infections, and chronic (graft-versus-host disease) GvHD. Predictive factors for late severe bacterial infections were infections before transplant, total body irradiation and GvHD. Incidence and risk factors for other late events including, chronic GvHD, late infections, osteonecrosis, cataract, endocrine- cardiac- and lung-complications, cancer and performance status at last follow-up were also studied. The analysis strongly suggests that the combination of pretransplant factors such as chemotherapy and conditioning, and posttransplant factors such as chronic GvHD had a major impact on late nonrelapse morbidity and mortality.

A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: results from the French Bone Marrow Transplantation Society.

SUMMARY: Philadelphia chromosome (Ph) acute lymphoblastic leukemia-positive (ALL) is a subgroup of ALL with a poor prognosis. We sought to evaluate the results of allogeneic hematopoietic stem cell transplantation (HSCT) in this situation. From 1992 to 2000, 121 patients with Ph- positive ALL enrolled in one of the three main French prospective ALL chemotherapy trials and receiving allogeneic HSCT were reported to the registry of the French Society of Bone Marrow Transplantation (SFGM-TC). The median age was 35 years (range, 1-53). In all, 76 patients received HSCT in first complete remission and 45 in a more advanced disease stage. Minimal residual disease was evaluated just before the graft: 35 patients of the 52 patients in first remission had persistent BCR-ABL transcript detectable while 17 had no detectable minimal residual disease. Bone marrow and/or peripheral blood samples from 94 patients were submitted for reverse transcriptase polymerase chain reaction analysis at variable points after transplantation. Estimated 2-year survival and relapse rate for patients in CR1 were 50 and 37%, respectively, significantly better than for patients with more advanced disease (P=0.0001 and 0.01, respectively). There was no difference in survival or in relapse rates in terms of the donor used. Relapse was the most common cause of treatment failure. Hematological status at the time of transplant and the occurrence of acute graft-versus-host disease (GvHD) were the only two prognostic factors identified for relapse (P=0.02 and 0.02, respectively). Detection of BCR-ABL transcripts after transplantation had a predictive value on relapse occurrence. Finally, donor lymphocyte infusions were successfully used to treat some relapses. The graft-versus-leukemia effect of HSCT in Ph-positive ALL appears to be supported by (1) the lack of prognostic significance of pretransplant BCR-ABL transcript detection, (2) the efficacy of donor lymphocyte infusions in cases of relapse, and (3) the role of GvHD as protecting against relapse.

DPB1 disparities contribute to severe GVHD and reduced patient survival after unrelated donor bone marrow transplantation.

In order to evaluate the impact of HLA-DBP1 incompatibilities on the occurrence of acute graft-versus-host disease (GVHD) in unrelated hematopoietic cell transplantation, we studied 57 donor/recipient pairs characterized by their allelic identity for HLA-A, B, C, DRB1 and DQB1 and also for DRB3, 4, 5 loci and aimed to correlate DPB1 mismatches to already described risk factors for GVHD using multivariate Cox regression analysis. DPB1 identity between donor and recipient was observed in 24% and DPB1 compatibility (GVHD vector) in 42%. Two factors were independently associated with severe acute GVHD: two DP incompatibilities (RR = 8.25, 95% confidence interval (CI): 1.67-40.10, P = 0.010) and disease risk (RR = 10.23, 95% CI: 1.12-93.13, P = 0.012). Two DPB1 incompatibilities appeared also to be a factor in poorer survival independent of its effect on acute GVHD (RR = 4.97, 95% Cl: 1.80-13.71, P = 0.002). A correlation between acute GVHD and matching for each individual DPB1 polymorphic region and for residue 69 of the DP beta molecule, which seems to be a key residue in the alloimmune response, was not observed. Our data indicate that the outcome of unrelated hematopoietic cell transplantation in terms of GVHD but also survival, could be improved through HLA-DPB1 matching or at least by avoiding two DPB1 mismatches.

Toxoplasmic pneumonitis leading to fatal acute respiratory distress syndrome after engraftment in three bone marrow transplant recipients.

Toxoplasmosis is a rare but severe complication of bone marrow transplantation. Here, we report three patients in whom toxoplasmic pneumonitis developed, leading to fatal acute respiratory distress syndrome (ARDS). All patients had positive pretransplantation tests for Toxoplasma gondii and were therefore at risk to develop toxoplasmosis reactivation. They all recovered from aplasia, but soon after they died from brutal and severe ARDS. The possible role of an immunopathologic response to T gondii in the lungs in triggering ARDS is discussed.Early screening of parasitemia using highly sensitive polymerase chain reaction methods in seropositive patients with unexplained fever may be needed.

Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients.

To evaluate the long-term immune reconstitution after allogeneic haematopoietic stem cell transplantation (SCT), we prospectively screened standard immune parameters in a series of 105 patients, at a median time of 15 months after SCT. Analysing lymphoid phenotypes, in vitro immune functions and immunoglobulin levels, we found that, more than 1 year post SCT, cellular and humoral immunity was still altered in a significant number of patients. CD4+ T cells were < 200/microl in one third of patients, and the CD4/CD8 ratio was still reversed in 78% of patients. Almost all patients showed positive T-cell responses against mitogens, but antigen-specific proliferation assays identified 20% to 80% of non-responders. B-cell counts were reconstituted in 61% of the patients, but levels of total immunoglobulins were still low in 59%. In multivariate analyses, human leucocyte antigen (HLA) disparity between donor and recipient and chronic graft-versus-host disease were the leading causes affecting immune reconstitution. Interestingly, cytomegalovirus (CMV) infections were strongly associated with normal CD8+ T-cell counts. Studying the impact of impaired immune reconstitution on the rate of infections occurring in the 6 years following screening, we identified three parameters (low B-cell count, inverted CD4/CD8 ratio, and negative response to tetanus toxin) as significant risk factors for developing such late infections.