Busulfan-based Conditioning Regimen Research Articles

Hepatic Veno-Occlusive Disease in Children after Hematopoietic Stem Cell Transplantation: Incidence, Risk Factors, and Outcome

Veno-occlusive disease (VOD) is one of the most frequent complications after hematopoietic stem cell transplantation (HSCT). We conducted this study to describe recent characteristics of incidence, risk factors, treatment and outcome of VOD in children undergoing autologous or allogeneic HSCT. Patients who underwent HSCT with hematological malignancies, solid tumors, or nonmalignant diseases at Asan Medical Center, National Cancer Center, Samsung Medical Center, and Seoul National University Children's Hospital in Korea, from January 2005 to December 2007, were assessed with chart review. VOD was defined according to McDonald criteria and classified as severe on the basis of persistent symptoms after day 100 or death before day 100 with ongoing VOD. All other patients were considered to have mild or moderate VOD. Descriptive statistics and univariate and multivariate analyses of risk factors are presented. Four hundred sixty-seven HSCTs (217 autologous and 250 allogeneic HSCTs) were performed in 374 patients for the treatment of leukemia (n=177, 37.9%), neuroblastoma (n=103, 22.1%), brain tumors (n=69, 14.8%), nonmalignant diseases (n=62, 13.3%), and other solid tumors (n=56, 12.0%). For VOD prophylaxis, heparin was used in 116 transplants, heparin + prostaglandin E1 (PGE1) in 230 transplants, PGE1 ± ursodeoxycholic acid in 86 transplants, and defibrotide + heparin in 35 transplants. Among 467 transplant procedures, VOD developed in 72 transplants (15.4%) at median 10 days (range, 1–64) after HSCT. Five patients had recurrent VOD in their tandem transplantation. VOD was mild or moderate in 62 transplants and severe in 10 transplants. For treatment of VOD, PGE1, tissue-plasminogen activator, defibrotide, or antithrombin III were given alone or in combination of each other in 42 transplants. In remaining 30 VOD-positive transplants, patients were treated with supportive care only, such as restriction of sodium and fluid intake, diuretics and hematologic support. The median duration of VOD was 12 days (range, 3–80). Hepatomegaly was the most common sign of VOD (n=63). Ascites and inversion of portal flow were found in 17 (23.6%) and 8 (11.1%) of 72 VOD-positive transplants, respectively. VOD-related respiratory dysfunction and renal dysfunction were more frequent in transplants with severe VOD (7/10 and 7/10) compared to transplants with mild or moderate VOD (9/62 and 8/62) (P=0.001 and P<0.0005). Multivariate analysis showed that total body irradiation (TBI) or busulfan containing regimen (P=0.003), VOD prophylaxis without PGE1 (P=0.005), pre-transplant serum ferritin (P=0.005), and number of previous HSCT (P=0.038) were independent risk factors for developing VOD. Underlying disease, stem cell source, donor type, age at transplantation, pre-transplant serum aspartate aminotransferase, and alanine aminotransferase did not influence the development of VOD. In addition, ascites (P=0.017) and number of previous HSCT (P=0.037) were significant risk factors for severe VOD by multivariate analysis. Deaths within 100 days after transplantation occurred in 13 of 72 VOD-positive transplants, the cause of death being VOD-related multi-organ failure in 5 cases. The risk of death within 100 days after HSCT was 2.8 times higher (95% CI: 1.718, 4.563) for VOD-positive transplants (P<0.0005). TBI or busulfan-based conditioning regimen, VOD prophylaxis without PGE1, pre-transplant ferritin level, and repeated HSCT increased significantly the incidence of VOD in children after HSCT. The results can be used to identify high risk patients who are to undergo an HSCT. The encouraging result of our study is to justify the role of PGE1 in the prophylaxis of VOD, however prospective randomized trials are needed to confirm the superior efficacy of PGE1 in preventing VOD. Despite the combination of supportive cares and VOD therapy, significant numbers of patients are still suffering from VOD. Continued research for prevention and effective treatment of VOD will be necessary to improve the outcome of HSCT.

Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors

About one third of patients requiring allogeneic hematopoetic stem cell transplantation (HSCT) would not find a matched sibling or alternative donor. Allogeneic HSCT from matched unrelated and mismatched donors carries an increased risk of graft-vs-host disease (GVHD) and transplant-related mortality (TRM). We used anti-thymocyte globulin (ATG-Fresenius) at a median dose of 90 mg/kg body weight as part of a total body irradiation or busulfan-based conditioning regimen for prevention of serious GVHD. All patients received cyclosporine A and short-course methotrexate. We compared outcomes of 65 recipients of human leukocyte antigen (HLA)-mismatched unrelated grafts and 194 recipients of HLA-matched unrelated grafts. Mismatches involved one or two loci. Both groups were comparable in age, graft source, diagnosis, stage of disease, and conditioning regimen, and differed only in dose of ATG administered. For matched and mismatched transplants, respectively, there was no significant difference in graft failure (0.5% vs 3%; p = 0.16), in the cumulative incidence of grade II to IV acute GVHD (45% vs 35%; p = 0.14) and no difference in overall chronic GVHD (42% vs 40%; p = 0.68). Estimated overall survival (OS) and disease-free survival (DFS) at 5 years were 55% vs 50% (p = 0.99) and 47% vs 47% (p = 1.0), respectively. The cumulative incidence of relapse and TRM at 5 years were 24% vs 25% (p = 0.63), and 29% vs 27% (p = 0.59), respectively. Inclusion of ATG-Fresenius in the conditioning regimen permits HSCT from mismatched unrelated donors without excess TRM and GVHD, resulting in identical OS and DFS of recipients of HLA-matched and HLA-mismatched grafts.

Risk‐adjusted monitoring of veno‐occlusive disease following Bayesian individualization of busulfan dosage for bone marrow transplantation in paediatrics

In order to assess the performance of Bayesian individualization of busulfan (BU) dosage regimens, veno-occlusive disease (VOD) rate was monitored for paediatric patients undergoing allogeneic bone marrow transplantation (BMT). Consecutive patients undergoing allogeneic BMT with BU as conditioning regimen during 5-years period (January 2000-February 2006) were reviewed. VOD was a major outcome variable. Preconditioning risk of VOD was estimated for each patient using a scoring system that included type of transplant, recipient CMV-positive status and total parenteral nutrition (TPN) provided pretransplantation. A risk-adjusted cumulative sum method was used to compare observed versus predicted outcome by assigning a risk score, based on log-likelihood ratios, to each patient. These cumulative scores were sequentially plotted with preset control limits for 'signalling' where results were substantially different than expected (doubling or halving of odds ratio). Sixty-six children received BMT after oral busulfan-based conditioning regimen with median age 3.9 years, 63.6% of male. Median preconditioning risk of VOD was 0.34 ranging from 0.23 to 0.84. Observed VOD rate was 16.7% (n = 11) which was 60.7% (17) fewer than the expected number estimated by the risk score. The resulting risk-adjusted score for each patient was plotted sequentially. This plot adopted early a negative slope, crossing the lower control limit twice, after 27 and 66 patients, indicating improved results compared to those expected. Bayesian individualization of oral busulfan dosage regimens is useful to reduce the VOD rate in children undergoing allogeneic BMT.

Pre-Transplant Test Dose vs. PK Studies during Conditioning Regimen To Target iv Busulfan in Allogeneic Hematopoietic Stem Cell Transplantation.

In this study we tested the efficacy of a test dose of iv busulfan in targeting blood levels of this drug during the conditioning regimen prior to an allogeneic hematopoietic stem cell transplant. We analyzed blood samples of 22 patients undergoing allogeneic hematopoietic stem cell transplantation with a busulfan-based conditioning regimen. Patients received a test dose of busulfan at 0.8 mg/kg as a 60 minute intravenous infusion. Serial blood samples were drawn at eight time points: 15 minutes before dose, at end of infusion, 15 minutes after completion, 30 minutes after completion, 60 minutes after completion, 2 hours after completion, 4 hours after completion, and 6 hours after completion. Pharmacokinetics (PK) studies were then performed at the Seattle Cancer Care pharmacokinetics laboratory. The AUC was determined using WinNonlin Professional software. The conditioning dose of busulfan was calculated by multiplying the test dose in mg/AUC × 4800. After the first dose of busulfan was administered, the same protocol was used to test busulfan PK. If the Busulfan AUC was therapeutic (between 4800 μM*min and 5200 μM*min) then the same dose was continued. If the Busulfan AUC was low or high then the third and fourth doses of busulfan were adjusted. The test dose of 0.8 mg/kg intravenous did not have any hematological side effects. The mean historic dose (solely based on weight) was 3.2 ± 0.1 mg/kg and the mean dose based on the test dose was 3.5 ± 0.5 mg/kg (p=0.02). In 12 patients where we also analyzed PK after the first day of conditioning regimen, AUC values of busulfan obtained during test dose and after day 1 dose were not different (p=0.7). The mean dose of busulfan based on test dose was 3.5 ± 0.6 mg/kg while the final dose based on day 1 busulfan PK was 3.6 ± 0.7 mg/kg (p=0.9). Nevertheless, in 2 CML patients who were on treatment with dasatinib or nilotinib at the time of the test dose, a higher AUC was observed (AUC 6065 and 6200, respectively). A pre-transplant busulfan test dose can be safely performed anytime prior to transplant and allows targeting the dose of busulfan efficiently, thus avoiding the requirement of PK studies during the conditioning regimen.

Risk Factors Analyses for Outcomes after Unrelated Cord Blood Transplantation for Children with Myelodysplastic Syndromes. An Analysis on Behalf of EWOG-MDS and Eurocord Groups.

Myelodysplastic syndromes (MDS) are very rare diseases in children and hematopoietic stem cell transplantation remains the only curative treatment. This is a retrospective registry-based study of 42 children with MDS (refractory cytopenia n=21, refractory anemia with excess of blasts n=15, and refractory anemia with excess of blasts in transformation n=6), who underwent unrelated cord blood transplantation (UCBT). Both databases from Eurocord and EWOG-MDS group were used. Diagnosis of MDS was established by each reporting center based on the WHO classification modified for pediatric patients. Median age was 7.4 years, median cell dose infused was 4.2 × 107/Kg and median follow-up was 39 months. All patients received one cord blood unit, with 0 or 1 HLA disparity in 22, and 2 or more in 20. Twenty-five children received a Busulfan-based conditioning regimen. The association of Cyclosporine A and prednisone was used in 69% of patients. The 60-day cumulative incidence (CI) of engraftment was 69±7%, in a median time of 25 days. In multivariable analysis, ABO match (Hazard Ratio=2.94, 95% Confidence Interval=1.23–6.66, p=0.01) and refractory cytopenia (HR=2.38, 95% Confidence interval=1.01–5.55, p=0.05) were favorable factors associated with neutrophil recovery. Thirteen patients developed acute GVHD grades II–IV. Moreover, 16 children had skin, 5 liver, 6 gastrointestinal involvements (stages 2–4). The 100-day CI of aGVHD was 29±7%. Of 20 evaluable patients, 10 developed chronic GVHD and the 1-year CI of cGVHD was 24±7%. The 2-y CI for treatment-related mortality was 56±8%. In univariable analysis, recipient's weight was the only statistical significant factor associated with TRM (47% for children weighting less than < 38Kg versus 80% for remainders, p=0.05). In addition, there was a trend of higher TRM for patients who received CBU with 2 or more HLA disparities (p=0.09). The 2-y overall survival and disease-free survival were 37±8% and 32±8% respectively. In multivariable analysis, OS improved when recipient's weight at UCBT was lower than 38kg (HR= 2.53, 95% confidence interval=1.16–5.55; p=0.02). In conclusion, since hematopoietic stem cell transplantation is the only treatment with curative potential, UCBT is a reasonable option for children without an identical sibling donor. Moreover, outcomes might be improved with better donor and patient's selection.

Influence of Underlying Disease on Busulfan Disposition in Pediatric Bone Marrow Transplant Recipients: A Nonparametric Population Pharmacokinetic Study

Busulfan is an alkylating agent used in a conditioning regimen prior to bone marrow transplantation. Busulfan has a narrow therapeutic index, giving rise to major liver toxicity (veno-occlusive disease), and a wide interpatient and intrapatient pharmacokinetic variability. This report presents the results of a population pharmacokinetic analysis leading to models based on underlying diseases requiring bone marrow transplantation. One hundred children received oral busulfan-based conditioning regimens between March 1998 and February 2006. Busulfan pharmacokinetic parameter estimates (Ka, first order absorption rate constant; Vs, volume of distribution related to the body weight; and Cl/F, apparent clearance) were estimated by using the nonparametric adaptative grid (NPAG) algorithm in patients divided into four groups according to initial diagnosis: metabolic diseases, hemoglobinopathies, hematological malignancies, and immune deficiencies. Ka and Vs did no differ significantly in the four subgroups. Cl/F and areas under the plasma concentration curve were significantly different in the four groups. Cl/F was significantly higher in the hemoglobinopathies group (P = 0.002), with a mean value of 7.78 L . h, whereas the immune deficiencies group was characterized by the lowest Cl/F (3.59 L . h). Interindividual variability was shown by high interindividual parameter percent coefficients of variation (CV%) but, nevertheless, with less diversity in the population parameter distributions for Vs in the three subgroups-metabolic diseases, hemoglobinopathies, and malignant diseases-and in Cl/F for patients with hemoglobinopathies. The fit was good for busulfan concentration predictions based on Bayesian individual posterior values, with little bias and good precision. In comparison with the overall population, the only model of subgroup presenting a greater precision was patients with hemoglobinopathies (P = 0.002). Use of these more specific models of a given disease may well result in more accurate individualization of busulfan dose regimens, especially in very sparse blood sampling situations.

Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease in Children.

Veno-occlusive disease (VOD) of the liver is a major complication of allogeneic or autologous stem cell transplantation (HSCT), particularly after busulfan-based conditioning regimens. Clinically, VOD is characterized by fluid retention, weight gain, hyperbilirubinemia and painful hepatomegaly. Efficacy and safety of defibrotide for the treatment of VOD, especially in pediatric patients, has not been adequately confirmed or the results are still preliminary. This retrospective report describes experience with defibrotide in children with hepatic veno-occlusive disease (HVOD) following HSCT in a single institution.Materials and Method: Children who had undergone HSCT between April 2005–June 2006 and who received defibrotide for the treatment of HVOD during their admission were identified. Demographic data and clinical information of these patients were abstracted from their health records.Results: Eight children (median age: 4.5 years; range: 1–14 years) who underwent HSCT during the study period received defibrotide for the treatment of HVOD; 5 were boys and 3 were girls. Three patients underwent HSCT for hematologic malignancies, 2 for neuroblastoma, 1 for hemoglobinopathy, 1 for severe combined immunodeficiency (SCID) and 1 for fanconi aplastic anemia. Conditioning regimens included busulfan (16 mg/kg) in four, melphelan (140 mg/m2) in two and total body irradiation in 1 patient as being risk factors for HVOD. Two patients with neuroblastoma had undergone autologous HSCT, three patients had been transplanted from matched sibling donor and the other three were either unrelated donor or unrelated cord blood transplantation. HVOD was diagnosed on transplant day +4 to +19 (median: +12 ). The median initial defibrotide dose was 31.5 mg/kg/day (25–46 mg/kg/day). The median duration of defibrotide therapy was 27 days (1–46 days). Defibrotide was discontinued due to clinical improvement (5), gastrointestinal hemorrhage (2), death (1). Two patients in whom defibrotide was discontinued because of gastrointestinal hemorrhage died. The primary cause of death in these two children was: progressive HVOD and multiorgan failue following sepsis.As a result of this experience and under the light of literature, we believed that defibrotide is an effective treatment for children with HVOD and should be instituted in each children without delay in the event of at least one of the criteria for HVOD is established. But it is necessary to carry out further studies in larger group of patients with longer follow-up to validate the efficacy and safety of defibrotide.

Conversion from Mycophenolate Mofetil to Enteric-coated Mycophenolate Sodium (myfortic??) in a Patient with Graft-versus-host Disease

The patient was 58 years old in September 2002 when he was diagnosed with chronic myeloid leukaemia (CML). He was first treated using IFNa, to which aracytine was soon added. By February 2003, hyperleukocytosis with myelocytosis was still present so the interferon was replaced by imatinib. The patient’s condition continued to deteriorate, and the haematopoietic cell count started to increase in August 2003. In September 2003, the patient underwent allogeneic haematopoietic stem cell transplantation with peripheral stem cells from a human leukocyte antigen-matched brother after a busulfan-based non-myeloablative conditioning regimen. Graftversus-host disease (GVHD) prophylaxis consisted of cyclosporine 3mg/kg per day and short-course methotrexate. Subsequent changes in the immunosuppressive regimen are summarised in table I. On day 15 posttransplant, a differential count clearly indicated recrudescence of the CML, with a total white blood cell count of 65 000 10/l, including 70% myeloid cells. In response to this, cyclosporine was discontinued because there was no evidence of GVHD, and treatment with imatinib (400mg/day) and low-dose busulfan (2mg/day by mouth) was started. A complete cytogenetic and molecular remission was observed unexpectedly within 2 months. On day 19, grade II cutaneous GVHD developed, with no gastrointestinal symptoms. The patient was given methylprednisolone followed by anti-IL-2 antibody therapy (Leucotac) for 4 days. The symptoms failed to improve by day 46, however, and treatment with mycophenolate mofetil (MMF) was started at a dose of 1000mg twice a day. The patient quickly developed severe diarrhoea two to three times a day responsible for a body weight loss of 5% within one week, and 18 days after the introduction of MMF (i.e. on day 64) it was withdrawn and replaced with enteric-coated mycophenolate sodium (EC-MPS; myfortic) at a dose of 720mg twice a day. The gastrointestinal symptoms quickly resolved after conversion from MMF to EC-MPS and the GVHD steadily waned. In January 2004, 4 months posttransplantation, the GVHD flared up again so the corticosteroid dose was increased to 80mg/day, and tacrolimus 2mg twice a day was started. In the face of persistent GVHD, this regimen of EC-MPS 720mg twice a day, prednisolone 80mg/day and tacrolimus 2mg twice a day was maintained until March 2004 when the patient developed acute kidney failure and tacrolimus was discontinued. As the GVHD appeared to be under control, the corticosteroid dose was tapered downwards, starting in May 2004. The patient is still alive in good condition and in complete molecular remission from his CML. CASE REPORT Drugs 2006; 66 Suppl. 2: 29–31 0012-6667/06/0002-0029/$44.95/0

Outcomes of Older Patients with Myeloid Leukemias Treated with Myeloablative Intravenous Busulfan-Based Conditioning Regimens and Allogeneic Blood or Marrow Transplantation.

Older age (e.g. > 55–60 yrs) is a commonly cited indication for reduced-intensity conditioning regimens (RIC) in the treatment of myeloid leukemias. These diseases, however, may benefit from the highest possible dose intensity that can be safely delivered. Here we analyze our experience treating patients (pts) older than 55 yrs. with intravenous (IV) busulfan (Bu)-based preparative regimens.Methods: Fifty-six pts older than age 55 yrs. with MDS (n=13), AML (n=33), or CML/myeloproliferative disorder (n=10) were transplanted from 6/1997 to 12/2004 on two consecutive protocols. Conditioning were IV fludarabine (Flu) 40 mg/m2 and IV Bu 130 mg/m2 over 3 hr (days -6 till -3) given once daily (BuFlu; n=36), and IV Bu 0.8 mg/kg over 2 hr every 6 hr for 16 doses (days -7 till -4), followed by Cyclophosphamide (Cy) 60 mg/kg on days -3 and -2 (IV BuCy2; n=20). Pts with an unrelated (UD) or mismatched donor received ATG. Graft-versus-host disease (GVHD) prophylaxis was based on tacrolimus and mini-methotrexate.Results: Median age was 58.4 yrs (55–66.8); 14 pts were older than 60 yrs. Most pts were not in complete remission (CR) at BMT (n=38, 68%, with similar distribution in pts older and younger than age 60). Donors were HLA-compatible siblings (SIBS) in 59% (n=33) and UD in 41% (n=23). UD were used in 5 pts >59 yrs (36%) and in 18 < 60 yrs (43%). Stem cell source was bone marrow (n=23) or peripheral blood (n=33). All but one pt had documentation of donor cell engraftment. Median follow-up of surviving pts (June 2005) was 15 mos (range, 4–49; n=23). Grade II-IV acute (a) and chronic (c) GVHD rates were as follows (pts <60 vs >59 yrs): 38% vs 64% and 45% vs 54%, respectively. 100-day treatment-related mortality (TRM) was 11% (due to graft rejection (n=1), toxicity (n=2); pulmonary hemorrhage with fungal pneumonia (n=1) and aGVHD (n=2). All early 100-day TRM pts were < 60 yrs. Overall, 17 pts relapsed and 33 pts have died. One-year TRM: 29%, n=16 (due to GVHD, n=7, infections, n=4; rejection, n=1; unknown causes, n=1; toxicity, n=2, bleeding, n=1). Only 2 pts > 59 yrs are alive, while the others died of cGVHD (n=5) and disease relapse (n=7).Conclusion: In this older population of predominantly relapsed pts with myeloid leukemias, major cause of treatment failure was not the preparative regimen employed, but GVHD and disease relapse. An association between intensity of the regimen, age and GVHD cannot be ruled out in this analysis. These results would suggest that age per se should not be used as the main reason for selecting a reduced intensity regimen in patients up to at least age 60 with myeloid leukemias. [Display omitted]

Risk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia

Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to identify risk factors for BO using data from the International Bone Marrow Transplant Registry. Registry data on 6,275 adult patients with leukemia who received human leukocyte antigen-identical sibling transplants from 1989 to 1997 and survived at least 100 days after transplantation were evaluated for the study. Risk factors for BO were analyzed using proportional hazards regression. Seventy-six patients were found to have BO, with an incidence rate of 1.7% at 2 years after transplantation. The Kaplan-Meier estimate of median time to onset of BO was 431 days. Histologic evaluation was performed in 36 patients (47%). In 28 patients (37%), diagnosis was based on pulmonary function tests, CT scans of the chest, or a combination of both. On multivariate analysis, the factors that were associated with an increased risk for BO included the following: peripheral blood-derived stem cell, a busulfan-based conditioning regimen, interval from diagnosis to transplant > or = 14 months, female donor to male recipient sex match, prior interstitial pneumonitis, and an episode of moderate-to-severe acute graft-vs-host disease (GVHD). In addition to corroborating previously reported risk factors, such as acute GVHD and a busulfan-based conditioning regimen, we found that peripheral blood stem-cell transplantation, long duration to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are associated with an increased risk for BO.

Incidence of Extramedullary Relapse of Acute Myeloid Leukemia Following Transplantation with Busulfan-Based Conditioning Regimens.

Rates of extramedullary relapse are reported to be more than twice as high following transplantation with busulfan-based conditioning regimens (Simpson et al, Bone Marrow Transplantation 1998, Lee et al, Bone Marrow Transplantation 2000) compared to total body irradiation (TBI)-based regimens (Mortimer et al, J. Clin Oncol 1989) in acute myeloid leukemia (AML). Up to 50% of relapses following transplantation with busulfan-based therapies are reported to be extramedullary, with more than 25% as isolated extramedullary relapses. We analyzed 228 consecutive AML patients who underwent allogeneic (n=192) or autologous (n=36) transplantation following busulfan-based conditioning regimens between 2/84 and 12/03. One hundred twenty-three patients were in remission at the time of transplantation, 67 had relapsed disease, and 38 had never achieved remission. One hundred twenty-seven patients received BuCy, 77 received BuCyVP16, and 24 (all autologous) received BuVP16. All patients had a lumbar puncture demonstrating no evidence of leukemia, and all received intrathecal methotrexate prophylaxis prior to receiving busulfan. Seventy-nine patients (35%) relapsed (any site) at a median of 6 months (range, 1 to 44 months) after transplantation. Fifteen patients (7%) relapsed at extramedullary sites, including 7 in the CNS. Ten patients (4%) had isolated extramedullary relapses at a median of 13 months (range, 1 to 44 months) after transplantation. Four had isolated CNS relapses, and 4 had isolated cutaneous relapses. Of patients transplanted in remission, only 2 relapsed at extramedullary sites, including one patient with an isolated CNS relapse.This retrospective study includes a substantially larger cohort of patients with longer follow-up than prior studies examining extramedullary relapse in patients with AML following transplantation with busulfan-based conditioning. In contrast to other reports, these results demonstrate that the incidence of extramedullary relapse is comparable to that reported with TBI-based conditioning regimens for patients with AML.

Prevention of Veno-Occlusive Disease in Hematopoietic Stem Cell Transplantation Due to Defibrotide Prophylaxis.

Veno-occlusive disease (VOD) is a serious complication of intensive chemotherapy regimens used in hematopoietic stem cell transplantation (HSCT). Incidence ranges from 10–60% (Chopra et al., 2000). Despite numerous therapeutic attempts described such as rtPA, TIPS and defibrotide mortality remains 80% (Fried et al., 1996). Risk factors for developing VOD are previous high-dose chemotherapy, unrelated donor transplants and busulfan-based conditioning regimens. In face of the frequency and high mortality due to absence of effective therapeutic options there is need for prophylaxis. We incorporated defibrotide into the supportive regimen for high risk patients undergoing a HSCT with busulfan containing conditioning regimens. From 01/2003 to 08/2004 44 patients (median age 52y, 24 male) receiving a busulfan containing regimen for HSCT (2 autologous, 42 allogeneic, 23 unrelated donors) were treated prophylactically with defibrotide as 800mg/24h continuous infusion from start of conditioning chemotherapy up to day +21 (group 1). Underlying diseases were: 10 AML, 24 NHL, 3 HD, 6 MM, 1 CML. Median number of previous regimens were 3. 27 patients had high-dose chemotherapies followed by autologous HSCT as prior therapy. From 07/2001 to 12/2002 16 patients (median age 45y, 11 male) receiving busulfan-based conditioning for allogeneic HSCT (7 unrelated donors) received heparin (300IE/h) for prophylaxis of VOD and catheter related thrombosis (group 2). Disease entities were 7 AML, 7 NHL, 1 HD, 1 ALL. Median number of previous regimen was 3. 11 patients had high-dose therapies followed by autologous HSCT as prior therapy. While in the latter group 1/16 patients developed and finally died of VOD, 3/44 in the defibrotide group did so. Date of VOD diagnosis in the patient not prophylatically treated with defibrotide was day +13 after HSCT compared to day +21, +25 and +27 in patients who received defibrotide prophylaxis. There were no serious adverse events (e.g. bleeding) attributable to defibrotide. Overall incidence of VOD in both groups is low (6,8% group 1; 6,3% group 2). Although patients in group 1 were at high risk of VOD, no VOD occurred during the period of defibrotide prophylaxis. We conclude that defibrotide is save and efficient in prevention of VOD. Defibrotide delayed the onset of VOD beyond its application. However, with defibrotide prophylaxis late onset of VOD has to be encountered. The optimal application period has to be determined.

Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens.

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.