melphalan and Hepatic-Veno-Occlusive-Disease

Sinusoidal obstruction syndrome is a rare complication of autologous hematopoietic stem cell transplantation. This syndrome is mainly described following conditioning regiment with busulfan, cyclophosphamide and/or total body irradiation.. We report for the first time two cases of sinusoidal obstruction syndrome occurring lately after BeAM conditioning regiment (bendamustine, etoposide, aracytine, melphalan) for autologous stem cell transplantation in patients treated for malignant lymphoma.. Our observations highlight the difficulty to diagnose this complication with often non-specific clinical presentation and possible delayed occurrence after to transplantation, but also the therapeutic challenges, defibrotide being the only agent currently efficient. Physiopathology and potential responsibility of bendamustine in the sinusoidal obstruction syndrome occurrence will be discussed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Carmustine; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Melphalan; Middle Aged; Transplantation Conditioning; Transplantation, Autologous

CAMT is a bone marrow failure syndrome that usually presents with isolated thrombocytopenia soon after birth. HSCT is curative, and MAC is associated with increased transplant-related morbidity and mortality, especially in the unrelated setting. We used a RIC regimen with alemtuzumab, fludarabine, and melphalan in a seven-month-old patient with CAMT who underwent a MUD HSCT. The transplant was well tolerated with few complications. Neutrophil and platelet engraftment occurred on day +12 and +29, respectively, and she had 100% donor chimerisms on days +19.

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Blood Platelets; Congenital Bone Marrow Failure Syndromes; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infant; Melphalan; Methylprednisolone; Mucositis; Neutrophils; Thrombocytopenia; Transplantation Conditioning; Vidarabine

To evaluate long-term survival of the first cohort of stage-4 neuroblastoma patients treated with the N7 induction chemotherapy, surgery of the primary tumor and high-dose chemotherapy (HDC) containing Busulfan-Melphalan (Bu-Mel) followed by autologous stem cell transplantation (ASCT).. From 1998 to 1999, 47 children were included in the NB97 trial and treated with induction chemotherapy according to the N7 protocol, followed by surgery of the primary tumor. HDC (Busulfan, 600 mg/m(2) Melphalan, 140 mg/m(2) ) was administered in patients with partial response of metastases with no more than 3 mIBG spots. Radiotherapy was delivered to the primary tumor site when tumors displayed MYCN amplification.. Thirty-nine patients received Bu-Mel (83%): 23 who had achieved complete response (CR) of metastases, 20 after induction treatment and 3 after second-line chemotherapy, and 16 in partial response (PR). The toxicity of the whole treatment was manageable. The main HDC related-toxicity was hepatic veno-occlusive disease grade > 2 occurring in 15% of the patients. The 8-year EFS of the whole cohort was 34% (95% CI, 22-48%). The 8-year EFS of the 39 patients who received Bu-Mel and ASCT was 41% (95% CI, 27-57%). Patients who achieved a CR of metastases at the end of induction chemotherapy had a significantly better outcome than the others (8-year EFS, 52% vs. 20%; P = 0.02).. The long-term results of this first prospective cohort of patients with metastatic disease treated with the N7 induction chemotherapy and HDC (Bu-Mel) confirm published data with stable survival curves but with a longer follow-up.

Topics: Abdominal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Consolidation Chemotherapy; Disease-Free Survival; Follow-Up Studies; Gene Amplification; Genes, myc; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infant; Kaplan-Meier Estimate; Melphalan; Myeloablative Agonists; Neuroblastoma; Proportional Hazards Models; Remission Induction; Thoracic Neoplasms; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome

Hepatic veno-occlusive disease (HVOD) is a frequent complication during hematopoietic stem-cell transplantation (HSCT). A strong relationship has been demonstrated between busulfan exposure and HVOD for busulfan-cyclophosphamide and allogeneic HSCT in adults. Busulfan disposition after the first intake was studied in 77 children treated for solid malignancies with high-dose busulfan-containing regimens and autologous HSCT. Busulfan was combined with cyclophosphamide and melphalan (n=30), melphalan (n=27), and thiotepa (n=20). No relationship was observed between busulfan exposure and HVOD. In contrast, plasma ferritin at baseline was higher in patients with HVOD (750 ng/ml (20-3,110)) compared with those without HVOD (189 ng/ml (8-3,967), P=0.012). Multivariate analysis showed that a ferritin level exceeding 300 ng/ml was the only risk factor for HVOD with an odds ratio of 4.0 (confidence interval 95% (1.5-11.2), P=0.0071). A high ferritin level at baseline was explained by the diagnosis of neuroblastoma, related treatments and transfusions.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Ferritins; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Iron; Male; Melphalan; Neoplasms; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Severity of Illness Index; Thiotepa; Transferrin; Transplantation, Homologous; Treatment Outcome

Veno-occlusive disease of the liver (VOD) is a potentially severe complication of high-dose cytoreductive therapy (HDT) used for stem cell transplantation (SCT). This complication is uncommon after HDT for autologous SCT (ASCT) in patients with multiple myeloma (MM). The Spanish Myeloma Group/PETHEMA conducted a study (MM2000) for patients with newly diagnosed MM consisting of induction with alternating VBMCP/VBAD chemotherapy followed by intensification with busulfan/melphalan (Bu/MEL) with a second high-dose therapy procedure in patients not achieving at least near-complete remission with the first procedure. After 2 years of the trial, a number of episodes resembling classical VOD but with a late onset were recognized. Consequently, the protocol was modified, and Bu/MEL was replaced by melphalan 200 mg/m(2) (MEL-200). Three years later, after a total of 734 patients had undergone first autologous SCT, the incidence and characteristics of VOD episodes were analyzed in the whole series. Nineteen cases of VOD (8%) were observed among the first 240 patients receiving Bu/MEL, whereas only 2 (0.4%) were observed among the 494 patients treated with MEL-200 (P < .0001). VOD manifestations in the Bu/MEL group appeared at a median of 29 days (range, 3-57 days) after ASCT. Mortality directly attributable to VOD was 2% in the Bu/MEL group and 0.2% in the MEL-200 group (P = .026). This high incidence of severe VOD probably had a multifactorial origin (busulfan followed by melphalan and previous use of BCNU). This observation should be kept in mind when designing future trials for the treatment of MM.

Topics: Adult; Aged; Busulfan; Dose-Response Relationship, Drug; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Spain; Transplantation Conditioning; Transplantation, Autologous

CBV and BEAM are the two most frequently used regimens for patients with lymphoma undergoing autologous hematopoietic stem-cell transplantation (ASCT). This study compared their morbidity and transplant-related mortality (TRM) in 113 patients with non-Hodgkin's lymphoma (69) and Hodgkin's disease (44) undergoing ASCT between 1990 - 2004. CBV (cyclophosphamide, 6000 mg m(-2); VP-16, 750 mg m(-2); and high-dose BCNU, 800 mg m(-2)) was administered to 75 patients and 38 received BEAM (BCNU, 300 mg m(-2); VP-16, 800 mg m(-2); cytarabine, 800 mg m(-2); melphalan, 140 mg m(-2)). Patients in the BEAM group had a significantly higher median age (p = 0.002) and were more heavily treated before ASCT (p = 0.003). More patients showed active disease at transplant in the BEAM group (p = 0.04). Sinusoidal obstruction syndrome (SOS) was more frequent in the CBV group (11% vs 0%, p = 0.048). There were 20 (18%) transplant-related deaths, 18 in the CBV and two in the BEAM group. Infectious complications (12 patients, seven with pneumonia) and SOS (four) were the most frequent causes of death. The cumulative incidences of TRM were 25% in the CBV and 7% in the BEAM group (p = 0.02). CBV thus produced a higher incidence of SOS and TRM than BEAM in this series.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cyclophosphamide; Cytarabine; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infections; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Male; Melphalan; Middle Aged; Morbidity; Mortality; Podophyllotoxin; Transplantation Conditioning; Transplantation, Autologous

A strong relationship has been demonstrated between high systemic exposure to busulfan and the occurrence of hepatic veno-occlusive disease (HVOD) after a busulfan-cyclophosphamide regimen (BU CY). We report a prospective study aimed at exploring the pharmacodynamics of high-dose busulfan combined with either melphalan (BU MEL) or thiotepa (BU TTP) followed by autologous stem cell transplantation in children and adolescents with a malignant solid tumor. Busulfan was given orally at a total dose of 600 mg m(-2). In all, 45 patients with a median age of 6.3 years were included in the study: 25 received BU MEL and 20 received BU TTP. The incidence of HVOD was 44% (CI 95% [23-65%]) in the BU MEL group and 25% (CI95% [9-49%]) in the BU TTP group. In the BU TTP group, patients who developed HVOD had a significantly higher AUC 0-6 h after the 13th dose (6201+/-607 h ng ml(-1)) than those who did not (5024+/-978 h ng ml(-1)) (P<0.05). In the BU MEL group, there was no difference in terms of systemic exposure to busulfan between patients who developed HVOD and those who did not. In conclusion, the guidelines established for monitoring BU CY cannot be extrapolated when busulfan is combined with another drug.

Topics: Adolescent; Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Busulfan; Child; Child, Preschool; Drug Interactions; Drug Monitoring; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Male; Melphalan; Neoplasms; Pharmacokinetics; Thiotepa; Transplantation, Autologous

We conducted a phase I/II trial, to evaluate the efficacy and safety of an intravenous liposomal formulation of busulphan (LBu) as a myeloablative agent for stem cell transplantation (SCT). The liposomal busulphan was administered as a 3 h infusion twice daily over 4 consecutive days. Six adults received 1.6-2 mg/kg/dose and 18 children received 1.8-3 mg/kg/dose. Pharmacokinetic parameters were studied after the first and the last dose of busulphan. No significant difference in clearance, AUC, elimination half-lives or distribution volume between the first and the last dose was found in either groups. A significantly (P < 0.005) higher clearance was observed in children after the first and the last dose (3.61 and 3.79 ml/min/kg, respectively) compared to adults (2.40 and 2.33 ml/min/kg, respectively). The elimination half-lives after the first and the last dose were significantly (P < 0.005) shorter in children (2.59 and 2.72 h, respectively) compared to adults (3.35 and 3.61 h, respectively). Clearance correlated significantly with age. However, no significant correlation with age was observed when clearance was adjusted to the body surface area. Two cases of VOD following a total dose of 24 mg/kg were observed. Six patients experienced mucositis. No other organ toxicity was observed. We conclude that intravenous liposomal busulphan pharmacokinetics is age dependent. A dosage schedule based on body surface area should be used especially in young children to reduce the age-dependent difference in kinetics. An intravenous liposomal dose of busulphan of 500 mg/m(2) is suggested to reach a similar systemic exposure and myeloablative effect in both children and adults. Moreover, the novel liposomal form of busulphan showed a favorable toxicity profile and seems safe as a part of the high-dose therapy prior to SCT.

Topics: Adult; Age Factors; Busulfan; Child; Cyclophosphamide; Drug Administration Schedule; Drug Carriers; Female; Genetic Diseases, Inborn; Graft vs Host Disease; Half-Life; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Infant; Infusions, Intravenous; Liposomes; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Stomatitis; Transplantation Conditioning

The purpose of this study was to determine the incidence of veno-occlusive disease (VOD) after a high-dose regimen of busulfan, melphalan, and thiotepa and the risk factors for a more severe outcome. We followed 253 consecutive patients with malignant disorders who received autologous transplants after stem cell harvest followed by 12 mg/kg busulfan, 100 mg/m2 melphalan, and 500 mg/m2 thiotepa. Diagnosis of VOD was based on weight gain, hepatomegaly, and jaundice. Risk factors for moderate or severe VOD were identified using logistic regression models. VOD occurred in 70 of 253 patients (28%), of whom 31 (12%) had moderate and 11 (4%) severe VOD. The median day of onset of hyperbilirubinemia was day 9, significantly later than the onset of jaundice after our cyclophosphamide-based regimens (p < 0.001). Resolution of weight gain and jaundice, followed by their reappearance several weeks later, occurred in 23 of 70 patients with VOD and was an adverse prognostic sign. Risk factors for moderate or severe VOD were a diagnosis of lymphoma or myeloma (odds ratio [OR] 2.65 compared with breast cancer), tumor involvement in the liver (OR 3.95), fever in the month before transplant (OR 3.32), and prior radiation therapy (OR 2.70). We conclude that VOD after busulfan, melphalan, and thiotepa was less frequent and less severe and developed later than VOD after our historical cyclophosphamide-based regimens. Significant risk factors included a diagnosis other than breast cancer, hepatic metastases, persistent fever, and prior radiation therapy. This study suggests that alkylating agents of comparable overall toxicity differ in their liver toxicity.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents, Alkylating; Busulfan; Child; Child, Preschool; Cyclophosphamide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Incidence; Liver Diseases; Male; Melphalan; Middle Aged; Multiple Organ Failure; Multivariate Analysis; Radiotherapy; Risk Factors; Survival Rate; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Whole-Body Irradiation

Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012)) and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041) were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.

Topics: Busulfan; Child; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Melphalan; Neuroblastoma; Transplantation Conditioning

Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a "standard" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child, Preschool; Ferritins; Hepatic Veno-Occlusive Disease; Humans; Immunotherapy; Immunotherapy, Adoptive; Infant; Killer Cells, Natural; Liver Failure; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Neuroblastoma; Peripheral Blood Stem Cell Transplantation; Systemic Inflammatory Response Syndrome; Transplantation Conditioning

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carmustine; Computed Tomography Angiography; Cytarabine; Dexamethasone; Etoposide; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Lymphoma, Mantle-Cell; Male; Melphalan; Organoplatinum Compounds; Syndrome

This mono-institutional observational study was conducted to determine incidence, severity, risk factors, and outcome of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) in high-risk Ewing sarcoma (ES) patients treated with intravenous busulfan and melphalan (BU-MEL) followed by autologous stem cell transplantation (ASCT). During the past 10 years, 75 consecutive ES patients resulted evaluable for the analysis. After diagnosis of SOS/VOD, defibrotide therapy was started as soon as the medication was available. The variables analyzed as potential risk factors were: gender, patient's age at diagnosis, primary tumor site, disease stage, and prior radiation therapy (RT) given, focusing on RT liver exposure. The median age at diagnosis was 18.8 years. Five patients developed moderate to severe SOS/VOD (cumulative incidence, 6.67%). None of 32 pediatric patients (≤17 years) developed SOS/VOD (p = 0.0674). In univariate analysis, prior RT liver exposure resulted statistically significant (p = 0.0496). There was one death due to severe SOS/VOD. This study reports the largest series of high-risk ES patients treated with intravenous BU-MEL before ASCT. The incidence of SOS/VOD was lower when compared with other studies that used oral busulfan. Any prior RT liver exposure should be avoided. Earlier defibrotide treatment confirms to be effective.

Topics: Adolescent; Adult; Busulfan; Child; Child, Preschool; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Polydeoxyribonucleotides; Radiotherapy; Risk Factors; Sarcoma, Ewing; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Treatment Outcome; Young Adult

The optimal autologous stem cell rescue (HDC-SCR) regimen for children with high-risk neuroblastoma (HR-NBL) is not defined. Carboplatin/etoposide/melphalan (CEM) is the current US standard; however, European data suggest busulfan/melphalan (Bu/Mel) may have less toxicity. Published data regarding toxicities associated with CEM and Bu/Mel are limited. We conducted a single-institution retrospective cohort study of children with HR-NBL who received CEM or Bu/Mel preparative regimens. Toxicity data were analyzed using χ(2) or Fisher's exact, Wilcoxon two-sample or log-rank tests. Sinusoidal obstruction syndrome (SOS) was observed in 7/44 CEM (15.9%) and 5/21 (24%) Bu/Mel patients (P=0.50). Median time to SOS was longer following Bu/Mel than CEM (20 versus 9 days, P=0.02). Pulmonary hypertension (PHTN) was observed in ~20% of children after Bu/Mel and none after CEM (P=0.01). CEM patients had more nephrotoxicity (P=0.001), packed red blood cell (P=0.02) and platelet transfusions (P=0.008), and days on maximum pain support (P=0.0007). Time to engraftment, length of stay, documented infection rates and HDC-SCR-related mortality were similar. Nephrotoxicity and resource utilization associated with cytopenias and mucositis were greater after CEM. Pulmonary toxicities were more severe after Bu/Mel, and increased vigilance for PHTN may be warranted, particularly in children with hypoxemia out of proportion to respiratory distress.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carboplatin; Child; Child, Preschool; Cohort Studies; Etoposide; Female; Hepatic Veno-Occlusive Disease; Humans; Hypertension, Pulmonary; Infant; Kidney Diseases; Male; Melphalan; Mucositis; Myeloablative Agonists; Neuroblastoma; Pancytopenia; Retrospective Studies; Stem Cell Transplantation; Transplantation Conditioning; Young Adult

Gilbert's syndrome is a common inherited disorder of bilirubin metabolism, characterised by mild, unconjugated hyperbilirubinaemia. However, the effect of Gilbert's syndrome on the disposition of some drugs can lead to unexpected toxicity. We tested the hypothesis that patients undergoing myeloablative conditioning and haemopoietic cell transplantation would have different mortality outcomes depending on whether or not they had laboratory evidence of Gilbert's syndrome.. In this retrospective cohort study, we used clinical and laboratory data of patients who had haemopoietic cell transplantation from Jan 1, 1991, to Dec 31, 2011. Patients were included if they had received high-dose conditioning regimens of cyclophosphamide plus total body irradiation (CY/TBI), busulfan plus cyclophosphamide (BU/CY), busulfan plus melphalan plus thioTEPA (BUMELTT), or melphalan before transplant. Patients were excluded if their original consent forms to report transplant outcomes were not signed, if consent was withdrawn, or if they were a prisoner. Patients with Gilbert's syndrome were defined as having laboratory values before the start of conditioning therapy for unconjugated serum bilirubin concentrations of at least 17·1 μmol/L (≥1 mg/dL), normal conjugated serum bilirubin, and no evidence of hepatitis, cholestasis, or haemolysis. We assessed the association of Gilbert's syndrome with overall mortality and non-relapse mortality using adjusted Cox regression models at day 200 after transplantation.. Our study cohort was 3379 patients-1855 (55%) allograft and 1524 (45%) autograft recipients. 211 (6%) patients had Gilbert's syndrome and 3168 (94%) did not have this condition. Most patients were adults (median age 45·8 years [IQR 33·2-55·5]) with haematological malignancies. For overall mortality 664 (20%) patients had died by day 200 after transplant (47 [22%] of 211 who had Gilbert's syndrome vs 617 [19%] of 3168 who did not have Gilbert's syndrome), and for non-relapse mortality 499 (92%) patients had died before relapse was recorded (38 [18%] who had Gilbert's syndrome vs 461 [15%] who did not have Gilbert's syndrome). The effect of Gilbert's syndrome on the risk of overall mortality and non-relapse mortality by transplant day 200 varied between the conditioning regimens and donor groups. In patients conditioned with a myeloablative regimen that contained busulfan (n=1131), those with Gilbert's syndrome (n=60) were at a significantly increased risk of death and non-relapse mortality by day 200 compared with those without Gilbert's syndrome (n=1071; hazard ratio [HR] 2·30, 95% CI 1·47-3·61, p=0·00030; and 2·77, 1·71-4·49, p<0·0001). In patients who received CY/TBI or melphalan conditioning regimens, those with Gilbert's syndrome had similar outcomes to those without Gilbert's syndrome (overall mortality at day 200 HR 0·90, 95% CI 0·60-1·34, p=0·60; non-relapse mortality at day 200: 0·90, 0·56-1·45, p=0·65). Analyses of causes of death and busulfan disposition provided no mechanistic explanation for the differences in mortality.. Overall mortality and non-relapse mortality at day 200 after transplant were significantly worse in patients with Gilbert's syndrome who received busulfan-containing myeloablative conditioning regimens, compared with non-Gilbert's syndrome patients. Patients with Gilbert's syndrome should receive busulfan-containing myeloablative conditioning regimens with caution.. US National Institutes of Health.

Topics: Adult; Bilirubin; Busulfan; Cohort Studies; Cyclophosphamide; Dose-Response Relationship, Drug; Female; Gilbert Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Recurrence; Retrospective Studies; Risk Factors; Thiotepa; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Washington; Whole-Body Irradiation

Topics: Adult; Busulfan; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Infusions, Intravenous; Lymphoma, Non-Hodgkin; Male; Melphalan; Middle Aged; Myeloablative Agonists; Thiotepa; Transplantation Conditioning; Transplantation, Autologous

We report the case of a 58-year-old man with multiple myeloma stage III A who received tandem autologous stem cell transplantation after induction by two courses of VAD and three cycles of bortezomib-dexamethasone, due to progression under chemotherapy. The second transplantation was complicated by severe hepatic veno-occlusive disease (HVOD). The patient received defibrotide with total recovery. The occurence of HVOD after conditioning by melphalan is uncommon and the role of bortezomib was questioned.

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Dexamethasone; Doxorubicin; Etoposide; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloablative Agonists; Pyrazines; Stem Cell Transplantation; Transplantation Conditioning; Transplantation, Autologous

Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant problems after RICBT, and that GVHD and blood stream infection contribute to their pathogenesis.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Busulfan; Chemical and Drug Induced Liver Injury; Cholangitis; Cord Blood Stem Cell Transplantation; Cyclosporine; Female; Hematologic Diseases; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunosuppressive Agents; Incidence; Infant, Newborn; Liver Diseases; Liver Function Tests; Male; Melphalan; Middle Aged; Postoperative Complications; Risk Factors; Tacrolimus; Tissue Donors; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation

Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-Hodgkin's lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n = 48) and an RIR (n = 40) of fludarabine 125 mg/m(2) and melphalan 140 mg/m(2). Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine + methotrexate +/- prednisone for the CMR and with cyclosporine + mycophenolate +/- methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P = .05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR (P = .40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR (P = not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity (P = .03; relative risk [RR] = 35%) and absence of previous autologous transplantation (P = .0007; RR = 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation (P = .05; RR = 57%) and absence of previous autologous transplantation (P = .002; RR = 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse.

Topics: Adolescent; Adult; Aged; Busulfan; Cause of Death; Cohort Studies; Cyclophosphamide; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Infections; Kaplan-Meier Estimate; Lung Diseases, Interstitial; Lymphoma, Follicular; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Melphalan; Middle Aged; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Proportional Hazards Models; Reoperation; Retrospective Studies; Risk Factors; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine; Whole-Body Irradiation

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.

Topics: Adolescent; Alkylating Agents; Area Under Curve; Bayes Theorem; Bone Marrow Transplantation; Busulfan; Child; Child, Preschool; Cyclophosphamide; Etoposide; Female; Genetic Diseases, Inborn; Graft Survival; Hematologic Neoplasms; Hepatic Veno-Occlusive Disease; Humans; Incidence; Infant; Life Tables; Male; Melphalan; Prospective Studies; Severe Combined Immunodeficiency; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome

Patients with multiple myeloma (MM) and chronic renal failure have generally been excluded from myeloablative therapy programs followed by hematopoietic stem cell support because of the potential increase in transplant-related morbidity and mortality. We here report our experience treating six MM patients with moderate to severe renal insufficiency, with autologous stem cell transplantation. One of these patients required chronic hemodialysis since the diagnosis of MM was made. Peripheral blood stem cell collection was performed with either cyclophosphamide 5.5-7 g/m2 + G-CSF, 5 microg/kg/day (patients 1-3, 5 and 6) or G-CSF, 15 microg/kg/day alone (patient No. 4). Four patients (Nos 1-4) received autotransplant as front-line therapy, while the last two patients were treated in relapse, which occurred following prior autologous stem cell transplantation in support of melphalan, 200 mg/m2 (No. 5) or maintainance therapy with alpha-interferon (No. 6). High-dose chemotherapy administered as preparation to transplant included busulfan 12 mg/kg + melphalan 80 mg/m2 (patients 1-3 and 6) or melphalan 80 mg/m2 alone (patients 4 and 5) in order to reduce mucosal damage. Following transplant, prompt and sustained recovery of hematopoiesis was documented in all the patients; 500 PMN/microI and 20000 platelets/microI were reached after a median of 13 and 14 days, respectively. None of the patients suffered from WHO grade 3-4 infectious complications. Transplant-related toxicity included grade 3-4 oral mucositis (patients 1, 4 and 5) and veno-occlusive disease (patient No. 3). Renal function either improved or remained stable throughout the transplant period. All the patients but one responded to therapy, three of them are progression free after 2, 15 and 26 months; two relapsed after 16 and 4 months and one died from cholangiocarcinoma 7 months after transplant, while still in remission. Although our experience is limited so far, these results appear promising and support the investigational use of myeloablative therapy in MM patients with chronic renal failure.

Topics: Adult; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Cholangiocarcinoma; Combined Modality Therapy; Creatinine; Cyclophosphamide; Dexamethasone; Doxorubicin; Female; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperbilirubinemia; Immunologic Factors; Interferon-alpha; Kidney Failure, Chronic; Male; Melphalan; Metabolic Clearance Rate; Middle Aged; Multiple Myeloma; Neoplasms, Second Primary; Remission Induction; Renal Dialysis; Safety; Stomatitis; Survival Analysis; Transplantation, Autologous; Treatment Outcome; Vincristine

Eighteen patients with poor risk Ewing's sarcoma (including 11 patients with metastatic disease at presentation) received consolidation therapy of busulphan and melphalan with autologous stem cell rescue. There were nine females. The median age at diagnosis was 14.2 years (range 2.75-30 years). There was one early death due to cytomegalovirus pneumonitis. One patient developed a single generalised convulsion during busulphan therapy. Severe renal toxicity was not encountered. One patient developed veno-occlusive disease of the liver (VOD) which eventually resolved. With a median follow up of 2 years, 13 patients survive including six with initial metastatic disease. We conclude that high-dose busulphan/melphalan is well-tolerated and should be evaluated for efficacy in a larger series of patients with high risk Ewing's sarcoma.

Topics: Adolescent; Adult; Anticonvulsants; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Busulfan; Child; Child, Preschool; Clonazepam; Combined Modality Therapy; Contraindications; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Male; Melphalan; Neoplasm Metastasis; Phenytoin; Remission Induction; Sarcoma, Ewing; Seizures; Survival Analysis; Transplantation Conditioning; Treatment Outcome

Bone marrow transplant (BMT) complications such as graft-versus-host disease (GVHD), veno-occlusive disease (VOD) and cytomegalovirus (CMV) infection are associated with high levels of circulating tumour necrosis factor-alpha (TNF), much of which may be monocyte derived. We therefore studied monocyte activation after BMT in 36 patients (18 allografts and 18 autografts); plasma neopterin and in vitro secretion of superoxide, neopterin and TNF by peripheral blood monocytes were assessed. Monocyte respiratory burst was raised at regeneration but returned to near-normal within 7 days. Plasma neopterin, and in vitro secretion of neopterin and TNF, were greater than twice normal at regeneration and remained raised for up to 6 weeks after BMT. Plasma neopterin was higher following allogeneic BMT than autologous BMT and was independent of GVHD or VOD. Low levels were seen in one patient who failed to engraft. There is evidence of increased activation of monocytes at the time of and for several weeks after engraftment post-BMT. Abnormal monocyte activation may predispose to, rather than result from, the development of complications in the early post-transplant period.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biopterins; Bone Marrow Transplantation; Busulfan; Carmustine; Cells, Cultured; Combined Modality Therapy; Cyclophosphamide; Cytarabine; Disease Susceptibility; Female; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Leukemia; Lymphoma; Male; Melphalan; Middle Aged; Monocytes; Neopterin; Podophyllotoxin; Respiratory Burst; Superoxides; Tumor Necrosis Factor-alpha; Whole-Body Irradiation

Twenty-four children with relapsed or refractory non-Hodgkin's lymphoma underwent high-dose chemotherapy (HDC) with bone marrow transplantation (BMT). HDC comprised in all cases busulfan (16 mg/kg or 600 mg/m2), with either cyclophosphamide (200 mg/kg or 4.4 g/m2) and/or melphalan (140 mg/m2). Twenty-three of these children had received second-line therapy before receiving HDC. There were 16 B cell and eight T cell lymphomas. Twenty-three patients were evaluable at day 30 post-BMT; 19 were in complete remission, four did not respond. Eight patients are long-term survivors between 62 and 296 weeks after BMT. Among the seven children with resistant disease before HDC, only one is a long-term survivor. No toxic deaths occurred. The main adverse side effect was hepatic veno-occlusive disease which occurred in four patients, but resolved completely in all cases. Comparisons with other classic HDC regimens in relapsed childhood lymphomas show that HDC containing busulfan with BMT appears reasonably safe and is effective in refractory or relapsed lymphomas, even in these highly previously treated patients.

Topics: Adolescent; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Hepatic Veno-Occlusive Disease; Humans; Incidence; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma, T-Cell; Male; Melphalan

Topics: Adult; Bone Marrow Transplantation; Busulfan; Female; Hepatic Veno-Occlusive Disease; Humans; Melphalan

Two cases of veno-occlusive disease (VOD) occurring in metastatic neuroblastoma patients are reported. Treatment included a remission induction by conventional chemotherapy and surgery followed by an early consolidation with massive chemotherapy, total body irradiation and cleared autologous bone marrow transplantation (ABMT). Both patients had multiple halothane anesthesias. Liver complications occurred 10 and 21 days respectively after ABMT. The first patient had a precocious and severe clinical and biological VOD, heparinotherapy and symptomatic treatment were ineffective and he died 12 days after ABMT. The second patient had a moderate and later syndrome which was controlled by heparin therapy (100 U/kg/day) delivered by continuous infusion; he is now alive free of hepatic disturbance 28 months after ABMT. The potential iatrogenic factors are discussed, with special focus on the use of halogenated anesthetic drugs.

Topics: Adolescent; Anesthesia; Bone Marrow Transplantation; Child, Preschool; Halothane; Hepatic Veno-Occlusive Disease; Humans; Iatrogenic Disease; Male; Melphalan; Whole-Body Irradiation

The authors attempted to induce hepatic veno-occlusive disease (VOD) in 64 dogs. Preparative treatments included combinations of total-body irradiation (TBI) or localized hepatic irradiation (LI) or both and chemotherapy consisting of dimethylbusulfan (DMB), L-phenylalanine mustard (L-PAM), methotrexate, or monocrotaline. VOD occurred infrequently in those dogs given 9.2 Gy TBI and DMB (1/10), TBI and/or LI (9.2-27 Gy) with L-PAM (2/36) or high dose methotrexate and LI (0/2). Specifically, VOD occurred in the dogs with a shorter interval between TBI and DMB or in the dog that received the glutathione reductase inhibitor, buthionine sulfoximide (BSO) before L-PAM. In contrast, among 17 dogs given monocrotaline, 8 developed VOD, particularly when used with L-PAM +/- irradiation (7/13). The major cause of death, early gastrointestinal toxicity, was further augmented by higher doses of irradiation, by shortening the interval between LI and L-PAM administration to less than 4 weeks, and administering BSO or monocrotaline before L-PAM. Gastrointestinal toxicity was lessened by giving low dose cyclophosphamide given before L-PAM. VOD can be produced in dogs especially with monocrotaline or BSO given before and L-PAM +/- irradiation. However, gastrointestinal toxicity renders the study of VOD beyond the acute phase difficult. Nevertheless, this approach appears useful for the study of VOD in other animals and for developing agents aimed at preventing VOD.

Topics: Animals; Busulfan; Buthionine Sulfoximine; Cyclophosphamide; Disease Models, Animal; Dog Diseases; Dogs; Hepatic Veno-Occlusive Disease; Liver; Melphalan; Methionine Sulfoximine; Methotrexate; Monocrotaline; Pyrrolizidine Alkaloids; Radiation Injuries, Experimental; Radiography