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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4568-4572
Norethisterone Treatment, a Major Risk-Factor for
Veno-Occlusive Disease in the Liver After Allogeneic Bone Marrow
Transplantation
By
Hans Hägglund,
Mats Remberger,
Sven Klaesson,
Berit Lönnqvist,
Per Ljungman, and
Olle Ringdén
From the Departments of Transplantation Surgery, Clinical Immunology,
Paediatrics, and Medicine, Karolinska Institute, Huddinge Hospital,
Huddinge, Sweden.
 |
ABSTRACT |
In this single-center study, we retrospectively analyzed incidence
and risk factors for hepatic veno-occlusive disease (VOD) in 249 consecutive patients who underwent allogeneic hematopoietic stem cell
transplantation between January 1990 and June 1995. Twenty-four of the
249 transplanted patients developed VOD. The probabilities of
developing VOD were 17% among women and 7% in men (P = .01). In women treated with norethisterone, the incidence was 27%
compared with 3% in women without this treatment (P = .007).
One-year survival rates were 17% and 73% in patients with (n = 24)
or without VOD (n = 225), respectively. The use of heparin prophylaxis (100 IE/kg/24 hours for 1 month) did not alter the incidence or 1-year mortality of VOD. In multivariate analysis, the
following risk factors were significant: norethisterone treatment (P < .001), bilirubin >26 µmol/L before bone marrow
transplantation (BMT) (P = .002), one HLA-antigen mismatch
(P = .003), previous abdominal irradiation (P = .02), and conditioning with busulphan (P = .02). Our
conclusion is that norethisterone treatment should not be used in
patients undergoing BMT and heparin prophylaxis did not affect the
incidence or mortality of VOD.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
HEPATIC VENO-OCCLUSIVE disease (VOD) is a
common and serious complication after allogeneic bone marrow
transplantation (BMT).1 In studies from the International
Bone Marrow Transplant Registry (IBMTR) and the European Group for
Blood and Marrow Transplantation (EBMT), the incidences were 6% and
9%.2,3 VOD is a clinical syndrome consisting of jaundice,
ascites, and/or unexplained weight gain, as well as
hepatomegaly and/or right upper quadrant abdominal pain.4,5 Many studies have identified a variety of risk
factors for VOD after BMT. Conditioning with busulphan and
cyclophosphamide, pretransplant Karnofsky score <90%, pretransplant
fungal infection, older age, previous liver disease, and previous
abdominal irradiation seem to be the main risk factors.2,3
Three previous reports showed an increased risk for VOD in women. In
these studies, an association between hormonal treatment and VOD was
suggested. Norethisterone is often given to prevent menstrual
hemorrhages during the thrombocytopenic phase after BMT. We analyzed
norethisterone treatment and other possible risk factors for VOD in 249 consecutive bone marrow recipients. Heparin prophylaxis to prevent VOD
was also studied.
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MATERIALS AND METHODS |
Patients.
Two hundred and forty-nine consecutive BMT patients receiving the first
transplant between January 1990 and June 1995 were studied
retrospectively. There were 156 (63%) men and 93 (37%) women. The
median age was 28 (range, 1 to 51) years. Diagnoses were:
acute myeloid leukemia (63), acute lymphoblastic leukemia (49), chronic
myeloid leukemia (63), myeloma (14), myelodysplastic syndrome (9),
lymphoma (6), chronic lymphatic leukaemia (1), myelofibrosis (1),
severe aplastic anemia (SAA) (22), metabolic disorders (20), and one
neuroblastoma. One hundred and fifty-five patients had early disease (1 complete remission [CR], 1 chronic phase [CP], or nonhematological
malignancies) and 94 advanced disease (>1 CR or >1 CP).
Donors.
Among the donors, 161 (65%) were HLA-A-B and -DR identical siblings,
one identical twin, four HLA-A-B and -DR identical parents, 11 (4%)
1-antigen mismatched related donors, 70 (28%) HLA-A-B and -DR
identical unrelated, and two 1-antigen mismatched unrelated. There were
156 men and 93 women. The median age was 33 (range, 1 to 67) years.
Conditioning.
One hundred and fifty-four (62%) patients with hematologic
malignancies were treated with cyclophosphamide (Cy) 60 mg/kg for 2 days, in combination with total body irrradiation (TBI) in a total dose
of 10 Gy in a single fraction (9 Gy towards the lungs) at a dose rate
of 4 cGy/minute.6 Fifty-one (20%) received busulphan (Bu)
4 mg/kg on 4 consecutive days, followed by Cy 60 mg/kg for 2 days.7
In two recipients of T-cell-depleted bone marrow, total lymph node
irradiation (TLI, 2 Gy) was given on each of 3 successive days before
chemotherapy. Cy 120 mg/kg was given before TBI 7.5 Gy and the lungs
shielded to receive no more than 7.0 Gy (26 cGy/minute).8 Fourteen (6%) patients with SAA and HLA identical sibling donors have
been treated with Cy 50 mg/kg for 4 consecutive days, four of these
patients received additional irradiation and another 2 Bu. Among SAA
patients given unrelated hematopoietic stem cells, six received Cy and
TBI, two Cy and TLI. Twenty (8%) patients with metabolic disorders
were given Bu (80 mg/m2) and Cy (2 g/m2).9 All patients who received stem cells
from unrelated donors and those with SAA regardless of donor, were
given antithymocyte globulin (ATG) (3 to 5 mg/kg) or
orthoclone-3 (OKT-3; 5 mg) for 5 days.10
Graft-versus-host disease prophylaxis (GVHD).
Thirteen (5%) patients were given methotrexate (MTX), one cyclosporin
A (CsA), 231 (93%) patients received MTX+CsA, one CsA+prednisolone, and two T-cell-depleted bone marrow.8 One twin received no prophylaxis.
Definition of VOD.
The diagnosis of hepatic VOD was based on the following clinical
criteria: bilirubin >34 µmol/L within 1 month after BMT and two of
the following: painful hepatomegaly, ascites or >5% weight gain.4
Heparin prophylaxis.
Between September 1992 and June 1995, all patients, except SAA
patients, were given heparin 100 IE/kg in a continuous infusion over 24 hours, as prophylaxis against VOD.11 Heparin (Lövens Läkemedel AB, Malmö, Sweden) was given to 114 of 249 (46%)
recipients grafted between 1990 and June 1995, 135 (54%) received no
prophylaxis. The two groups were similar regarding age, diagnosis, and
norethisterone treatment. There was a trend for more patients with late
disease (>1 CR/>1 CP, accelerated phase, or relapse) (P = .06) and busulphan was used more frequently, 44% versus 12%
(P < .001), in the nonheparin compared with the
heparin group.
Progesterone treatment.
Norethisterone [17-OH-19-nor-17-alphapregn-4-en-20yn-3-one] (Primolut
Nor; Schering Nordiska AB, Stockholm, Sweden) or Norethindrone (Aygestin; Wyeth-Ayerst, Philadelphia, PA) in USA, 10 mg daily was
given from day -7 until platelet recovery ( 30 × 109/L) to women (15 to 50 years) to prevent menstrual
hemorrhage. Fifty-five of 93 women were treated with norethisterone.
Before October 1990, two of 10 adult women received norethisterone,
after October 1990, norethisterone had been given to all adult women at
risk for menses, 53 of 59 were treated, and six women without menses
before BMT were not treated.
Statistical analysis.
Analyzed risk factors that might have influenced the development of
hepatic VOD are shown in Table 1. VOD
within 1 month after BMT was regarded as study outcome. Risk factors
significant at the P < .05 level in the univariate logistic
regression analyses were entered into a multivariate logistic
regression analysis using a backward stepwise procedure. Additional
analyses with respect to transplantation-related mortality (TRM),
patient survival (PS), etc were analyzed by the life-table method with
the log-rank (Mantel-Haenzel) test.12
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Table 1.
Risk Factors for VOD in 249 Patients Grafted Between
January 1990 and June 1995, Univariate Analysis, Logistic
Regression
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RESULTS |
Incidence of VOD.
Among the 249 patients, a total of 24 (9.6%) had VOD between January
1990 and June 1995. The probability of developing VOD among female
recipients was 17% (n = 14), compared with 7% (n = 10) in male
recipients (P = .01) (Fig
1). In women treated with norethisterone, the incidence was 27%
compared with 3% (one patient) (P = .007) in women without
treatment (Fig 2). In patients receiving a
second transplant (not included in the risk factor analysis), the
incidence was three of 14 (21%). Twenty-seven patients with bilirubin
>34 µmol/L ± one criteria were diagnosed as follows: toxicity,
12; septicemia, 5; acute GVHD, 4; acute GVHD/septicemia, 3; hemolysis,
1; and unknown, 2 (Table 2).
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| Fig 1.
Observed probability of VOD among female versus male
recipients grafted between 1990 and June 1995.
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| Fig 2.
Observed probability of VOD in women treated with
norethisterone compared with women without treatment during the time
period 1990 and June 1995.
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Clinical features.
Of the 24 patients with VOD, 13 were treated with norethisterone and 11 were not treated. Day of diagnosis, liver histology, and outcome in the
two groups are given in Table 3.
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Table 3.
Day of Diagnosis, Liver Histology, and Survival in
Patients Who Develop VOD With or Without Norethisterone Treatment
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VOD prophylaxis.
Among the heparin-treated recipients, 10 of 114 (9%) developed VOD
compared with 14 of 135 (10%) in the untreated recipients. The 1-year
TRM rates in patients with VOD were 72% and 79% (not significant
[NS]), with or without heparin, respectively.
Risk factors for VOD.
In the univariate analysis, the following factors were significant:
norethisterone (P < .001), bilirubin >26 µmol/L before BMT (P < .001), 1- antigen mismatch (P = .02),
recipient sex female (P = .03), and recipient age >17 years
(P = .04) (Table 1).
Significant risk factors (P < .05) in the univariate analysis
were included in the multivariate analysis. In addition, previous abdominal irradiation (P = .06) and busulphan were included in the multivariate analysis, as both factors have been associated with
VOD in previously published studies.2,3 Significant factors
were: norethisterone treatment (P < .001), bilirubin >26 µmol/L before BMT (P = .002), 1-HLA antigen mismatch
(P = .003), previous abdominal irradiation (P = .02), and busulphan conditioning (P = .02) (
Table 4).
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Table 4.
Risk Factors for VOD in 251 Patients Grafted Between
1990 and June 1995, Multivariate Analysis, Logistic Regression
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For fatal VOD, defined as death within 100 days after BMT in patients
with VOD (n = 16), norethisterone (P = .002) and HLA-mismatch (P = .007) were significant in multivariate analysis.
Mortality and VOD.
Among 249 patients, the day-100 and 1-year TRM rates were 67% and 81%
in patients with VOD (n = 24) as compared with 8% (P < .01) and 17% (P < .001) in patients without VOD (n = 225). One-year observed survival rates were 17%, 44%, and 73% in
patients with VOD, with bilirubin greater than 34 µmol/L ± one
criteria, or without VOD, respectively. The day-100 and 1-year patient
survival among women treated with norethisterone (n = 55) were 78% and 53% as compared with 86% (ns) and 72% (P = .007) in patients
(n = 194) without norethisterone during the time period 1990 to June 1995.
| |
DISCUSSION |
In this retrospective analysis of risk factors for hepatic VOD, only
patients with three clinical features of VOD were included. Twenty-four
of 249 (9.6%) BMT patients grafted between 1990 and June 1995 fulfilled the VOD criterion.
Our incidence of VOD, 10%, is comparable to that reported by IBMTR and
EBMT. However, this is lower compared with several other reports, being
up to 70% (reviewed in Shulman and Hinterberger13). The
reasons for the discrepant frequency of VOD may be due to patient
selection, incidence of risk factors, and criteria used for diagnosis.
We found that norethisterone was the most significant risk factor for
developing VOD (P < .001). Since 1990, 55 of 93 female recipients have been treated with norethisterone (Primolut nor) 10 mg
daily, starting 1 week before BMT, to prevent menstrual hemorrhage
during the thrombocytopenic period. Among 55 women treated with
norethisterone, 13 developed VOD, compared with one of 38 women without
treatment.
Three groups have previously reported an increased risk of VOD after
BMT among women, with a possible relationship to hormonal treatment.14-16 Ganem et al14 found an
incidence of VOD in women of 17.7% and in men, 6.7%. In that study,
almost all female recipients received lynesterol, one of its major
active metabolites being norethisterone. Progestogens, as well as
oestrogens, have been incriminated in the production of venous
obstruction, also involving the small hepatic veins.17-18
Cholestatic liver reactions were reported in 5.6% of patients with
breast cancer, treated with high-dose gestagen preparations (10 mg × 3 to 4 daily).19 Hepatocellular reactions have also been reported, with use of norethisterone 40 mg daily in 23 of 29 breast cancer patients who developed grade 3 or 4 liver toxicity, according to the World Health Organization
(WHO).20 Liver damage from oestrogen is a well-known
complication,21 and three recent studies have shown an
increased risk of venous thromboembolism among oestrogen
users.22-24 The WHO collaborative study of cardiovascular and steroid hormone contraception shows an increased risk of acute myocardial infarction among women with known risk factors and among
those who have not been effectively screened, particularly for high
blood pressure and use of combined oral contraceptives.25 A
metabolic conversion from norethisterone to ethinyl oestradiol has been
described,26 which may contribute to the liver toxicity of
progestogens. The relationship between VOD and norethisterone may be
due to an interaction between norethisterone and other drugs with known
hepatotoxicity used for BMT, such as busulphan, cyclophosphamide,
methotrexate, and cyclosporin.7,27,16,28 Superficial venous
thrombosis, myocardial infarction, and stroke were found in women with
oestroprogestative therapy, related to the dose of
progestogens.29-31 Norethisterone could therefore increase the risk of microthrombosis in the small hepatic veins. Cholestasis, causing inhibition of bile flow and the biliary excretion of bilirubin and bile salts, may be another explanation of increased toxicity with
the use of norethisterone and other drugs. Both hepatocellular and
cholestatic reactions could also have a greater effect on a patient
previously treated with chemotherapy and/or irradiation, which
make the liver more vulnerable to drug toxicity.
Increased bilirubin before conditioning was an important risk factor
for VOD. This finding may have been expected, and it suggests that
previous chemoirradiation therapy or infections have damaged the liver
in those patients. In patients receiving mismatched bone marrow, an
explanation of the increased incidence of VOD may be that a higher dose
of cyclosporin was used. Furthermore, an alloimmune GVHD reaction
causing a release of cytokines, such as tumor necrosis factor
(TNF)- , may damage endothelial liver cells.32,33 In line
with this, other groups report less VOD among recipients of autologous,
twin, and T-cell-depleted HLA-identical sibling
transplants.34,35
Previous abdominal irradiation also increased the risk of VOD, as
reported in the EBMT survey.3 Patients treated with
busulphan containing myeloablative regimen developed VOD more often. An increased risk of VOD with the use of busulphan was found in a prospective randomized study comparing busulphan versus TBI as conditioning before BMT.7 Hepatotoxicity associated with
busulphan was also reported after BMT.2,3
We could not confirm previously reported risk factors such as
pretransplant fungal infection, pretransplant elevated transaminases, pretransplant fever, antimicrobial or antiviral therapy, and unrelated donor transplants.1,2,36 One reason for the low incidence of VOD in our patients who received transplants from unrelated donors
may be the low incidence of grades II-IV acute GVHD, ie, around
20%.10 Heparin prophylaxis (100 IE/kg/24 hours), given from the start of the conditioning regimen until 1 month after BMT or
discharge, did not influence the incidence or mortality of VOD compared
with no prophylaxis. In a randomized trial of heparin to prevent VOD,
Attal et al11 found heparin to be highly effective in
preventing VOD, but there were no significant differences in the number
of patients who died of VOD.
Because we observed that norethisterone treatment was the strongest
risk factor for VOD and no life-threatening bleeding in nonnorethisterone-treated women have occurred, we have stopped using
this drug to prevent menstruation in women undergoing BMT. We also
recommend that other centers stop using norethisterone after BMT.
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ACKNOWLEDGMENT |
The authors thank Susanne Öhman and Lena Iwarsson for data
collection, Bo Nilsson for statistical advice, the Nursing Staff at the
Bone Marrow Transplant Unit for excellent patient care, and Francis and
Zoe Walsh for scrutinizing the language.
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FOOTNOTES |
Submitted February 3, 1998;
accepted August 6, 1998.
Supported by grants from the Swedish Cancer Foundation
(0070-B95-09XCC), the Children's Cancer Foundation (1995/035), the Swedish Medical Research Council (B96-16X-05971-16C), the FRF Foundation, the Tobias Foundation, and the Ellen Bachrach Foundation.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Hans Hägglund, MD,
Department of Transplantation Surgery, Huddinge Hospital, B56, S-141 86 Huddinge, Sweden; e-mail: hans.hagglund{at}transpl.hs.sll.se.
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Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: A cohort study of 355 patients.
Ann Intern Med
118:255, 1993[Abstract/Free Full Text]
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Abstract
Introduction