|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2005.01.5016 on January 17 2006 © 2006 American Society of Clinical Oncology. Characteristics and Outcome of Diffuse Large B-Cell Lymphoma in Hepatitis C Virus–Positive Patients in LNH 93 and LNH 98 Groupe d'Etude des Lymphomes de l'Adulte ProgramsFrom the Service d'Hématologie, Service d'Anatomo-Pathologie; Service d'Hépatologie, Hôpital Necker-Enfants Malades, APHP; Université René Descartes CNRS; Institut d'Hématologie, Hôpital Saint-Louis, INSERM ERM 0220, Paris; Service d'Hématologie, Hôpital Bicêtre, Le Kremlin Bicêtre; Département d'Information Hospitalier, Département de Pathologie; Hôpital Henri-Mondor, Créteil; Service d'hématologie, Hôpital de Lens; Service d'Hématologie, CHU Nancy Brabois; Département d'Immunologie, AZ Saint Jan, Brugge, Belgique; Service d'Hématologie, Centre Henri Becquerel, (Rouen); Service d'Hématologie, Centre Hospitalier Lyon Sud Address reprint requests to Olivier Hermine, MD, PhD, Service d'Hématologie Adulte, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, 75743 Paris cedex 15, France; e-mail: hermine{at}necker.fr
PURPOSE: Epidemiologic studies show an association between hepatitis C virus (HCV) and B-cell non-Hodgkin's lymphoma (NHL). Treatment and outcome of patients with diffuse large-cell lymphoma (DLCL) and HCV infection are still a matter of debate. PATIENTS AND METHODS: We studied the HCV-positive patients with B-cell DLCL included in the Groupe d'Etude des Lymphomes de l'Adulte (GELA) programs LNH 93 and LNH 98. They were compared with the other patients with DLCL included in these programs. HCV infection prevalence was 0.5% (26 of 5,586 patients). RESULTS: Histologic types of HCV-positive DLCL were more frequently transformed from low-grade lymphoma than DLCL in HCV-negative patients (32% v 6%, P = .02). This is also supported by more frequent spleen involvement in HCV-positive patients (46% v 17%, P < .001). HCV-positive patients had more frequently elevated lactate dehydrogenase levels than other patients (77% v 55%, P = .02). Outcome of HCV-positive patients was poorer for overall survival (P = .02) but not for event-free survival (P = .13). After matching on age and prognosis factors, at 2 years of follow-up, the overall survival was 56% (95% CI, 33% to 76%) among HCV-positive patients, versus 80% (70% to 89%), and the event-free survival was 53% (33% to 72%) versus 74% (64% to 84%). The short-term hepatic toxicity of chemotherapy was strongly increased among HCV-positive patients. After exclusion of the two subjects with chronic hepatitis B virus infection, the overall proportion of subjects undergoing hepatic toxicity was 65% (15 of 23 patients). CONCLUSION: HCV-positive patients with DLCL differ from other patients both at presentation and during chemotherapy. Specific protocols evaluating antiviral therapy should be designed for these patients.
Numerous studies in high prevalence area of hepatitis C virus (HCV) infection have shown that the frequency of HCV infection was higher in patients with B-cell lymphoma, particularly those with low-grade marginal-zone lymphoma and primary hepatosplenic B-cell lymphoma.1-8 A meta-analysis concluded that HCV prevalence in patients with B-cell non-Hodgkin's lymphoma (NHL) was approximately 15%, significantly higher than in general population (1.5%).9We have recently reported in patients with splenic lymphoma with villous lymphocytes and HCV infection that clearance of HCV infection led to regression of the tumor burden.10,11 This finding provides further evidence for the causal role of HCV in the occurrence of NHL. Studies have also shown an increased prevalence of HCV infection among patients with diffuse large-cell lymphoma (DLCL).7,12,13 Treatment and outcome of patients with DLCL and HCV infection are still a matter for debate. Particularly, the liver toxicity of aggressive and/or intensive chemotherapies in patients with HCV infection is not well known. In this report, we have analyzed the characteristics, treatment-related toxicity, and outcome of patients with HCV infection with DLCL.
Patients We analyzed HCV-positive patients enrolled on Groupe d'Etude des Lymphomes de l'Adulte (GELA) programs LNH 93 and LNH 98. These programs recruited adult patients with intermediate or high grade lymphoma according to the Working Formulation.13 Patients were not included if they had: primary cerebral lymphoma, history of low-grade lymphoma, positive serology to human immunodeficiency virus, previous treatment with chemotherapy, radiotherapy or organ transplantation, previous cancer, congestive heart failure, recent myocardial infarction, uncontrolled diabetes mellitus, and kidney failure. Patients with abnormal liver tests (WHO grade > 2) could only be included if it was estimated that these abnormalities were related to lymphoma involvement. Each GELA program consisted of different trials (LNH 93/98-1,14 LHN 93-2, LNH 93-3,15 LNH 93/98-4,16 LNH 93-5,17 LNH 93-6, LNH 93-7, LNH 98-2,18 LNH 98-3,19 LNH 98-5,20 LNH 98-6) where patients were enrolled according to age and number of factors of the age-adjusted international prognostic index.21 Investigations were performed after approval by a local Human Investigations Committee (Comité Consultative pour la Protection des Personnes dans les Recherches Biomédicales [CCPPRB]) and approved by the French Department of Health and Human Services. Informed consent was obtained from each subject. HCV serology results were requested at inclusion in the LNH 98 program but were not mandatory in the LNH 93 program. HCV infection was defined by the detection of anti-HCV antibodies by enzyme-linked immunosorbent assays, and/or by polymerase chain reaction (PCR; in 19 patients). At the time of the analysis, the median follow-up for the patients was 47 months (range, 0 to 112 months). Hepatic toxicity was defined by the standard National Cancer Institutes of Canada criteria. We compared the general characteristics of HCV-positive patients with DLCL with all other patients at inclusion. We then compared their histologic features to those of a control group of 35 individuals with DLCL randomly chosen among HCV-negative patients included in the GELA program in our pathology department. Outcome and toxicity analysis was performed after matching on age, sex, arm protocol, stage, and performance status. Each HCV-positive patient was matched with three other patients. Two patients with chronic hepatitis B virus (HBV) infection have been excluded from the outcome and toxicity analysis. The files of the controls of the LNH 93 program were reviewed in order to exclude the patients with a history of HCV infection. The controls of the LNH 98 program were randomly chosen among patients with HCV-negative serology at inclusion.
Histology and Immunohistochemistry
Statistical Analysis
Patients' Demographic Characteristics The frequency of HCV-positive patient was 14 (0.3%) of 4,625 in LNH 93 program and 12 (1.2%) of 961 in LNH 98 program. Overall, 26 patients were HCV-infected (0.46%) significantly (data not shown; Table 1) . The HCV-infected patients were significantly younger than other patients (P = .03). The risk factors of HCV infection among these patients were unknown in most cases except for six patients (intravenous drug abuse, three patients; origin from an endemic region, two patients; transfusion, one patient). The HCV genotype was known in three cases (1b, 2, 3a). No patient had a previous clinical history of cirrhosis. Five patients were known to have a chronic hepatitis. Liver biopsies had been performed in four patients before treatment of DLCL. Among them, three patients had metavir scores of A1F0, A1F1, and A1F2. The other one had a chronic active hepatitis (no metavir scoring had been performed). Only two of the 26 patients had been previously treated for HCV. Four patients had been coinfected with HBV; two patients were chronically infected with HBV defined by positive anti-HBs Ag. Transaminase levels (AST, and ALT) at inclusion were normal in 17 cases, grade 1 in six cases, grade 2 in two cases with hepatic NHL and grade 3 in one case.
Histology and Immunohistochemistry Twenty five of the 26 DLCL patient cases included in this study have been reviewed for pathological analysis (Table 2) . Fifteen cases were "typical" classical DLCL. They involved lymph nodes in nine cases and extranodal sites in the six others (Fig 1). Seven patients had features of transformation from a low-grade B-cell lymphoma with pleiomorphic features and with the presence of small to medium "monocytoid-like" B cells (Fig 2). One other case was retrospectively diagnosed as a follicular lymphoma. In all patients, the lymphoma cells strongly expressed CD20 and were negative for CD3 (Table 2). The expression of CD10 was detected in only four patients (two typical DLCL and 2 DLCL likely developed on low-grade NHL). The expression of bcl-6 was detected in six patients of typical DLCL and in none of the lymphomas with features of transformation. In a randomly selected control group of 35 HCV-negative patients with DLCL, the proportion exhibiting the same features of DLCL probably transformed from low-grade lymphomas was significant lower (two of 35 v seven of 22, P = .02).
Pretreatment Characteristics of NHL Patients Performance status, extranodal involvement, and stage did not differ between the two groups of patients (Table 1). The proportion of HCV-positive patients with spleen involvement was significantly higher than among other patients (46% v 17%, P < .001). Four HCV-positive patients had liver involvement confirmed by liver biopsies, which does not differ significantly from other patients (15% v 9%, P = .30). Among HCV-positive patients, the proportion with elevated lactate dehydrogenase (LDH) levels was increased. The proportion of HCV-positive patients with elevated LDH did not differ with histological subtypes or initial hepatic cytolysis. Overall, the proportion of high and high-intermediate International Prognostic Index (IPI) was higher among HCV-positive patients (P = .03).
Outcome
The impact of histological feature, stage, LDH level, and performance status were studied among the 23 HCV-positive patients who either survived in long-lasting remission or died of progressive disease. The outcome tended to be better among patients with transformed low-grade NHL than among patients with typical DLCL (P = .07; Fig 5A). Only eight (47%) of 17 patients with stage III/IV remained in complete remission, versus five (83%) of six patients with stage I/II (P = .18; Fig 5B). Increase of LDH level upper the normal value did not affect survival of HCV-positive patients (P = 1; Fig 5C). Patients with poor performance status had a worse outcome than other patients (P = .05; Fig 5D). Overall, IPI was not significantly associated with disease outcome (P = .38). Among the nine patients who died of progressive disease one had suffered from severe hepatic toxicity leading to treatment interruption. The other patients did receive their scheduled chemotherapy.
Hepatic Toxicity A 39-year-old man with hepatic and gut NHL died from acute gastrointestinal bleeding following the second course of ACVBP (adriblastin, cyclophosphamide, vindesine, bleomycin, prednisone) regimen was not assessed for hepatic toxicity. A high incidence of hepatic toxicity occurred among the 23 remaining HCV-positive patients without HBV chronic infection (Fig 6). Fifteen patients (65%) had a hepatic toxicity during chemotherapy; among them, seven had a grade 3 to 4 hepatic toxicity (Table 3) . The proportion of HCV-positive patients with hepatic toxicity and the severity of toxicity tended to increase with the number of chemotherapy courses (Table 3). Except for the first cycle, the proportions of hepatic toxicity among the matched HCV-negative patients were significantly lower than those observed in HCV-positive patients. In the matched patients, only one patient experienced grade 3 hepatic toxicity. Hepatic toxicity led to a modification of the protocol treatment for seven HCV-positive patients (Table 3).
Hepatic toxicity required hospitalization for four patients. The first was a 36-year-old man with bowel NHL with good tumoral response following induction therapy (patient 1, Table 3). He had no hepatic toxicity until the second cycle of consolidation (ifosfamide, vindesine, aracytine, methotrexate [IVAM]). He was hospitalized in the intensive care unit following this cycle for ileus, severe dehydration, and acute grade 3 hepatic cytolysis. Chemotherapy was then withdrawn, and the patient remained in long-term remission. A 66-year-old woman with spleen and retroperitoneal lymphoma developed severe ascitis and edema decompensation after the fifth cycle of oral chemotherapy (idarubicine, cyclophosphamide, methylprednisolone [ZEM]; patient 2, Table 3). She had no previous history of cirrhosis, and she did not have any hepatic toxicity during the four previous cycles of the same chemotherapy. Following resolution of ascitis with symptomatic treatment, she received the last cycle of chemotherapy at a reduced dose. She died 4 months later with cirrhosis and uncontrolled lymphoma progression. The third patient died of the direct consequences of toxicity during induction treatment. This 77-year-old woman with stage I cervical lymphoma died from acute cholestasis and hepatic cytolysis after the third cycle of CHOP (cyclophosphamide, adriblastin, vincristine, prednisone) chemotherapy (patient 3, Table 3). She was in complete remission. The last patient died of a secondary hepatic NHL following interruption of chemotherapy for acute hepatic toxicity. This 49-year-old man with stage 4 NHL had severe hepatic toxicity after three cycles of ACVBP, leading to interruption of chemotherapy and hospitalization in hepatology unit (patient 4, Table 3). A liver biopsy concluded to HCV-related acute fibrosing cholestatic hepatitis. It was confirmed by very high HCV-RNA levels (40 million copies/mL). The patient received antiviral treatment. Ten weeks after interruption of chemotherapy, hepatic relapse was diagnosed on a second liver biopsy, and the patient died of progression of NHL 2 weeks later. Viral load was measured in four patients with hepatic toxicity. It was highly positive in all cases. Liver biopsy was performed in one case both before chemotherapy and after grade 3 hepatic toxicity: METAVIR score rose from A1F1 to A2F2, with histological signs of both toxic and viral hepatic injury after chemotherapy. No patient, except the one previously described, received a specific antiviral treatment during chemotherapy. Three patients have received an antiviral treatment during long-term follow-up. No patient died from hepatic disease during long-term follow-up. There was no association between the initial severity of hepatic disease and subsequent liver drug toxicity. Moreover, the only patient who had a severe hepatic cytolysis before the beginning of chemotherapy, out of the context of a liver NHL involvement, did not have any hepatic toxicity following chemotherapy. No association could be found between the drug received and the incidence of toxicity. Toxicity in the 7 auto-grafted patients was grade 0 (n = 1), grade 1 (n = 1), grade 2 (n = 3), grade 3 (n = 1), grade 4 (n = 1). Only one patient of the study received anti-CD20 monoclonal antibody, and it was not followed by hepatic toxicity. Of note, the two patients chronically coinfected with HCV and HBV had grade 3 and grade 4 hepatic toxicity.
Here we report an exhaustive study of the characteristics and outcome of DLCL in HCV-positive patients in the GELA LNH 93 and LNH 98 programs. The proportion of HCV infection in this series of DLCL was low (0.46%). A higher proportion of DLCL in HCV-positive patients had features of transformation from low-grade B-cell NHL (P = .02). HCV-infected patients with NHL had a higher proportion of spleen involvement than other patients (P < 10–3), and a higher LDH level than other patients (P = .02). HCV positive patients had a high incidence of hepatic toxicity following chemotherapy leading to frequent modifications of chemotherapy protocol schedule or doses. There was a pejorative long-term outcome of the HCV-positive patients. The prevalence of HCV infection in this population of patients is lower than the one reported in France (1%).22 A low prevalence of HCV infection in specialized hematological center has been previously reported.23 This difference is probably the consequence of several inclusion biases. Since HCV related NHL seems to occur more frequently among patients with a long lasting chronic hepatic disease,13,24,25 due to inclusion criteria in these GELA programs, most of HCV-related lymphoma have been excluded from the present study. Moreover, HCV serology was not mandatory in the LNH 93 program and some cases of HCV-associated lymphomas may have been underdiagnosed. This would decrease the sensitivity of our findings. Lastly, HCV infection is known to be more preferentially associated with low-grade NHL than with DLCL. The pathological review showed a significantly higher proportion of patients with low-grade transformed NHL than among HCV-negative patients. This finding is in accordance with previous reports of HCV related low-grade NHLs, showing that HCV infection is closely associated with marginal zone lymphoma.2,7 Moreover, this is reinforced by the negativity of bcl-6 expression in all cases and by the frequent negativity of CD10 expression in these cases. As reported in other series, spleen involvement was more frequent in HCV-positive patients.13 These findings also suggest that these lymphomas may occur as a transformation of low grade lymphomas likely of marginal type. The higher level of LDH that we observe among HCV positive patients had not been previously reported. We suggest that HCV infection per se can be associated with mild increase of LDH level since increased LDH levels were observed in four of 22 HCV-positive patients without NHL (data not shown). Moreover, LDH level did not seem to have a prognostic value in our patients. Typical DLCL, advanced stage, and/or poor performance status tended to have a negative prognostic value. Overall, IPI did not seem to affect outcome in our small series of patients. The complete remission rate of HCV-positive patients did not differ from other patients, as previously reported in other series.8,26 The event-free survival does not differ significantly between the two groups of patients (P = .13). However, there is a worse overall survival among HCV-positive patients (P = .02). The difference in 2-year survival between HCV-positive patients and HCV-negative patients is partly due to the increased incidence of hepatic toxicity among these patients, leading to three deaths of 24 HCV-positive patients. Hepatotoxicity also led to several treatment discontinuations, dose reductions, and delays of chemotherapy. Two cases of HCV-related fulminant hepatitis following chemotherapy had been previously reported in the literature.27 A previous study of hepatic toxicity among HCV-positive patients undergoing autologous stem-cell transplantations revealed an incidence of severe hepatitis in two of 13 cases.28 This is in sharp contrast with previous reports considering toxicity of chemotherapy in HCV-positive patients as a marginal phenomenon.29,30 The high incidence of modification of chemotherapy due to hepatic toxicity that we observed, might be related to the use of aggressive chemotherapy regimen in the GELA programs.13 In accordance with previous reports, we confirm that the severity of hepatic toxicity is related neither to pretreatment liver abnormalities27 nor to a specific drug intensification. This excludes a mechanism of hepatotoxicity to a specific drug. Hepatic toxicity increased in frequency and severity, continuously with chemotherapy cycles. The occurrence of a mild hepatic toxicity increased the risk of severe hepatic toxicity in the following chemotherapy courses. No conclusion can be drawn concerning the potential toxicity of rituximab since only one patient of this series had received this treatment. However, rituximab is known to increase the risk of HBV reactivations in HBV-infected patients,31 and careful monitoring of HCV infected patients under rituximab is recommended. Hepatic toxicity may reflect various nonexclusive mechanisms. Direct cytotoxicity of HCV associated with the marked enhancement of HCV replication by chemotherapy may lead to the so-called fibrosing cholestasis hepatitis observed in two patients. Hepatitis of immune reactivation may be also associated with the enhanced immune response after discontinuation of chemotherapy as reported for HBV. Finally, the reduction of drug metabolism associated with HCV hepatitis could participate in drug-related toxicity, like observed with antiretroviral drugs or immunosuppressive regimen. In conclusion, DLCL in HCV-positive patients have frequent spleen localizations and are in a high proportion transformed from low-grade NHL. This study highlights the frequent hepatic toxicity among these patients. HCV testing should be drawn on all patients with lymphomas, similar to HBV and HIV. Patients with HCV should be excluded from standard lymphoma studies. A careful follow-up of liver function tests and viral load during chemotherapy and/or rituximab is recommended. The role of antiviral therapy during chemotherapy must be further evaluated to improve their outcome.
The authors indicated no potential conflicts of interest.
We thank Mr Nicolas Nio for excellent technical assistance in statistical work. We are grateful to Chafika Coppeaux and Emmanuelle Come for assistance in pathological studies. We thank the pathologists for sending the pathological materials and the clinicians for sharing the patients' medical data.
Presented in part as a poster at the Annual Meeting of the American Society of Hematology, Philadelphia, PA, December 6-10, 2002. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Zuckerman E, Zuckerman T, Levine AM, et al: Hepatitis C virus infection in patients with B-cell non-Hodgkin lymphoma. Ann Intern Med 127:423-428, 1997 2. Silvestri F, Pipan C, Barillari G, et al: Prevalence of hepatitis C virus infection in patients with lymphoproliferative disorders. Blood 87:4296-4301, 1996 3. Ferri C, Caracciolo F, Zignego AL, et al: Hepatitis C virus infection in patients with non-Hodgkin's lymphoma. Br J Haematol 88:392-394, 1994[Medline] 4. Guida M, D'Elia G, Benvestito S, et al: Hepatitis C virus infection in patients with B-cell lymphoproliferative disorders. Leukemia 16:2162-2163, 2002[CrossRef][Medline] 5. De Rosa G, Gobbo ML, De Renzo A, et al: High prevalence of hepatitis C virus infection in patients with B-cell lymphoproliferative disorders in Italy. Am J Hematol 55:77-82, 1997[CrossRef][Medline] 6. Mazzaro C, Zagonel V, Monfardini S, et al: Hepatitis C virus and non-Hodgkin's lymphomas. Br J Haematol 94:544-550, 1996[CrossRef][Medline] 7. Mele A, Pulsoni A, Bianco E, et al: Hepatitis C virus and B-cell non-Hodgkin lymphomas: An Italian multi- center case-control study. Blood 102:996-999, 2003 8. Vallisa D, Berte R, Rocca A, et al: Association between hepatitis C virus and non-Hodgkin's lymphoma, and effects of viral infection on histologic subtype and clinical course. Am J Med 106:556-560, 1999[CrossRef][Medline] 9. Gisbert JP, Garcia-Buey L, Pajares JM, et al: Prevalence of hepatitis C virus infection in B-cell non-Hodgkin's lymphoma: Systematic review and meta-analysis. Gastroenterology 125:1723-1732, 2003[CrossRef][Medline] 10. Hermine O, Lefrere F, Bronowicki JP, et al: Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 347:89-94, 2002 11. Saadoun D, Suarez F, Lefrere F, et al: Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: A new entity? Blood 105:74-76, 2005[Medline] 12. Luppi M, Longo G, Ferrari MG, et al: Additional neoplasms and HCV infection in low-grade lymphoma of MALT type. Br J Haematol 94:373-375, 1996[CrossRef][Medline] 13. De Vita S, Sacco C, Sansonno D, et al: Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood 90:776-782, 1997 14. Reyes F, Lepage E, Munck JN, et al: Superiority of the ACVBP regimen over a combined treatment with three cycles of CHOP followed by involved fields radiotherapy in patients with low-risk localized aggressive non-Hodgkin's lymphoma: Results of the LNH93-1 study. Blood 96:832, 2000 (abstr 3595) 15. Gisselbrecht C, Lepage E, Molina T, et al: Shortened first-line high-dose chemotherapy for patients with poor-prognosis aggressive lymphoma. J Clin Oncol 20:2472-2479, 2002 16. Fillet G, Bonnet C, Mounier N, et al: Radiotherapy is unnecessary in elderly patients with localized aggressive non Hodgkin's lymphoma: Results of the GELA LNH93-4 study. Blood 100:92, 2002 (abstr 337) 17. Tilly H, Lepage E, Coiffier B, et al: Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood 102:4284-4289, 2003 18. Morel P, Mounier N, Brière J, et al: Autologous stem cell transplantation (ASCT) as consolidation therapy for patients with low-intermediate (LI) risk diffuse large B-cell lymphoma (DLBCL) and overexpression of bcl2 protein: Results of the first interim analysis of the GELA trial LNH98-B2. J Clin Oncol 22, 2004 (abstr 6505) 19. Haioun C, Mounier N, Emile JF, et al: Nothing after high dose consolidative first line chemotherapy with autologous stem cell transplantationin poor risk diffuse large B-cell lymphoma: LNH98-B3 GELA study. Blood 102:399a, 2003 (abstr 1447) 20. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 21. A predictive model for aggressive non-Hodgkin's lymphoma: The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med 329:987-994, 1993 22. Dubois F, Desenclos JC, Mariotte N, et al: Hepatitis C in a French population-based survey, 1994: Seroprevalence, frequency of viremia, genotype distribution, and risk factors: The Collaborative Study Group. Hepatology 25:1490-1496, 1997[CrossRef][Medline] 23. Germanidis G, Haioun C, Pourquier J, et al: Hepatitis C virus infection in patients with overt B-cell non-Hodgkin's lymphoma in a French center. Blood 93:1778-1779, 1999 24. Ascoli V, Lo Coco F, Artini M, et al: Extranodal lymphomas associated with hepatitis C virus infection. Am J Clin Pathol 109:600-609, 1998[Medline] 25. Izumi T, Sasaki R, Miura Y, et al: Primary hepatosplenic lymphoma: Association with hepatitis C virus infection. Blood 87:5380-5381, 1996 26. Luppi M, Longo G, Ferrari MG, et al: Clinico-pathological characterization of hepatitis C virus-related B- cell non-Hodgkin's lymphomas without symptomatic cryoglobulinemia. Ann Oncol 9:495-498, 1998 27. Vento S, Cainelli F, Mirandola F, et al: Fulminant hepatitis on withdrawal of chemotherapy in carriers of hepatitis C virus. Lancet 347:92-93, 1996[CrossRef][Medline] 28. Locasciulli A, Bruno B, Alessandrino EP, et al: Hepatitis reactivation and liver failure in haemopoietic stem cell transplants for hepatitis B virus (HBV)/hepatitis C virus (HCV) positive recipients: A retrospective study by the Italian group for blood and marrow transplantation. Bone Marrow Transplant 31:295-300, 2003[CrossRef][Medline] 29. Kawatani T, Suou T, Tajima F, et al: Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies. Eur J Haematol 67:45-50, 2001[CrossRef][Medline] 30. Zuckerman E, Zuckerman T, Douer D, et al: Liver dysfunction in patients infected with hepatitis C virus undergoing chemotherapy for hematologic malignancies. Cancer 83:1224-1230, 1998[CrossRef][Medline] 31. Tsutsumi Y, Kanamori H, Mori A, et al: Reactivation of hepatitis B virus with rituximab. Expert Opin Drug Saf 4:599-608, 2005[CrossRef][Medline] Submitted February 4, 2005; accepted November 22, 2005.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
2 test, and the Fisher's exact test. Tests were bilateral. The differences were considered significant at P < .05. Survival curves for patients were calculated by the Kaplan-Meier method. Comparisons between survival curves were made with Wilcoxon test. Statistical analysis was performed with SAS software version 6.2 (SAS Institute, Cary, NC). 
