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.

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.

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.

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.

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.

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.

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.

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.

Influence of CD34 cell selection on the incidence of mixed chimaerism and minimal residual disease after allogeneic unrelated donor transplantation.

Marrow transplantation from unrelated donors has been linked with an increased risk of graft-versus-host disease (GVHD). In an attempt to lower the risk of acute GVHD we used CD34 marrow cell selection for T cell depletion. Since T cell depletion has been linked to an increased risk of relapse and an increased risk of marrow failure, we used PCR amplification of minisatellite sequences to investigate donor cell engraftment and RT-PCR amplification of recurrent chromosomal translocations to investigate the residual disease post-transplant. Twenty-three patients who underwent BMT after positive selection of the CD34-positive cell population were studied. Results were then compared with those of 37 patients who underwent transplantation with unmanipulated marrow graft. Among the 23 patients who received CD34+ selected cell grafts, seven (30%) had evidence of full donor engraftment, 14 had evidence of residual recipient cells (61%), one had a non-take, and one autologous bone marrow recovery. Analysis of the chimaerism status post-transplant in 36 patients who received unmanipulated marrow grafts showed that 31 patients (86%) had evidence of full donor engraftment. The difference in the incidence of mixed chimaerism profile between patients who received unmanipulated marrow graft and those receiving CD34+ selected cell grafts was statistically significant (P< 0.01). Nine patients who received CD34+ selected cell grafts could be analysed for the presence of minimal residual disease post-transplant (one with t(9;22) acute lymphoblastic leukaemia and eight with CML). In the patient transplanted for a Ph-positive acute leukaemia, and in two out of the eight patients with CML, the search fora fusion transcript was consistently negative after transplantation. Among the six patients with evidence of residual disease, three patients also had a mixed chimaerism profile and were given donor lymphocyte infusions. Minimal residual disease study was performed post-transplant in 16 patients who received unmanipulated marrow grafts. In 10 of 14 patients with CML, and in two patients with acute leukaemia the search for a fusion transcript was consistently negative after transplantation. The difference in the incidence of minimal residual disease between patients who received an unmanipulated marrow graft and those receiving CD34+ selected cell grafts was not statistically significantly significant, but numbers of patients included in this analysis are still few. In conclusion, our study highlights the strong influence of graft manipulation on the incidence of mixed chimaerism after transplantation from an unrelated donor.

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.

[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.

Influence of bone marrow graft lymphocyte subsets on outcome after HLA-identical sibling transplants.

OBJECTIVE: The aim of this study was to analyze bone marrow lymphocyte subsets and CD34 cell dose and their influence on the outcomes of bone marrow transplantation. MATERIALS AND METHODS: Forty-eight patients (median age 30 years, range 5-54) receiving HLA-identical sibling bone marrow transplantation for hematologic malignancies were analyzed. RESULTS: Median number (range) of nucleated cells and CD34+ cells infused were 2.4 (0.4-6.0) x 10(8)/kg and 3.5 (0.5-13.0) x 10(6)/kg, respectively. Probability of neutrophil recovery was 97%. In a multivariate analysis, time to neutrophil recovery was shortened when a higher number of CD3/CD8 cells was infused (> or =1.0 x 10(7)/kg) (hazard ratio [HR] = 2.13, p = 0.018); when the patient was female or had negative cytomegalovirus serology (HR = 2.03, p = 0.03; HR = 0.41, p = 0.009; respectively). The incidence of grade II to IV acute graft-vs-host disease (GVHD) was 47%. Infusion of >1 x 10(7) CD4 infused/kg increased the risk of acute GVHD (HR = 2.86, p = 0.03). Nineteen of 40 patients at risk experienced chronic GVHD, the risk of which was increased by diagnosis of chronic leukemia (p = 0.03), <2.0 x 10(8) nucleated cells infused/kg (p = 0.05), and a low number of all lymphocyte subsets, except CD19. Estimated 3-year survival rate was 54%. Risk of death was increased in patients receiving <3.5 x 10(6)CD34 infused/kg (HR = 0.37, p = 0.02). Only six patients relapsed. CONCLUSIONS: A high cell dose of CD3/CD8 is associated with faster neutrophil recovery, whereas a high cell dose of CD4+ cells increases the incidence of acute GVHD. A high number of nucleated cells and CD34+ cells infused was associated with decreased risk of chronic GVHD and improved survival, respectively.

Cystectomy for severe hemorrhagic cystitis in allogeneic stem cell transplant recipients.

BACKGROUND: Hemorrhagic cystitis (HC) is a common complication following allogeneic stem cell transplantation (SCT). In rare cases, it can be severe, inducing kidney failure and sepsis, and become life-threatening. METHODS: We report three cases of severe HC in stem cell transplant recipients. Risk factors and the management of these patients were studied, as well as severe HC cases reported in the literature. RESULTS: All three patients received high-dose cyclophosphamide in addition to total body irradiation or busulfan in their preparative regimen. They underwent allogeneic SCT, one of them from unrelated cord blood. BK viruria was detected in two cases at the onset of hematuria. HC lasted for more than 3 months, resulting in urinary tract obstruction and sepsis. Ultimately, cystectomy was the last therapeutic procedure available to treat this life-threatening complication. CONCLUSION: We describe three patients, among a total of more than 1300 patients treated in our unit by allogeneic bone marrow transplantation, in whom HC was severe and long lasting enough to require cystectomy as a life-saving procedure.

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.

Transient cyclic neutropenia following GM-CSF in a patient with chronic granulocytic leukemia transplanted with HLA-identical T cell-depleted donor bone marrow.

Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.

Changes in height, weight and plasma leptin after bone marrow transplantation.

Short stature can be a severe side-effect of bone marrow transplantation (BMT). Because of the effect of weight changes on growth rate and on plasma insulin-like growth factor (IGF I), we analyzed changes in height and body mass index (BMI) in 53 patients given BMT. Group 1 (n = 22) was given 12 Gy total body irradiation (TBI) as six fractions, group 2 (n = 14) 10 Gy TBI (one dose), group 3 (n = 8) 6 Gy total lymphoid irradiation (one dose), and group 4 (n = 9) chemotherapy alone. At the first evaluation, 13/36 patients in groups 1 and 2 had low growth hormone (GH) peaks after stimulation. The mean plasma IGF I concentrations (z score) were similar in groups 1 (-2.9 +/- 0.3) and 2 (-2.5 +/- 0.3), and in groups 3 (-1.4 +/- 0.3) and 4 (-1.4 +/- 0.7), but those of group 1 were lower than those of groups 3 (P < 0.01) and 4 (P < 0.05), and those of group 2 than those of group 3 (P < 0.05). BMI during the 5 years after BMT did not change in groups 1 and 2, decreased in group 3, and increased in group 4. However, these changes were not significant. Most of the patients given TBI had BMI below the mean at 2 (66%) and 5 (57%) years later. Their BMI and leptin concentrations correlated positively with each other (P = 0.005), and negatively with GH peak (P = 0.02 for BMI and 0.007 for leptin). In conclusion, this study suggests that TBI actually decreases GH secretion and is followed by a persistent low BMI. The negative relationship between GH peak and leptin may indicate that both are markers of a TBI-induced hypothalamic-pituitary lesion.

Factors affecting gonadal function after bone marrow transplantation during childhood.

Conditioning for bone marrow transplantation (BMT) may alter viability of germ cells and production of gonadal hormones. We analyzed the risk factors for gonadal failure after 12 Gy total body irradiation (TBI) given as six fractions (n = 31, group 1), 10 Gy (one dose) TBI (n = 20, group 2), 6 Gy (one dose) total lymphoid irradiation (TLI, n = 17, group 3) and chemotherapy alone (n = 7, group 4), given at 7.7 +/- 0.4 (0.6-13.6) years. Among the 34 girls, seven (20.6%) had normal ovarian function with regular spontaneous menstruation and normal plasma follicle-stimulating (FSH) and luteinizing (LH) hormones, five (14.7%) had partial ovarian failure with regular menstruation but increased FSH and/or LH, and 22 (64.7%) had complete ovarian failure. The 24 girls with chronological and bone ages >13 years included similar percentages, with increased FSH or LH in all four groups. There was a positive correlation between age at BMT and FSH (r = 0.54, P < 0.01), but not with lh, and between fsh and lh (r = 0.8, P = 0.0003). Plasma FSH concentrations had returned to normal spontaneously in six cases, and those of LH in two cases. Among the 41 boys, 16 (39%) had normal testicular function and 25 (61%) had tubular failure and increased FSH. Of these, 10 also had Leydig cell failure (three complete and seven partial). The 18 boys with chronological and bone ages >15 years included similar percentages with increased FSH or LH in groups 1 to 3, and testicular volume was significantly lower in group 2 than in group 3 (P = 0.008). There was no correlation between age at BMT and FSH, LH or testosterone, but there was a negative correlation between FSH and inhibin B (rho = -0.87, P < 0.003). we conclude that girls are more likely to suffer ovarian failure the older they are at bmt, and that early ovarian recovery is possible. the negative correlation between fsh and inhibin b in boys suggests that this parameter is an additional indicator of tubular function.

Unusual localization of cutaneous chronic graft-versus-host disease in the radiation fields in four cases.

Chronic graft-versus-host disease (GVHD) is a very heterogeneous entity with variable clinical expression. The pathophysiology involves autoimmune disorders and features of fibrosis. Four patients transplanted for severe aplastic anaemia conditioned with cyclophosphamide and thoraco-abdominal irradiation developed skin scleroderma specifically localized in the irradiation fields. This syndrome was remarkable for its late onset and the absence of factors known to trigger chronic GVHD. It is postulated that irradiation used in this protocol may induce keratinocyte damage and trigger chronic GVHD.

Prevalence and clinical features of hepatitis G virus infection in bone marrow allograft recipients.

To study the prevalence and clinical features of hepatitis G virus (HGV)/GB virus C (GBV-C) infection in bone marrow transplantation (BMT), we examined frozen serum samples from 95 bone marrow allograft patients for HGV/GBV-C RNA by RT-PCR. Twenty-eight out of 95 (29.5%) were positive and 14 of the HGV+ patients were already positive before transplantation. The mean numbers of blood donors to whom the HGV and HGV+ populations were exposed before BMT were not significantly different (Kruskal-Wallis test, P = 0.08, NS) but did reveal that the HGV+ population had been transfused more often. Moreover, all but one of the patients who were HGV+ before graft, had had hematological diseases which needed heavy transfusion protocols suggesting, a role of blood products in HGV transmission. Fifty out of the 95 patients received Gammagard intravenous immunoglobulin (i.v.IG) batches suspected of having transmitted HCV. However, no significant difference appeared between these recipients and those receiving other i.v.IG. Despite their immunodeficiency, no clinical or biological evidence of liver disease potentially linked to HGV infection has as yet been observed. The clinical outcome, in terms of acute GVHD, chronic GVHD or veno-occlusive disease was similar in HGV+ and HGV- recipients suggesting the absence of adverse effects of HGV infection on the early outcome of allogenic BMT. Long-term evolution remains to be prospectively studied.

Ovarian function after bone marrow transplantation during childhood.

Ovarian failure is often brought about by the conditioning protocol used for bone marrow transplantation (BMT). We monitored ovarian function in 31 girls conditioned for BMT at 10.3 +/- 0.6 (s.e., 3.2-17.5) years by chemotherapy alone (group 1, n = 8) or chemotherapy plus body irradiation (12 Gy, fractionated in group 2, n = 9, or 10 Gy single total body in group 3, n = 7, and 5 or 6 Gy single thoraco-abdominal in group 4, n = 7, irradiation) at 13.4 +/- 0.4 (11.7-18.6) years. Breast development was normal (n = 11), did not occur (n = 14), or did not progress spontaneously (n = 2) after BMT. The other four girls who menstruated before BMT had permanent amenorrhea. Basal plasma gonadotropin concentrations were measured in 29; follicle-stimulating hormone was increased in them all and luteinizing hormone in 23. At the last clinical evaluation at 16.3 +/- 0.4 (12.1-21.6) years, 23 girls had complete ovarian failure, two had partial ovarian failure, and six had normal ovarian function. Three of these were the youngest group 1 patients and those who had not received busulfan. We conclude that conditioning for BMT given during childhood frequently prevents normal estrogen secretion at puberty. Adequate substitutive treatment may be necessary to induce growth acceleration and sexual development.