Risk Of Veno-occlusive Disease Research Articles

Prior Treatment with Chemotherapy Associated to Gemtuzumab Ozogamicin (GO) Does Not Increase the Risk of Veno-Occlusive Disease (VOD) after Allogeneic Stem Cell Transplantation (all-SCT).

The combination of chemotherapy and GO is increasingly used for the treatment of CD33+ AML patients either at diagnosis or at time of relapse. GO is classically known to induce liver toxicity, that may significantly increase the risk of VOD, especially in patients receiving allo-SCT. A single study by Wadleigh et al (Blood, 2003) suggested an increased risk of VOD in patients who underwent myeloablative HSCT within a short interval from GO administration (<3.5 m.). However, no large series have comprehensively assessed this risk thus far. Here, we analysed the outcome of a cohort of 44 HSCT patients who had received previous combination of chemotherapy + GO in the course of their disease. This retrospective study included 44 patients (males, n=21) who received allo-SCT between Dec. 2001 and June 2008 after prior exposure to GO. Median age was 50 (range:3–67). There were 41 CD33+ AML, 2 CD33+ ALL and 1 CD33+ myeloid sarcoma. Before allo-SCT, 37 patients received the MIDAM regimen (GO: 9 mg/m², n=36; or GO 4.5 mg/m², n=1 at day 4 + Ara-C 1g/m²/12 hours day 1–5 + Mitoxantrone 12 mg/m²/day day 1–3). In 3 patients receiving MIDAM, Mitoxantrone was omitted. GO 9 mg/m² + other combinations of chemotherapy were used in the remaining 4 patients. Indications for the GO-based chemotherapy were as follow: first induction, n=3; second induction, n=4; primary refractory disease, n=14; first relapse, n=19; second relapse, n= 4. Only 1 patient developed VOD after receiving GO. In this series, 5 patients received an additional course of consolidation with GO+chemotherapy. Of note, 15 patients (34%) received prior auto-SCT. Median interval between last administration of GO and allo-SCT was 4.2 (range, 0.8–26.3) months, with 19 patients allografted <3.5 months from GO administration. At time of allo-SCT, 33 patients were in CR, and 11 remained refractory. The majority of patients (n=36; 82%) received a reduced intensity conditioning (RIC) regimen prior to allo-SCT, while 8 patients received a myeloablative regimen. The stem cell source was PBSC in 26, cord blood in 15, bone marrow in 2 and a CD34+ selected PBSC in 1 patient. Eleven patients received an allograft from an HLA matched related donor (MRD), 1 from an HLA mis-MRD, 16 from an HLA matched unrelated donor (MUD), and 1 from an HLA mis-MUD. All patients (but one who received defibrotide because of a prior history of VOD) received low-dose heparin as VOD prophylaxis. Engraftment was observed in 34 patients (77%) at a median of 15 (range, 8–43) days after allo-SCT. With a median FU of 15 (range, 1.1–63) m. for surviving patients, OS and DFS after allo-SCT were 45% (95%CI, 30–61%) and 38% (95%CI, 24–54%) at 3 years respectively. At time of analysis, 22 patients were still alive, while 22 patients died. The causes of death included: disease progression in 13, 1 fungal infection, 2 acute GVHD, 1 chronic GVHD, 3 multi organ failures, 1 ARDS, and one case of VOD, for an overall incidence of TRM of 20% in this high risk population. The incidence of Grade ¾ hyper-bilirubinemia was 13.5% (n=6), with this being 21% in patients with a short (<3.5 m.) GO-allograft interval (n=4/19) vs. 8% in all others (P=NS). In all, the incidence of VOD was 7% (n=3), with this being 10.5% (n=2/19) in patients with a short GO-allograft interval (<3.5 m.) vs. 4% (n=1/25) for all others (P=NS). Also, a myeloablative regimen was not associated with an increased risk of VOD (12.5%, n=1/8 vs RIC 5.5%, n=2/36, P=NS). Overall, these encouraging results suggest that GO-based (mostly salvage) therapy in combination with chemotherapy prior to allo-SCT is feasible and does not result in an excessive rate of toxicity, especially VOD, after allo-SCT.

Genetic Variations in CYP2B6 and Risk of Cyclophosphamide Toxicity in Patients Undergoing Myeloablative Stem Cell Transplantation.

In myeloablative stem cell transplantation (SCT), most patients receive cyclophosphamide (CPA) conditioning based on body weight or body surface area, under the assumption that each individual will metabolize the drug with the same efficiency. However, CPA requires biological activation, primarily by cytochrome P450 2B6 (CYP2B6), to exert its effects; therefore, patients with increased protein activity, as reported for *4 and *6 allelic variants, may have an increased risk for CPA-associated toxicity compared to patients with decreased protein activity, as reported for *5 and *7 allelic variants. In this study, we determine the relationship between allelic variants of CYP2B6 and toxicity outcomes and attempt to clarify the influence of CYP2B6 on the development of severe cardiac toxicity, veno-occlusive disease (VOD), and idiopathic pneumonia syndrome (IPS) early after SCT. A total of 259 DNA samples were obtained from patients who received 3.6 g/m2 or 120 mg/kg of CPA as part of a myeloablative allogeneic SCT between 2002 and 2006. Genotyping was performed using pyrosequencing to detect three SNPs, 516A>G, 785A>G and 1459C>T, associated with four allelic variants: *4 (785A>G), *5 (1459C>T), *6 (785A>G, 516G>T) and *7 (785A>G, 516G>T, 1459C>T). The patients' clinical history was reviewed and any instance of hepatic VOD, severe cardiac toxicity (i.e. myopericarditis ≥ grade 3) or IPS from 0 to 100 days post-transplant was recorded. Overall, 60 (24%) patients experienced toxicity (cardiac = 20; VOD = 26; IPS = 14). The prevalence of the *4, *5, *6 and *7 alleles was 3%, 8%, 23% and 2%; respectively. Patients heterozygous for *4, *5, *6 and *7 allelic variants and homozygous for the *6 allelic variant had similar rates of toxicity to those patients without allelic variants of CYP2B6, even when comparing each toxicity separately (Table 1). However, patients with decreased protein activity, *1/*5 and *1/*7, had a lower rate of toxicity compared to those with wild-type or increased protein activity, *1/*1, *1/*4, *1/*6 and *6/*6 (14.6% (7/48) vs. 26.1% (53/203)). In conclusion, variant alleles of CYP2B6 may predict a decreased risk of VOD, IPS, or cardiac toxicity within the first 100 days of SCT, but do not appear to predict an increased risk of toxicity.Table 1. Association of toxicities with genotypesGenotypePatientsAll ToxicitiesCardiac Grade ≥3VODIPS* 1/*19727 (28%)7 (7%)12 (12%)8 (8%)* 1/*483 (38%)0 (0%)2 (25%)1 (13%)* 1/*5385 (14%)2 (6%)1 (3%)1 (3%)* 1/*68018 (23%)7 (9%)8 (10%)3 (4%)* 1/*7102 (20%)1 (10%)1 (10%)0 (0%)* 6/*6185 (28%)*3 (17%)2 (11%)1 (6%)*One patient had both cardiac and VOD toxicity

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.

Immunoglobulin Prophylaxis in Patients Undergoing Hematopoietic Stem Cell Transplantation - Systematic Review and Meta-Analysis.

Background: Many studies have evaluated the role of polyvalent immunoglobulins (IVIG) and CMV-hyperimmune IVIG (CMV-IVIG) prophylaxis in patients undergoing hematopoietic stem cell transplantation (HSCT), with inconsistent results and implications for practice.Objectives: To evaluate the role of IVIG and CMV- IVIG prophylaxis in HSCT.Methods: Systematic review and meta-analysis of randomized controlled trials comparing IVIG or CMV- IVIG with placebo or no intervention (control) for prophylaxis in HSCT. The Cochrane Library, MEDLINE, conference proceedings and references were searched until 2007. Primary outcome: all-cause-mortality ; Secondary outcomes: CMV infections, acute graft versus host disease (GVHD), interstitial pneumonitis (IP), veno-occlusive disease (VOD) and adverse events. Relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled.Results: Nineteen trials met inclusion criteria. IVIG was compared to control in 10 trials (7 IVIG in allogeneic HSCT, 2 allogeneic/autologous HSCT and 1 autologous HSCT). When IVIG was compared to control, there was no difference in all-cause mortality (RR 1.03; 95% CI 0.89–1.18, 6 trials, Fig.). There was a reduction in the number of CMV infections (RR 0.70; 95% CI 0.50–0.99, 4 trials) and in the number of episodes of IP (RR 0.61; 95% CI 0.43–0.87, 6 trials). There was no significant difference in the number of episodes of acute GVHD (RR 0.93; 95% CI 0.83–1.05, 6 trials). The risk for VOD was increased (RR 2.71; 95% CI 1.06–6.94, 3 trials) as were adverse events in the IVIG group (RR 8.12; 95% CI 3.15–20.9, 5 trials). CMV-IVIG was compared to control in 7 trials, all allogeneic HSCT. There was no difference in all-cause mortality (RR 0.86; 95% CI 0.63–1.16, 4 trials). In addition, there were no differences in the risk for developing CMV infections (RR 1.07; 95% CI 0.86–1.33, 7 trials), acute GVHD (RR 1.02; 95% CI 0.72–1.44, 5 trials) or IP (0.95; 95% CI 0.58–1.56, 5 trials).Conclusions: Our review demonstrates that IVIG prophylaxis for HSCT reduces the risk for CMV infections and IP without a significant influence on mortality. The beneficial effects should be weighed against the higher incidence of adverse events, VOD, and cost associated with the use of prophylactic IVIG in HSCT patients. Conversely, the use of CMV-IVIG was not associated with a change in any of the parameters.Outcomes SummaryOutcomeIVIG vs. controlCMV-IVIG vs. controlAll Cause MortalityRR 1.03; 95% CI 0.89–1.18RR 0.86; 95% CI 0.63–1.16CMV infectionsRR 0.70; 95% CI 0.50–0.99RR 1.07; 95% CI 0.86–1.33acute GVHDRR 0.93; 95% CI 0.83–1.05RR 1.02; 95% CI 0.72–1.44IPRR 0.61; 95% CI 0.43–0.87RR 0.95; 95% CI 0.58–1.56VODRR 2.71; 95% CI 1.06–6.94No dataAdverse eventsRR 8.12; 95% CI 3.15–20.9RR 7.0; 95% CI 0.38–129.34 [Display omitted]

Risk Factor of Hepatic Veno-Occlusive Disease: Analysis of Clinical Data of 5024 Patients Extracted from the Database of the Japan Marrow Donor Program.

Hepatic veno-occlusive disease (VOD) is one of the most serious complication of hematopoietic stem cell transplantation (HSCT). Various factors have been identified as increasing the risk of hepatic VOD, but few of them have been associated with a significantly increased risk. We retrospectively analyzed the clinical data of 5024 transplant recipients (median age28, range 0–68) which extracted from the Japan Marrow Donar Program. The diagnosis of VOD was made according to the McDonald's criteria, and 324 out of 4833 patients (6.7%) were eventually diagnosed with VOD. The possible risk factors based on the previous studies were counted on an initial univariate analysis, and cumulated significant factors were further analyzed for their potential value for VOD development in multivariate analysis. Variables correlated with an increased risk of VOD were: time of transplant >2 times (relative risk (RR) 2.7; p=0.006), pretransplant disease status (RR 2.3; p=0.000), prior liver disease (RR 2.1; p=0.017), ABO blood type mismatch (RR1.7; p=0.000). In patients receiving either busulfan or melphalan for conditioning increased VOD risk (RR 1.5 and 1.8; p=0.007 and 0.002, respectively). In our multivariate analysis, stem cell source, and prophylactic use of heparin and Ursodiol had no significant effect on VOD development. This analysis might contribute to revise the previously reported risk factors for VOD and the data could be used to know which patients might be suitable subjects for new trials for VOD prevention.

Prognostic Impact of Elevated Serum Ferritin in Patients Undergoing Myeloablative Stem Cell Transplantation.

Patients undergoing allogeneic stem cell transplantation (alloSCT) for hematologic malignancies are often highly transfused, and thus at risk for transfusion-associated iron overload. In other settings, such as thalassemia or hemochromatosis, iron overload has been associated with organ toxicity, particularly hepatotoxicity, as well as with an increased susceptibility to infection. Since hepatic and infectious complications are frequent and life-threatening in patients undergoing alloSCT, iron overload could potentially be an important contributor to treatment-related morbidity and mortality after transplantation. We studied 935 consecutive patients who underwent myeloablative alloSCT at our institution between 1997 and 2005. A pre-transplant serum ferritin level, which we used as a surrogate measure of iron load, was available for 600 of the 935 patients (64%). The median ferritin level was 864ng/ml. The percentage of patients with serum ferritin ≥1000ng/ml was 47%. This percentage varied significantly between disease types, being lowest (6%) in patients with CML and highest (79%) in patients with AML. A ferritin level ≥1000ng/ml was associated with significantly worse overall and disease-free survival, as shown in the figure. [Display omitted] This was confirmed in proportional hazards models using the following covariates: age, type and stage of disease, cytogenetic risk group for AML and MDS, conditioning regimen, HLA match, graft source, GVHD prophylaxis regimen, CMV serostatus, gender, prior transplant, and year of transplantation. In this model, the hazard ratio for mortality associated with ferritin ≥1000ng/ml was 1.7 (95%CI=1.3 to 2.4, p=0.0005). In competing risks regression analysis, using the same covariates, an elevated serum ferritin was associated with a significant increase in non-relapse mortality (NRM) (HR=1.6, p=0.02), but not with a significant increase in the risk of relapse. The greatest impact of elevated serum ferritin on survival and NRM was in patients with MDS (HR for mortality=3.0, p=0.001). Because serum ferritin is an acute phase reactant, we performed the same analyses using pre-transplant albumin level as an additional covariate that could reflect general inflammatory state. Although albumin level was of independent prognostic significance, its inclusion in the multivariate models did not alter the conclusions. Finally, in logistic regression analyses, elevated serum ferritin was associated with a non-significant increase in the risk of veno-occlusive disease (OR=1.6, p=0.09), but not in an increased risk of acute GVHD (OR=0.9, p=0.4) or specifically of acute liver GVHD (OR=1.2, p=0.5).Conclusions: in patients undergoing myeloablative alloSCT, and particularly in those with MDS, an elevated serum ferritin is associated with significantly higher NRM, as well as significantly lower disease-free and overall-survival. Our results could be helpful in estimating prognosis for patients who are candidates for myeloablative alloSCT. They also pave the way for prospective trials on the impact of iron overload and on the possible beneficial role of iron chelation in this patient population.

Use of prophylactic anticoagulation and the risk of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation: a systematic review and meta-analysis

Hepatic veno-occlusive disease is a serious regimen-related toxicity in patients undergoing hematopoietic stem cell transplantation. We performed a systematic review and meta-analysis of the literature on the effect of anticoagulation in preventing veno-occlusive disease. Several databases and online journals were searched for randomized controlled trials and cohort studies. Twelve studies (2782 patients) were eligible. Anticoagulation prophylaxis was associated with a statistically nonsignificant decrease in risk of veno-occlusive disease (pooled relative risk (RR), 0.90; 95% confidence interval (CI), 0.62-1.29). Results of one of three randomized controlled trials may have been affected by delayed introduction of anticoagulation. A second trial enrolled patients who received conventional chemoradiotherapy for early-stage disease (RR, 0.18; 95% CI, 0.04-0.78). The third trial was a pilot study with a small sample size (RR, 0.74; 95% CI, 0.53-1.04). Significant heterogeneity and methodologic weaknesses preclude drawing a meaningful conclusion from the pooled analysis. Despite some limitations, results of two of three eligible randomized controlled trials suggest that prophylactic anticoagulation may help prevent veno-occlusive disease. However, a large randomized controlled trial is needed for confirmation. Additionally, in future studies, owing to the wide spectrum of severity of veno-occlusive disease, outcomes such as 100-day mortality should strongly be considered.

Low Incidence of Hepatic Veno-Occlusive Disease after Fractionated Doses of Mylotarg and Autologous or Allogeneic Stem Cell Transplantation.

Background. Gemtuzumab ozogamicin (GO, Mylotarg®) is a humanized calicheamicin-conjugated monoclonal antibody targeted to the CD33 antigen present on myeloblasts. A 28% response rate in acute myeloblastic leukaemia (AML) in first relapse was reported in phase 2 single agent trials using Mylotarg at a dose of 9 mg/m2 for two doses at 14 days interval. Significant hepatotoxicity was observed and an increased risk (up to 60%) of developing veno-occlusive disease (VOD) was also reported in patients receiving stem cell transplantation (SCT) after GO exposure. Risk of VOD was correlated with a short interval, less than 3,5 months from GO administration to SCT. We report here the feasibility of an intensive consolidation therapy followed by autologous or allogeneic SCT in patients with AML in complete remission after a reduced and fractionated salvage therapy with GO.Patients and methods. We retrospectively collected the results from 10 consecutive patients (median age 47 years; 18 years to 62 years) treated in 4 haematological centers. All patients received 3 infusions of GO 3 mg/m2/d at day 1, day 4 and day 7 during the induction course. Consolidation modalities and conditioning regimens before HSCT were adapted in each center.Results. Eight patients were in relapse (first relapse, n=4; second and subsequent relapses, n=4) and 2 were primary refractory to induction therapy. After GO salvage therapy, 6 patients achieved a complete remission (CR) and 4 a CR without normalization of the platelets counts (CRp). A grade 1 toxicity and a non severe VOD were recorded during salvage therapy. Consolidation therapy was administered in 6 cases (based on Ara-C chemotherapy in 5 cases and GO administration (3 mg/m2 day 1) in 1 case). Five patients received an allogeneic SCT (genoidentical donors n=2, phenoidentical donors n=3, one of those after a non myeloablative conditioning regimen) and five patients received an autologous SCT after a conditioning regimen with busulfan and melphalan. Median interval between the last chemotherapy and the graft was 47 days (16 to 61 days) and median interval from the last dose of GO and the graft was 108 days (16 to 221 days). Three cases (30%) of hepatic toxicity were recorded (grade 1, n=1; grade 2, n=1; grade 3, n=1), including 2 cases with VOD (20%), one of them confirmed by liver biopsy. The two patients with VOD were successfully treated with defibrotide and normalization of the hepatic tests was obtained. In both cases, the conditioning regimen was TBI/EDX and the interval from the last GO infusion to SCT was short (30 days and 16 days). Of note, the patient who experienced hepatic toxicity during the fractionated induction course did not experienced hepatic toxicity during the intensive SCT phase. Overall, median DFS and OS post SCT were 6.4 months and 8.6 months respectively.Conclusion. This retrospective study argues in favour of a lower hepatotoxicity with fractionated doses of GO leading to a lower risk of VOD when stem cell transplant is used as post remission therapy.

Decreased incidence of hepatic veno-occlusive disease and fewer hemostatic derangements associated with intravenous busulfan vs oral busulfan in adults conditioned with busulfan + cyclophosphamide for allogeneic bone marrow transplantation

We investigated the occurrence of hepatic veno-occlusive disease (VOD) after allogeneic bone marrow transplantation (BMT) in 241 adults conditioned with busulfan + cyclophosphamide at a single institute and retrospectively compared 186 patients who received oral busulfan (O-Bu group) with 55 patients who received intravenous busulfan (I-Bu group). Various hemostatic parameters were determined at baseline and on days 0, 7, 14, and 21. Hepatic VOD occurred in 41.7% of the O-Bu group and in 18.5% of the I-Bu group. Multivariate analysis revealed that the I-Bu group had significantly decreased risk of VOD compared to the O-Bu group [p=0.006, odds ratio: (OR) 0.345]. Eleven patients in the O-Bu group and none of the I-Bu group developed severe VOD. A repeated measures analysis of variance (ANOVA) with a between-subjects factor revealed significant differences in post-transplant levels of antithrombin III, tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and D-dimer according to the occurrence of VOD. The level of antithrombin III was significantly lower, whereas the level of D-dimer was significantly higher, in the O-Bu group than in the I-Bu group. These findings show that, in adults conditioned with busulfan + cyclophosphamide, intravenous busulfan was associated with significantly decreased incidence of VOD and fewer hemostatic derangements after allogeneic BMT compared to oral busulfan.

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.

Veno-occlusive disease of the liver after hemopoietic cell transplantation.

The clinical syndrome of veno-occlusive disease (VOD) after hemopoietic cell transplantation is characterised by jaundice, painful liver enlargement, and fluid retention with weight gain. Cytoreductive therapy is presumably the primary cause of VOD, but several other agents (and a special susceptibility of the liver) can also play a role in its genesis. The risk of VOD can be predicted before BMT by analysing the presence or absence of the main risk factors. For the diagnosis of VOD most teams worldwide apply the clinical criteria developed by both the Seattle and Baltimore teams. Transjugular liver studies and some biological markers can help establish a correct differential diagnosis. In most cases clinical manifestations improve after several days, but 20-25% of patients could die of VOD. Data regarding whether or not pharmacological prophylactic measures are effective are contradictory. There a few therapeutical approaches directed towards the improvement of venular occlusion; recombinant tissue plasminogen activator and defibrotide can solve some cases of severe VOD.

Hormonal Therapy After Stem Cell Transplantation and the Risk of Veno-occlusive Disease

To the Editor: The elegant report from Hagglund et al[1][1] recently published in Blood raises a very important ethical issue in clinical hematology practice: primum non nocere. The authors describe the impact of norethisterone treatment, routinely used in the prevention of menstrual bleeding in

Veno-occlusive disease of the liver after bone marrow transplantation: is hypercoagulability really part of the problem?

Patients undergoing bone marrow transplantation (BMT) experience changes in various proteins with important functions in the coagulation and fibrinolysis system. Veno-occlusive disease (VOD) of the liver is a leading cause of non-relapse mortality after BMT. Because of the concurrent occurrence of changes in the coagulation and fibrinolysis system and development of VOD, most authors assume a causative relationship between these two observations, but the results leading to this conclusion are not unequivocal. Data currently available do not allow the conclusion that coagulation activation and local excess fibrin generation are key factors in the pathogenesis of VOD. One approach to deciding whether there is, in fact, excessive local fibrin generation during the development of VOD might be the monitoring of high risk patients with tools that enable differentiation of local and systemic hypercoagulability (e.g. anti-D-dimer immunoscintigraphy). Screening of patients at risk for VOD with special coagulation parameters pretransplant does not seem appropriate at present. However, markedly increased plasminogen activator inhibitor-1 levels (from baseline) seem to be appropriate tool to confirm the diagnosis of VOD when clinical suspicion exists. More research is needed in order to advance our understanding of the disease and to improve outcomes in both the prophylaxis and treatment of VOD.

Veno‐occlusive disease of the liver in children treated for Wilms tumor

Introduction Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. Methods To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) ± other drugs ± radiotherapy according to surgical stage and histology. Results Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during pre-operative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6–180 days using supportive therapy only. Conclusions (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patients. Med. Pediatr. Oncol. 29:245–251, 1997. © 1997 Wiley-Liss, Inc.

Veno-occlusive disease of the liver in children treated for Wilms tumor.

Hepatotoxicity consistent with the clinical diagnosis of veno-occlusive disease (VOD) of the liver has been suspected after conventional anti-cancer chemotherapy in children. To establish the incidence of hepatotoxicity and its relationship with VOD, we analyzed toxicity data obtained on 511 children affected by Wilms tumor and treated according to the SIOP-9 protocol. They all received pre- and postnephrectomy chemotherapy using dactinomycin (AD) and vincristine (VCR) +/- other drugs +/- radiotherapy according to surgical stage and histology. Sixty-four patients suffered at least one episode of hepatotoxicity and 41 satisfied the criteria for a clinical diagnosis of VOD. In this latter group, toxicity occurred during preoperative treatment in 15 patients and was confirmed histopathologically in 9 of the 16 liver biopsies obtained. There was a higher percentage of children aged less than 1 year at diagnosis in the VOD group than in the other patients (24% vs. 11.4%). The degree of liver damage in the younger patients seems important, as suggested by a higher increase in transaminases. VOD developed in 12% of the 68 irradiated children vs. 7% in the non-irradiated group. Statistical analysis showed an increased risk of VOD in younger patients (p < 0.001) and in those receiving radiotherapy (p < 0.001). All patients recovered after 6-180 days using supportive therapy only. (1) 8% of children treated according to the SIOP-9 protocol, developed hepatotoxicity consistent with VOD. Excluding patients who received radiotherapy, the incidence was 6%. These figures are much higher than in earlier reports, though different diagnostic criteria were used. (2) Chemotherapy with AD and VCR seems to be a major cause of VOD. (3) Risk factors are young age and concomitant radiotherapy. (4) VOD does not prejudice positive outcome for these patients.

Venoocclusive disease of the liver after chemotherapy with vincristine, actinomycin D, and cyclophosphamide for the treatment of rhabdomyosarcoma. A report of the Intergroup Rhabdomyosarcoma Study Group. Childrens Cancer Group, the Pediatric Oncology Group, and the Pediatric Intergroup Statistical Center.

Venoocclusive disease (VOD) of the liver is a common complication after allogenic and autologous bone marrow transplantation for malignant disease. The authors report the unusual and unexpected complication of VOD of the liver occurring in children with rhabdomyosarcoma who were receiving vincristine, actinomycin D, and cyclophosphamide (VAC) according to the chemotherapy regimens of the Intergroup Rhabdomyosarcoma Study (IRS) IV. The authors evaluated 821 patients with newly diagnosed rhabdomyosarcoma receiving treatment according to IRS IV who were considered at risk for VOD. Ten patients developed VOD of the liver for an overall incidence of 1.2%. VOD was found only after the administration of VAC chemotherapy. The highest incidence of VOD was observed among patients who had previously received vincristine and melphalan (Regimen 48). None of the patients receiving the chemotherapy regimen of vincristine and actinomycin D (Regimen 44) developed VOD. Patients receiving VAC-containing regimens on the IRS IV were found to be at risk for VOD. The VAC combination was used extensively in previous IRS studies (I, II, and III) and VOD was not reported during these studies, strongly suggesting that the escalation of the cyclophosphamide dose to 2.2 g/m2 (with the vincristine and actinomycin D doses and schedule remaining unchanged) triggered the development of VOD. The contributing role of previous therapy or events is unknown. At last follow-up, none of the nine surviving patients had developed recurrent VOD on continuation of chemotherapy.

Prophylactic heparin does not prevent liver veno‐occlusive disease following autologous bone marrow transplantation

Veno-occlusive disease (VOD) is a major cause of toxic death after autologous bone marrow transplantation (ABMT). We studied the potential role of continuous administration of low-dose heparin for VOD prevention in 234 consecutive patients who underwent ABMT in our institution. The population consisted of 98 patients autografted before October 1984 who did not receive heparin, and a series of 136 patients autografted from October 1984 to March 1989 containing 98 patients included in a randomized trial comparing heparin administration (n = 52) vs no heparin (n = 46), and an additional group of 38 patients who received non-randomized heparin in view of high-risk criteria to develop VOD (n = 31) or other reasons unrelated to VOD (n = 7). Overall, 90 patients (38%) received heparin and 144 (62%) did not. The global incidence of VOD was 13/234 (5-5%). Heparin did not reduce the risk of VOD in all subgroups studied. In particular, in the randomized trial, the incidence of VOD was 2.2% in the group without heparin vs 7-7% in the group receiving heparin. We analyzed in depth the 13 patients who developed VOD and we compared them to a control group of 13 patients pair-matched for age, sex, diagnosis and preparative regimen, who did not develop VOD. We found that abnormal LFT before ABMT predisposed patients to VOD; refractoriness to platelet transfusion was observed in 85% of the patients in the VOD group vs 15% in the control group (p less than 0.05). VOD patients had an increased requirement for red cells and platelet transfusions, a lower recovery (R less than 25%) after the second and third platelet transfusion, and shorter intervals separating the first four platelet transfusions. Further, the platelet reconstitution after ABMT in the VOD group was slower in comparison to the control group (p less than 0.01). Again, in this pair-matched analysis continuous infusion of low-dose heparin did not prevent VOD.

Use of prostaglandin E1 for prevention of liver veno‐occlusive disease in leukaemic patients treated by allogeneic bone marrow transplantation

Prostaglandin E1 (PGE1) was used to prevent veno-occlusive disease (VOD) of the liver after allogeneic bone marrow transplantation (BMT) for leukaemia. It was given in continuous i.v. infusion from day--8 to day 30 after BMT at a dose of 0.3 micrograms/kg/h. The patients were studied according to the risk factors for VOD: diagnosis, intensification of the conditioning and previous liver abnormalities. The diagnosis of VOD was made on at least two of the following factors: weight gain, hepatomegaly, jaundice, ascitis, pain of the right upper quadrant, increased platelet consumption. 109 patients were studied, 50 were treated by PGE1 and 59 did not receive it. The actuarial incidence of VOD was 12.2% in the PGE1 group and 25.5% in the non PGE1 group (P = 0.05). In acute leukaemia, the incidence was 39.1% in the non-treated group and 12.8% in the PGE1 treated group (P = 0.02). Patients with previous hepatitis had an incidence of 62.5% in the non treated group and 15.5% in the treated group (P = 0.05). A positive cytomegalovirus (CMV) serology seemed to increase the risk of VOD: the incidence of VOD was 31.4% in non-treated patients and 22% in PGE1 treated patients. The multivariate analysis of the risk factors for VOD shows that unfavourable factors were: recipient positive CMV serology (P = 0.06), hepatic disease prior to transplant (P = 0.02) and the absence of PGE1 treatment (P = 0.02). This study suggests that prophylactic PGE1 treatment may decrease the incidence of VOD in patients treated for leukaemia by allogeneic bone marrow transplantation.