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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3599-3604
By
From Hospital Clinic, IDIBAPS, Barcelona, Spain; University of
Freiburg, Freiburg, Germany; Universita degli Studi La Sapienza, Rome,
Italy; Hôpital Henri Mondor, Creteil, France; Hospital de la
Princesa, Madrid, Spain; Huddinge Hospital, Huddinge, Sweden; Hospital
San Orsola, Bologna, Italy; Hôpital Saint Louis, Paris, France;
Foothills Hospital, Calgary, Alberta, Canada; Hospital La Fe, Valencia,
Spain; Ospedale Civile, Pescara, Italy; University Hospital, Leuven,
Belgium; Institut Gustave Roussy, Villejuif, France;
Universitätskrankenhaus Eppendorf, Hamburg, Germany; Helsinki
University Central Hospital, Helsinki, Finland; Hôpital
Pitié Salpétrière, Paris, France; Hospital
Marqués de Valdecilla, Santander, Spain; Ospedale di Careggi,
Firenze, Italy; Sheba Medical Center, Tel-Hashomer, Israel; Charles
University Hospital, Pilsen, Czech Republic; Kantonsspital, Basel,
Switzerland; and Hammersmith Hospital, London, UK.
To determine the incidence and outcome of hepatic veno-occlusive
disease (VOD) after blood or marrow transplantation (BMT), we
prospectively evaluated all consecutive patients receiving a BMT during
a 6-month period in participating EBMT centers. All of them were
evaluated for occurrence of VOD according to previously defined
clinical criteria. The clinical course, outcome, value of prophylactic
and therapeutic interventions, and the influence of previously
described risk factors were analyzed. During the study period, 1,652 BMT were performed in 73 centers. VOD was diagnosed in 87 patients
(5.3%; 95% confidence interval [CI], 4.2% to 6.4%).
Fifty-six of 631 allogeneic BMT (8.9%) and 31 of 1,010 autologous BMT
(3.1%) developed this complication (P < .0001). VOD was
classified as mild in 7 (8%), moderate in 56 (64.4%), and severe in
24 (27.6%) cases. Sixteen patients died of VOD (corresponding to 1%
of the whole series, 18.4% of VOD patients, and 66.7% of severe VOD).
The use of unfractionated heparin did not significantly decrease the
incidence of VOD. Independent variables associated with an increased
risk of VOD were allogeneic BMT (relative risk [RR], 2.8; P < .001), pre-BMT elevation of serum aspartate aminotransferase (RR,
2.4; P = .001), high-dose cytoreductive therapy (RR, 2.3; P = .003), Karnofsky performance score less than 90% (RR,
2.7; P = .006), and prior abdominal radiation (RR, 2.9;
P = .03). In conclusion, this prospective study shows that
(1) the incidence of VOD is lower than that reported in smaller studies
from single centers, (2) about one fourth of cases of VOD progress to
severe disease, (3) main risk factors have a major impact on incidence of VOD, and (4) the use of prophylactic unfractionated heparin does not
seem to reduce the incidence of VOD.
LIVER DAMAGE IS A common complication of
cytoreductive therapy used for blood or bone marrow transplantation
(BMT).1,2 The most prominent site of damage is zone 3 of
the liver acinus. Hepatic venular occlusion, hepatic venular eccentric
luminal narrowing, phlebosclerosis, sinusoidal fibrosis, and hepatocyte
necrosis are the most common histologic features of this
damage.3 The clinical syndrome resulting from this hepatic
toxicity is commonly called veno-occlusive disease of the liver (VOD),
and it is characterized by hyperbilirubinemia, fluid retention, and
painful hepatomegaly appearing soon after BMT.1,2,4 Because
the high bleeding risk in the early transplant phase precludes a
percutaneous liver biopsy, clinical criteria for the diagnosis of VOD
have been developed by both the Seattle4,5 and Baltimore
groups.6 VOD has been considered a frequent and often fatal
complication of BMT. Results of large series of patients reported
incidences up to 53% and a case fatality rate up to
47%.4-6 Nevertheless, review of the literature shows that
the incidence of VOD ranges from 0% to 70% and that its fatality rate
can be as low as 3%.1,2,7 The reason for this disparity is
unknown. It most likely reflects diverse criteria for diagnosis, small
sample size, and variable distribution of risk factors for VOD in the
different series. To better determine the incidence, clinical course,
and outcome of VOD after BMT, the EBMT Chronic Leukemia Working Party
performed a prospective survey among EBMT teams.
Patients
Study design.
Prospective evaluation of all consecutive patients receiving a
BMT in participating centers between November 1, 1995 and
April 30, 1996.
Patient population.
During this 6-month period, 6,795 BMT (4,697 autologous and 2,098 allogeneic) were performed in 367 EBMT centers. Seventy-five of these
centers participated in this prospective study. Two of them reported
cases of VOD but did not report simultaneous patients who had not
developed VOD. These cases were therefore not included in the final
analyses. The remaining 73 centers (see Appendix) reported 1,652 patients. This cohort represents 24% of all EBMT transplants during
this period. The proportion of allogeneic and syngeneic BMT in the
cohort was slightly higher than in the whole group (38% v 31%
and 0.6% v 0.3%, respectively; P < .001;
Table 1). The median number of transplants
per center was 21 (range, 2 to 87).
Data Collection
Definitions
VOD.
The diagnosis of VOD was established in each participating center
according to previously described clinical criteria, ie, occurrence of
two or more of the following events before day 21 after hemopoietic
progenitor cell administration: hyperbilirubinemia (>34.2 µmol/L or
>2 mg/dL), ascites or sudden weight gain (>5% of baseline body
weight), and painful hepatomegaly. No other explanation for these signs
and symptoms (septicemia, cyclosporin toxicity, heart failure,
hepatitis, etc) could be present at the time of diagnosis.
Risk factors for VOD.
Two categories of factors previously associated to the development of
VOD1,3,6,7,10 were analyzed: (1) patient-related factors,
ie, age greater than 20 years, previous radiation therapy of the
abdomen, second BMT, previous liver disease, increased serum aspartate
aminotransferase (AST) before cytoreductive therapy, Karnofsky performance score less than 90%, and presence of
fungal infection 1 week before BMT; and (2) transplant-related factors, ie, type of transplant, type of donor, pretransplant acyclovir therapy,
vancomycin administration during cytoreductive therapy, and dose of
cytoreductive therapy. As previously reported,4 regimens
considered as high-dose cytoreductive therapy were those either
including both busulfan and cyclophosphamide (Cy), or Cy and total body
irradiation with a total radiation dose greater than 12 Gy, or Cy and
BCNU and etoposide, or those with an equivalent intensity. The
remaining regimens were classified as low-dose cytoreductive therapy.
Clinical course and outcome of VOD.
In cases of VOD, measures used for the treatment of VOD and the
evolution of VOD were evaluated. Those with a self-limiting VOD, ie,
not requiring treatment, were classified as having mild VOD. Those with
a complete resolution of all signs of liver damage but requiring
treatment (sodium restriction, diuretics, analgesics, etc) were
classified as having moderate VOD. Those whose liver damage did not
resolve before day 100 or the patient died, whichever occurred first,
were classified as having a severe VOD.4 To evaluate these
patients, additional information by day 100 posttransplant was required
from all centers reporting cases that had not resolved by the end of
the study.
Statistical Methods
Incidence of VOD VOD was diagnosed in 87 of 1,652 patients (5.3%; 95% confidence interval [CI], 4.2% to 6.4%). Fifty-four (62%) fulfilled two clinical criteria for VOD, whereas the remaining 33 (38%) had three clinical criteria. In 15 cases (17.2%), VOD was confirmed by means of a liver biopsy; only 4 (4.6%) were evaluated by a hemodynamic study. VOD was observed in 56 of 631 allogeneic BMT (8.9%) and in 31 of 1,010 autologous BMT (3.1%; P < .0001). There were no cases of VOD among patients receiving syngeneic BMT (Table 2).
Influence of Risk Factors for VOD Table 3 shows the incidence of VOD according to evaluated risk factors. In univariate analysis, the incidence of VOD was higher in allogeneic BMT than in autologous BMT (8.9% v 3.1%; P < .0001). The donor type did not influence VOD incidence, ie, HLA-identical sibling (9.8%), versus other relative (5%), versus unrelated donor (6.8%). The incidence of VOD was higher among patients with increased serum AST level before cytoreductive therapy (13.3% v 4.6%; P < .0001), with previous liver disease (12.8% v 4.9%; P = .0013), with high-dose conditioning (6.6% v 2.4%; P = .0003), with previous radiation therapy to the abdomen (13.2% v 5%; P = .009), and with Karnofsky performance score less than 90% before transplant (13% v 4.7%; P = .0002). The remaining risk factors analyzed did not influence the incidence of VOD. Independent variables associated with an increased risk of VOD in logistic regression analysis were (Table 3) allogeneic BMT (relative risk [RR], 2.8; P < .001), pre-BMT increased serum AST (RR, 2.4; P = .001), cytoreductive therapy with a high-dose regimen (RR, 2.3; P = .003), Karnofsky performance score less than 90% (RR, 2.7; P = .006), and previous abdominal radiation (RR, 2.9; P = .03). Similar results were obtained when the end-point of univariate and multivariate analyses were severe VOD or to die of VOD. Thus, the variables associated with a higher risk of this last complication were allogeneic BMT (RR, 2.8; P < .001), high-dose cytoreductive therapy (RR, 2.3; P = .004), pre-BMT increased serum AST (RR, 2.1; P = .01), previous abdominal radiation (RR, 2.9; P = .05), and Karnofsky performance score less than 90% (RR, 2.7; P = .06).
Influence of VOD Prophylaxis
Outcome of Patients With VOD
Eighty-seven of 1,652 (5.3%) transplant recipients (8.9% of allogeneic and 3.1% of autologous) developed VOD in this prospective survey. This is in accordance with the incidence reported in preliminary series,12-18 another multicentric analysis,10 a previous EBMT interim analysis (incidence of VOD 4%; unpublished), and the largest series from a single center.19 However, it contrasts with three large series on VOD in allogeneic and autologous BMT recipients.4-6 The first series was reported in 1984 by the Seattle group. In this retrospective analysis, using the current worldwide accepted clinical criteria for diagnosis of VOD for the first time, the incidence of VOD was 22% and the mortality rate 47%.5 In 1987, the Baltimore group, using their own clinical criteria for the diagnosis of VOD, reported an incidence of 21% with a fatality rate of 45%.6 Finally, in 1993, the Seattle group prospectively evaluated 355 consecutive patients receiving a BMT between 1987 and 1988 and modified their initial clinical criteria slightly. The incidence of VOD was 54% and the liver dysfunction caused or contributed to death in 28% of cases.4
The EBMT Chronic Leukemia Working Party thank the following centers for their participation in this survey (EBMT Center, city, physician[s], no. of patients reported in parentheses): University of Freiburg, Freiburg, H. Bertz/S. Fetscher (87); Università "La Sapienza" Rome, W. Arcese/G. Meloni (51); Hôpital Henri Mondor, Creteil, J.P. Vernant (46); Hospital La Princesa, Madrid, J.F. Tomás (46); Huddinge Hospital, Huddinge, H. Hägglund/P. Ljungman (45); Hammersmith Hospital, London, J.F. Apperley/L. Rule (45); Hospital S. Orsola, Bologna, G. Bandini/A. Bonini (42); Hospital Clínic, Barcelona, E. Carreras/M.C. Viguria (40); Hospital Saint Louis, Paris, H. Esperou (40); Foothills Hospital, Calgary, J.A. Russell (38); Hospital La Fe, Valencia, J. de la Rubia (37); Ospedale Civile, Pescara, G. di Girolamo (35); University Hospital, Leuven, H. Demuynck (35); Institut Gustave Roussy, Villejuif, O. Hartmann (34); Universitätskrankenhaus Eppendorf, Hamburg, J. Clausen (33); Helsinki University Central Hospital, Helsinki, T. Ruutu (33); Hôpital Pitié Salpétrière, Paris, V. Leblond/J. Manighetti (33); Hospital Marqués de Valdecillas, Santander, A. Iriondo (32); Ospedale di Careggi, Firenze, A. Bosi (31); Sheba Medical Center, Tel-Hashomer, I. Ben-Bassat (30); Charles University Hospital, Plzen, V. Koza (30); Hospital Universitario, Salamanca, D. Caballero (29); Hospital de Jerez, Jerez de la Frontera, A. León (28); Hospital Carlos Haya, Málaga, J. Maldonado/M.J. Pascual (26); Instituto Portugués de Oncologia, Porto, P. Pimentel (26); Hospital de la Santa Creu i Sant Pau, Barcelona, S. Brunet (25); Dr Daniel Den Hoed Cancer Centre, Rotterdam, J.J. Cornelissen (25); Kantonsspital, Basel, V. Rüd (24); General Hospital of Thessaloniki, Eoxkhi, A. Fassas (23); Royal Liverpool University Hospital, Liverpool, R.E. Clark (23); Clínica Puerta de Hierro, Madrid, G. Bravo/M.N. Fernández (22); Hospital Ramón y Cajal, Madrid, J. López-Jiménez (22); Ospedale V Cervello, Palermo, A.M. Cavallarao (22); Medical School of Hannover, Hannover, N. Bertenstein (22); Cliniques Universitaire St Luc, Brussels, A. Ferrant (22); Turku University, Turku, M. Kaynpls (22); Hospital Virgen del Rocío, Sevilla, I. Espigado (21); Addenbrookes NHS Trust, Cambridge, D. Johnson (21); Università Tor Verguata, Rome, L. Cudillo (20); AZ Sint-Jan, Brugge, D. Selleslag (20); Hospital San Maurizio, Bolzano, P. Coser (20); Università degli Studi di Milano, Milano, G. Lambertenghi (20); University Ulm, Ulm, M. Hafner (20); Hospital Ntra Sra de Aránzazu, San Sebastian, M.J. Vidal (18); University Hospital Charité, Berlin, A. Trittin (16); Hospital General Universitario, Murcia, J.M. Moraleda (16); Instituto Porgués de Oncologia, Lisboa, M. Abecasis (16); King's College Hospital, London, G.J. Mufti (15); University of Jena, Jena, D. Fuchs (14); Vicenza Presidio Ospidaliero, Vicenza, R. Raimondi/F. Rodeghiero (13); Our Children Leukemia Foundation, Istanbul, H. Bilgen (13); Hospital La Paz, Madrid, A.M. Martínez-Rubio (13); Klinikum Nurnberg, Nurnberg, V. Schäfer (13); Städt Kliniken Oldenburg, Oldenburg, B. Metzner (12); Shariati Hospital, Tehran, A. Ghavamzadesh (11); Centro Leucemie Infantili, Padova, S. Varotto (11); University of Medicine Wroclaw, Wroclaw, J. Boguslawska-Jaworska (10); Università di Palermo, Palermo, A. Cajozzo (10); Örebro Medical Center Hospital, Örebro, U. Tidefelt (10); Herlev Hospital, Herlev, H. Johnsen (10); Ospedale Regina Margherita, Torino, R. Miniero (19); Centro Trapanto Midollo Osseo, Cremona, A. Manna (9); Istanbul Medical School, Istanbul, Y. Tangün (8); Hospital Central de Asturias, Oviedo, F. Jonte (8); Tampere University Hospital, Tampere, S. Siitonen (8); St James's Hospital, Dublin, C. Duggan (8); Canterbury Health Laboratory, Christchurch, J. Sanders (8); Ospedale Regionales Microcetemie, Cagliari, F. Argioulu (6); Navy Hospital "Pedro Mallo," Buenos Aires, A.J. Robinson (6); Hôpital D'Enfants de la Timome, Marseille, C. Coze (6); YSBYTY Gwynedd, Bangor, R. Williams (3); University Medical Center, Ljubljana, J. Pretnar (3); Marmada University Hospital, Istanbul, B.A. Tülin (2).
Submitted May 4, 1998;
accepted July 15, 1998.
Address reprint requests to Enric Carreras, MD, BMT Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: bmtunit{at}medicina.ub.es.
1.
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Ann Intern Med
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  S. C. Maradei, A. Maiolino, A. M. de Azevedo, M. Colares, L. F. Bouzas, and M. Nucci Serum ferritin as risk factor for sinusoidal obstruction syndrome of the liver in patients undergoing hematopoietic stem cell transplantation Blood, August 6, 2009; 114(6): 1270 - 1275. [Abstract] [Full Text] [PDF]
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J. L. Gajewski, V. V. Johnson, S. G. Sandler, A. Sayegh, and T. R. Klumpp A review of transfusion practice before, during, and after hematopoietic progenitor cell transplantation Blood, October 15, 2008; 112(8): 3036 - 3047. [Abstract] [Full Text] [PDF]
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A. R. Gennery, K. Khawaja, P. Veys, R. G. M. Bredius, L. D. Notarangelo, E. Mazzolari, A. Fischer, P. Landais, M. Cavazzana-Calvo, W. Friedrich, et al. Treatment of CD40 ligand deficiency by hematopoietic stem cell transplantation: a survey of the European experience, 1993-2002 Blood, February 1, 2004; 103(3): 1152 - 1157. [Abstract] [Full Text] [PDF]
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M. Wadleigh, P. G. Richardson, D. Zahrieh, S. J. Lee, C. Cutler, V. Ho, E. P. Alyea, J. H. Antin, R. M. Stone, R. J. Soiffer, et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation Blood, September 1, 2003; 102(5): 1578 - 1582. [Abstract] [Full Text] [PDF]
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G. B. McDonald, J. T. Slattery, M. E. Bouvier, S. Ren, A. L. Batchelder, T. F. Kalhorn, H. G. Schoch, C. Anasetti, and T. Gooley Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation Blood, March 1, 2003; 101(5): 2043 - 2048. [Abstract] [Full Text] [PDF]
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G. K. K. Lau, Y.-h. Leung, D. Y. T. Fong, W.-y. Au, Y.-l. Kwong, A. Lie, J.-l. Hou, Y.-m. Wen, A. Nanj, and R. Liang High hepatitis B virus (HBV) DNA viral load as the most important risk factor for HBV reactivation in patients positive for HBV surface antigen undergoing autologous hematopoietic cell transplantation Blood, April 1, 2002; 99(7): 2324 - 2330. [Abstract] [Full Text] [PDF]
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Ph. Guardiola, R. Pasquini, I. Dokal, J. J. Ortega, M. van Weel-Sipman, J. C. W. Marsh, S. E. Ball, F. Locatelli, C. Vermylen, R. Skinner, et al. Outcome of 69 allogeneic stem cell transplantations for Fanconi anemia using HLA-matched unrelated donors: a study on behalf of the European Group for Blood and Marrow Transplantation Blood, January 15, 2000; 95(2): 422 - 429. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
2 statistics or Fisher's exact test as appropriate.
Significant variables at the P < .1 level were fitted to a
multiple logistic regression model using forward stepwise variable
selection. The relative risk of VOD associated with a single risk
factor was computed as the probability of VOD for patients with that
risk factor divided by the probability of disease for patients without that risk factor (BMDP Statistical Software, Los Angeles, CA). Additionally, the relative risk of VOD of patients with a risk factor was computed as the probability of VOD for patients with this
risk factor divided by the probability of disease for patients with
none of the examined risk factors.