Therapeutic Options in Patients With Lymphoma and Severe Liver Dysfunction

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Lymphoma Treatment in Severe Liver Dysfunction

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Original Article

Therapeutic Options in Patients With Lymphoma and Severe Liver Dysfunction IRENE M. GHOBRIAL, MD; ROBERT C. WOLF, PHARMD; DENISE L. PEREIRA, MD; RAFAEL FONSECA, MD; WILLIAM L. WHITE, MD; JOSEPH P. COLGAN, MD; THOMAS M. HABERMANN, MD; DAVID J. INWARDS, MD; SVETOMIR N. MARKOVIC, MD, PHD; STEPHEN M. ANSELL, MD, PHD; IVANA N. M. MICALLEF, MD; LUIS F. PORRATA, MD; AND THOMAS E. WITZIG, MD

•

Objectives: To determine the long-term outcome of

comitant rituximab. Twenty-two patients (54%) had sufficient improvement in liver function to receive subsequent standard chemotherapy. Nine patients (22%) are alive and disease-free at a median of 31 months (range, 4 to ≥87 months) after mechlorethamine treatment. Factors associated with improved overall survival included improvement in bilirubin levels (P<.001) and receiving subsequent standard chemotherapy (P=.001). • Conclusion: Mechlorethamine, high-dose corticosteroids, and rituximab are useful therapeutic interventions for this unique group of patients with lymphoma and severe liver dysfunction. Substantial clinical improvement and long-term survival are possible. Mayo Clin Proc. 2004;79:169-175

patients presenting with synchronous lymphoma and seOriginal Articl vere liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy. • Patients and Methods: We reviewed the clinical course of all patients diagnosed as having lymphoma who presented with severe liver dysfunction and received intravenous mechlorethamine between September 1988 and February 2003 at the Mayo Clinic in Rochester, Minn. • Results: Forty-one patients were identified, 33 (80%) of whom had newly diagnosed, previously untreated lymphoma. Thirty-seven (90%) had non-Hodgkin lymphoma, and 4 (10%) had Hodgkin disease. Thirty-four patients (83%) had stage IV disease, and 31 (84%) of 37 had an intermediate-high International Prognostic Index. The median total bilirubin level before therapy was 10.7 mg/dL (range, 2.5-30.2 mg/dL), and the median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L). In addition to mechlorethamine, 34 patients (83%) received concomitant corticosteroids, and 12 (29%) received con-

AST = aspartate aminotransferase; CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone; CT = computed tomography; HD = Hodgkin disease; IPI = International Prognostic Index; LDH = lactate dehydrogenase; NHL = non-Hodgkin lymphoma

C

Drugs that are effective in the treatment of lymphoma and are not activated or metabolized by the liver include mechlorethamine, corticosteroids, and rituximab. To our knowledge, no systematic studies to date have addressed the use of these agents in this unique subset of patients. The goals of this study were to determine the long-term outcome of patients presenting with synchronous lymphoma and severe liver dysfunction and to describe the outcome of patients treated with initial mechlorethamine-based therapy used as a bridge to more conventional chemotherapy.

linically apparent non-Hodgkin lymphoma (NHL) infiltration of the liver at presentation occurs in 5% to 14% of cases.1-4 In patients with advanced stages of NHL, the incidence increases to as high as 60%.4 Patients with lymphoma and severe liver dysfunction are usually unable to receive conventional chemotherapy with anthracyclines or vinca alkaloids because of the risk of toxic effects.5-8 In addition, they are not eligible to be enrolled in clinical trials of novel agents because the eligibility criteria typically exclude patients with bilirubin levels higher than 2 mg/dL. From the Division of Hematology and Internal Medicine (I.M.G., D.L.P., R.F., W.L.W., J.P.C., T.M.H., D.J.I., S.N.M., S.M.A., I.N.M.M., L.F.P., T.E.W.) and Hospital Pharmacy Services (R.C.W.), Mayo Clinic College of Medicine, Rochester, Minn. Dr Pereira is now with the Instituto Nacional do Cancer, Rio de Janeiro, Brazil.

PATIENTS AND METHODS We reviewed the Mayo Clinic patient database between September 1988 and February 2003 to identify patients with histologic proof of Hodgkin disease (HD) or NHL and severe liver dysfunction who had been treated with mechlorethamine. The use of concomitant corticosteroids or rituximab was also recorded. This retrospective study was approved by the Mayo Foundation Institutional Re-

This study was supported in part by grant CA97274 from the National Cancer Institute. Address reprint requests and correspondence to Thomas E. Witzig, MD, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: witzig.thomas@mayo .edu). Mayo Clin Proc. 2004;79:169-175

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© 2004 Mayo Foundation for Medical Education and Research

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Lymphoma Treatment in Severe Liver Dysfunction

Table 1. Baseline Characteristics of Study Patients (N=41)* Variable Median age (range) (y) >60 y >70 y Male Performance status 0 1 2 3 4 Stage 1 (including 1E) 2 3 4 Low IPI (0-2) (n= 37) Intermediate-high IPI (3-5) LDH (range) (U/L) (n=35) Elevated LDH level Alkaline phosphatase (range) (U/L) Total bilirubin (range) (mg/dL) Direct bilirubin (range) (mg/dL) AST (range) (U/L) Creatinine (range) (mg/dL) Biliary obstruction and stent placement Lymphomatous involvement proven by liver biopsy

No. of patients† 54 17 7 26

(29-82) (41) (17) (63)

1 4 3 9 24

(2) (10) (7) (22) (59)

4 0 3 34 6 31 538 31 982 10.7 6.6 132 1 6 18

(10) (0) (7) (83) (15) (76) (113-3352) (76) (233-3415) (2.5-30.2) (1.2-21.7) (14-1122) (0.5-4.6) (15) (44)

*AST = aspartate aminotransferase; IPI = International Prognostic Index; LDH = lactate dehydrogenase. †Values are median number (percentage) of patients unless indicated otherwise.

view Board and was conducted in accordance with the ethical guidelines mandated by the Declaration of Helsinki. Severe liver dysfunction was defined as one or more of the following: an alkaline phosphatase level that is 1.5 times the upper limit of normal (115 U/L) or a serum total bilirubin level greater than 3 mg/dL (upper limit of normal, 1.0 mg/dL). Patients with an elevated bilirubin level due to hemolytic anemia were excluded. All patients had imaging studies (computed tomography [CT] or ultrasonography) performed, the results of which were consistent with lymphomatous involvement of the liver. All patients were treated with intravenous mechlorethamine at standard doses (6 mg/m2 body surface area) on day 1; this could be repeated weekly. Patients treated with corticosteroids typically received intravenous high-dose methylprednisolone as a 2 g/d flat dose repeated at the discretion of the physician. Rituximab was given intravenously as 375 mg/m2 repeated weekly to patients who were CD20-positive. Rituximab was administered to patients treated after 1997, the year it was approved by the Food and Drug Administration. Medical records were reviewed for date of diagnosis of lymphoma, age, sex, Eastern Cooperative Oncology Group performance status, stage, International Prognostic Index

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(IPI) at the time of treatment with mechlorethamine, prior chemotherapy, subsequent chemotherapy after treatment with these agents, lactate dehydrogenase (LDH) level, alkaline phosphatase level, total and direct bilirubin levels, aspartate aminotransferase (AST) level, creatinine level, and hepatitis serologic test results. Tumor histologic findings and the results of any liver biopsy were also recorded. The number of days from the start of mechlorethamine therapy to the start of conventional chemotherapy or death and the duration of follow-up were also recorded. Laboratory values were recorded before and after treatment, which was defined as the last value before standard chemotherapy or before death. Improvement in bilirubin levels was defined as any improvement in bilirubin level after treatment. Descriptive statistics were used for the baseline patient characteristics. Survival analysis was plotted according to the method of Kaplan and Meier.9 Log-rank P values were reported. Exact (95%) binomial confidence intervals also were calculated when appropriate. Multivariate analysis was not performed because the factors used on univariate analysis are interdependent. RESULTS During the study period, 41 patients with lymphoma and severe liver dysfunction who had been treated with mechlorethamine were identified; baseline characteristics are summarized in Table 1. The median age was 54 years (range, 29-82 years), and 7 patients (17%) were older than 70 years. This patient population had advanced-stage lymphoma as evidenced by 34 patients (83%) with stage IV disease. The patients were ill: 24 patients (59%) had a performance status of 4; 31 (84%) of 37 had an intermediate-high IPI; and 31 (89%) of 35 had an elevated LDH level. All patients had a confirmed histologic diagnosis of lymphoma before initiation of mechlorethamine therapy. The diagnosis was NHL in 37 (90%) and HD in 4 (10%). Twenty-six patients (63%) had B-cell lymphoma, and 11 patients (27%) had T-cell lymphoma. Histologic characteristics are described in Table 2. Twenty patients (49%) underwent liver biopsy, and in 18 patients the biopsy specimen was positive for lymphoma; the other 2 patients had biopsy specimens that were negative for lymphoma. However, both of these patients had biopsy-proven NHL outside the liver. In 1 of these 2 patients, the liver biopsy was performed 2 months before the use of mechlorethamine and showed chronic hepatitis B with periportal fibrosis. The patient’s liver function subsequently deteriorated, and CT showed new, multiple lowattenuation lesions consistent with lymphoma. The clinical impression was progression of systemic lymphoma, and

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Lymphoma Treatment in Severe Liver Dysfunction

Table 2. Histologic Characteristics of Study Patients (N=41) Variable Non-Hodgkin lymphoma (NHL) Hodgkin disease B-cell NHL Posttransplantation lymphoproliferative Richter transformation Immunoblastic Intravascular large cell Diffuse large B cell Total T-cell NHL Peripheral T cell Anaplastic Natural killer cell γδ T cell Total

No. (%) of patients 37 (90) 4 (10) 2 2 1 1 20 26

(5) (5) (2) (2) (49) (63)

5 3 2 1 11

(12) (7) (5) (2) (27)*

*Sum of percentages does not equal 27% because of rounding.

another liver biopsy was not performed before the start of mechlorethamine treatment. The other patient’s liver biopsy specimen was nondiagnostic, showing no notable abnormalities. All patients had evidence of profound liver dysfunction. The median alkaline phosphatase level was 982 U/L (range, 233-3415 U/L), the median total bilirubin level was 10.7 mg/dL (range, 2.5-30.2 mg/dL), the median direct bilirubin level was 6.6 mg/dL (range, 1.2-21.7 mg/dL), and the median AST level was 132 U/L (range, 14-1122 U/L). Twenty-two patients (54%) had available serologic test results for hepatitis, and only 2 patients tested positive for chronic hepatitis B infection. Six patients (15%) had evidence of biliary obstruction, and a stent was successfully placed in 5 patients (Table 1). However, stent placement in these patients did not improve liver function enough to allow the use of conventional chemotherapy. Ten patients (24%) had a serum creatinine level higher than 2 mg/dL. Thirty-three patients (80%) had newly diagnosed lymphoma and received mechlorethamine as their first chemotherapy within 1 month of the diagnosis. The median time from the diagnosis of lymphoma to treatment with mechlorethamine for all 41 patients was 7 days (range, 1 day to 7.5 years). Thirty-four patients (83%) received concomitant corticosteroids. Thirty-two (78%) received high-dose intravenous methylprednisolone (2-g flat dose), typically given every day to every other day until improvement. Two patients (5%) received 40 to 60 mg/d of oral prednisone; 12 patients (29%) received concomitant rituximab; and 11 patients (27%) received all 3 agents (Table 3). Twenty-eight patients (68%) had improvement in total bilirubin levels, with a median improvement of 4.2 mg/dL (range, 0.3-28.0 mg/dL). Seven patients (17%) had im-

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Table 3. Therapeutic Interventions at Time of Elevated Liver Function Tests Median No. (%) of patients

Variable Mechlorethamine dose 1 2 3 Concomitant corticosteroids and mechlorethamine Concomitant rituximab and mechlorethamine All 3 agents

25 14 2 34 12 11

(61) (34) (5) (83) (29) (27)

provement of total bilirubin levels to less than 2.0 mg/dL. Nineteen patients (46%) had improvement in alkaline phosphatase and AST levels (Table 4). Nineteen patients did not improve with mechlorethamine-based therapy, and 17 did not receive additional chemotherapy. Twenty-four patients had additional chemotherapy. Two patients (5%) had immediate progression with mechlorethamine and were treated with dexamethasone, high-dose cytarabine, and cisplatin. Neither patient responded to this drug combination, and both died of progressive disease, 1 after 8 days and 1 after 30 days. Twentytwo patients (54%; 95% confidence interval, 37%-69%) had sufficient improvement in their liver function to proceed to standard chemotherapy. The median time to subsequent chemotherapy was 15 days (range, 3-45 days). The median level of bilirubin at the time of subsequent chemotherapy was 3.3 mg/dL (range, 0.8-17.6 mg/dL). The patient who had a bilirubin level of 17.6 mg/dL after mechlorethamine treatment received cyclophosphamide as a subsequent chemotherapy and did not improve. The median level of bilirubin at the time of subsequent cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP) therapy was 2.1 mg/ dL (range, 0.8-8.3 mg/dL). The patient who had a total bilirubin level of 8.3 mg/dL and then received CHOP chemotherapy did not improve. The chemotherapy regimens administered are summarized in Table 5. Three (7%) of those who responded to mechlorethamine subsequently received high-dose therapy with stem cell transplantation. One patient with HD reTable 4. Improvement in Liver Function Test Results Variable

Median No. (%) of patients

Bilirubin Any improvement Improved to a level <2.0 mg/dL Improved alkaline phosphatase Improved aspartate aminotransferase

28 (68) 7 (17) 19 (46) 19 (46)

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Table 5. Therapeutic Interventions After Mechlorethamine Therapy for Patients Who Improved Enough to Receive Subsequent Chemotherapy* Median No. (%) of patients

Variable Improved and received subsequent chemotherapy† Subsequent chemotherapy CHOP Rituximab and CHOP DHAP Cyclophosphamide and corticosteroids or etoposide ESHAP MOPP/ABV Cytarabine and carboplatin

22 (54) 13 (32) 1 (2) 1 (2) 2 1 3 1

(5) (2) (7) (2)

*CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone; DHAP = dexamethasone, high-dose cytarabine, and cisplatin; ESHAP = etoposide, methylprednisolone, cytarabine, and cisplatin; MOPP/ABV = mechlorethamine, vincristine, prednisone, procarbazine/doxorubicin, bleomycin, and vinblastine. †Time to subsequent therapy was 15 days (range, 3-45 days).

ceived a successful allogeneic transplant in his second complete remission. The other 2 patients eventually relapsed and received an autologous stem cell transplant after responding to salvage chemotherapy. The median survival of all 41 patients was 1.6 months (range, 3 days to ≥87 months). In this seriously ill patient population, the outcome of treatment with these agents was apparent soon after initiation of treatment (Figure 1). Of the 19 patients who did not respond to mechlorethamine-based therapy, the median survival was only 0.4 months (range, 0.1-1.9 months), whereas in those who responded to treatment, the median overall survival was 10 months (range, 0.5 to ≥87 months).

100 Patients who improved and received subsequent chemotherapy

Patients (%)

80

Patients who did not have improved liver function

60 40 20 0 0

500

1000

1500

2000

2500

3000

Days from initiation of mechlorethamine therapy

Figure 1. Overall survival from the date of mechlorethamine administration. Patients who improved and received subsequent conventional chemotherapy had a better survival rate than patients who did not respond (P<.001).

Thirty-two patients (78%) died of disease, and 9 (22%) are alive at a median follow-up of 31 months (range, 4 to ≥87 months). Of these 9 patients, 2 received mechlorethamine alone, 5 received concomitant corticosteroids, and 2 received concomitant corticosteroids and rituximab (Figures 2 and 3). None of those who did not respond to mechlorethamine, corticosteroids, or rituximab were longterm survivors. Alkaline phosphatase and total bilirubin levels for an 82-year-old woman who developed painless jaundice and weight loss are shown in Figure 2. A CT of the abdomen revealed a mass (6 × 3 cm) in the periportal area and a mass (2 × 3 cm) in the liver. Only a small stent could be placed. A liver biopsy specimen showed diffuse CD20-positive large cell lymphoma. Laboratory values were as follows: total bilirubin at diagnosis, 45.8 mg/dL; direct bilirubin, 33.9 mg/dL; AST, 147 U/L; and alkaline phosphatase, 1177 U/ L. Five days later and before mechlorethamine therapy, the total bilirubin level had improved to 30.0 mg/dL, direct bilirubin level to 21.0 mg/dL, AST level to 91 U/L, and alkaline phosphatase level to 914 U/L. However, the improvement was not sufficient for the use of standard chemotherapy. The patient received mechlorethamine (days 1 and 8) and high-dose methylprednisolone (2 g, 3 times a week). The total bilirubin level improved to 7.8 mg/dL, direct bilirubin level to 5.2 mg/dL, AST level to 77 U/L, and alkaline phosphatase level to 506 U/L after 13 days of therapy. The patient then received rituximab for 4 more cycles until her bilirubin level improved to 2.0 mg/dL and her alkaline phosphatase level to 257 U/L. She subsequently received CHOP chemotherapy and is tolerating it well without adverse effects. The CT scans of a 66-year-old man who presented with jaundice, weight loss, and abdominal pain (Figure 3) showed a pancreatic mass and multiple liver masses. A biopsy specimen showed a large cell lymphoma. Laboratory values were as follows: total bilirubin, 24.5 mg/dL; direct bilirubin, 18.5 mg/dL; AST, 170 U/L; and alkaline phosphatase, 944 U/L. A biliary stent was placed for biliary obstruction at the head of the pancreas, and high-dose methylprednisolone therapy (2 g, 3 times a week) was initiated. The total bilirubin level dropped to 7.3 mg/dL after 2 weeks. Mechlorethamine therapy (days 1 and 8) was initiated in addition to the methylprednisolone. One month later, the total bilirubin level was 1.2 mg/dL, direct bilirubin level was 0.6 mg/dL, AST level was 35 U/L, and alkaline phosphatase level was 802 U/L. CHOP chemotherapy was initiated; the patient received 6 cycles and was in complete remission at the last follow-up visit 27 months later. On univariate analysis, factors that predicted improved overall survival were prompt, steady improvement in liver

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Lymphoma Treatment in Severe Liver Dysfunction

Stent

SM

S R

S

SM

R

R R

1000

Alkaline phosphatase (U/L)

173

R CHOP 500 300 0 0

3

6

9

12

15

18

21

29

45

52

0

3

6

9

12

15

18

21

29

45

52

Total bilirubin (mg/dL)

40.0 30.0 20.0 10.0 1.0 0.0

Day Figure 2. Levels of total bilirubin and alkaline phosphatase in a patient treated with mechlorethamine, high-dose methylprednisolone, and rituximab. CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone; M = mechlorethamine; R = rituximab; S = methylprednisolone.

function test results, including total bilirubin (P<.001) and direct bilirubin (P=.001) levels, and the ability to subsequently receive standard chemotherapy (P<.001) (Table 6). Since these factors are interdependent, a multivariate analysis was not indicated. DISCUSSION Patients with lymphomatous involvement of the liver often present with liver dysfunction and may initially appear to have little hope of survival. Although treatment options for this group are limited, our data showed that mechlor-

A

B

ethamine, corticosteroids, and rituximab may produce a rapid tumor response and sufficient improvement in liver function to allow patients to proceed with standard chemotherapy. The eventual use of conventional combination chemotherapy is the goal of this temporary measure. Our study showed that a subset of patients with severe liver dysfunction will respond promptly to mechlorethamine, corticosteroids, and rituximab and be able to subsequently receive potentially curative conventional chemotherapy. Twenty-two (54%) of the patients in this cohort improved enough to receive standard chemotherapy, and 9 (22%)

C

Figure 3. Computed tomograms of the liver of a patient treated with mechlorethamine. A, Before treatment. B, One month after mechlorethamine treatment and before cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP) chemotherapy. C, One year after CHOP chemotherapy.

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Table 6. Univariate Analysis of Overall Survival Variable

P value

Improved bilirubin* Improved alkaline phosphatase* Improved aspartate aminotransferase Improved and received subsequent standard therapy Rituximab Corticosteroids All 3 agents

<.001 .46 .09 <.001 .74 .90 .90

*Defined as any improvement of bilirubin or alkaline phosphatase from level before mechlorethamine therapy.

achieved long-term survival after definitive treatment was provided. Mechlorethamine was one of the first chemotherapeutic agents available for treatment of hematologic malignancies.10-14 Its use, in combination with other agents, led to curative therapies for patients with advanced HD.15-18 Use of this agent paved the way for the development of modern chemotherapy.10,11 It is used infrequently today, other than in combination with other chemotherapy drugs for patients with relapsed HD.3,15,18,19 Mechlorethamine undergoes rapid chemical transformation and combines with water or reactive compounds of cells so that the drug is no longer present in active form a few minutes after administration. Because of its pharmacokinetic and safety profile, mechlorethamine has been administered to patients with severe compromise of hepatic function, when use of other agents would result in severe toxic effects.3,10 Other active agents for lymphoma that potentially could be administered to patients with severe liver dysfunction include corticosteroids and monoclonal antibodies, such as rituximab. The clinical value of corticosteroids has been established for more than 50 years and has been included in almost all treatment regimens for B-cell hematologic malignancies. High-dose corticosteroids have been shown to be effective in hematologic malignancies.20,21 A single-arm, phase 2 prospective clinical trial was performed at the Mayo Clinic20 to determine the efficacy of high-dose methylprednisolone in the treatment of patients with refractory or relapsed multiple myeloma. Twenty patients in whom at least 1 chemotherapeutic regimen had failed received 2 g of methylprednisolone 3 times a week for 8 weeks. After 8 weeks, those who responded received a maintenance dose of 2 g/wk with an 8-week reinduction at the time of relapse. There were 2 complete responses, 2 objective responses, and 3 minor responses. Other case reports and small series have shown the beneficial effect of corticosteroids, especially in liver dysfunction.21,22 Rituximab has proven efficacy as a single agent for treating NHL.23 None of the 12 patients who received rituximab at a time of severe liver dysfunction in our

study had unusual adverse reactions. One case series of 2 patients reported the use of rituximab in patients with posttransplantation lymphoproliferative disorder after liver transplantation.24 These 2 patients had evidence of cholestasis, but the rituximab therapy was well tolerated. One patient showed complete response to therapy, and the other showed 90% necrosis of tumor cells in a histologic sample after treatment. This report and our series suggest that the use of rituximab in patients with severe liver dysfunction due to lymphoma is safe and may be effective. To our knowledge, no previous studies have systematically addressed treatment of this unique group of patients with lymphoma and severe liver dysfunction. Case reports have shown that the use of conventional chemotherapy may result in remission and improvement of liver function.25,26 However, there are also reports in which use of conventional chemotherapy in patients with liver dysfunction was hazardous. It is well known that the adverse effects of chemotherapeutic drugs commonly used in the treatment of lymphoma, such as vincristine and doxorubicin, are enhanced in the presence of liver dysfunction.27,28 Investigation of the use of anthracyclines in liver dysfunction is ongoing. Recently, the evaluation of a novel dose-modification scheme for epirubicin was reported in a population of patients with breast cancer and liver dysfunction.29 However, it is unknown whether this strategy could be applied safely to patients with hepatic infiltration by lymphoma. Cyclophosphamide is an important agent in the standard therapy of lymphoma. The liver plays an essential role in the biotransformation and clearance of cyclophosphamide and its active metabolic byproducts. Although a study by Juma30 revealed no increased toxicity of this drug when used in patients with severe liver dysfunction, it is not known what effect the unpredictable metabolism has on clinical efficacy in patients with liver dysfunction.31 Two of the patients in our cohort had concomitant chronic hepatitis B with possible lymphomatous involvement of the liver. In this scenario, improvement of liver function with mechlorethamine therapy may be less likely. However, mechlorethamine is a possible therapeutic intervention for patients with lymphoma and concomitant liver dysfunction from other chronic diseases. Care must be taken if rituximab and chemotherapy are used in patients with antibodies to hepatitis B surface antigen because cases have been reported of reactivation of acute hepatitis B.32,33 There is inherent selection bias in our report because these patients, although ill, were not so ill that the treating physician deemed the intervention futile. In addition, because most patients received mechlorethamine and corticosteroids (and after 1998, commonly rituximab), it is not possible to determine the single-agent response rate. Be-

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cause of the seriousness of these patients’ condition, it is inappropriate to test each agent by itself with a period of observation for response between each agent. CONCLUSION We currently recommend that the unique group of patients with lymphoma and severe liver dysfunction receive mechlorethamine, high-dose methylprednisolone, and rituximab (if CD20-positive) concomitantly. This therapeutic regimen is useful as a bridge to conventional chemotherapy.

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15. 16. 17. 18. 19.

20. 21.

REFERENCES 1. 2. 3.

4. 5. 6. 7. 8. 9. 10.

11. 12.

13. 14.

Bagley CM Jr, Thomas LB, Johnson RE, Chretien PB, DeVita VT Jr. Diagnosis of liver involvement by lymphoma: results in 96 consecutive peritoneoscopies. Cancer. 1973;31:840-847. Birrer MJ, Young RC. Differential diagnosis of jaundice in lymphoma patients. Semin Liver Dis. 1987;7:269-277. Cervantes F, Briones J, Bruguera M, et al. Hodgkin’s disease presenting as a cholestatic febrile illness: incidence and main characteristics in a series of 421 patients. Ann Hematol. 1996;72:357360. Givler RL, Brunk SF, Hass CA, Gulesserian HP. Problems of interpretation of liver biopsy in Hodgkin’s disease. Cancer. 1971; 28:1335-1342. Black M. Liver disease and drug therapy. Med Clin North Am. 1974;58:1051-1057. Blaschke TF. Protein binding and kinetics of drugs in liver diseases. Clin Pharmacokinet. 1977;2:32-44. Bond WS. Clinical relevance of the effect of hepatic disease on drug disposition. Am J Hosp Pharm. 1978;35:406-414. Koren G, Beatty K, Seto A, Einarson TR, Lishner M. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother. 1992;26:363-371. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457-481. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. Nitrogen mustard therapy; use of methylbis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA. 1946;132:126-132. Karnofsky DA. Summary of results obtained with nitrogen mustard in the treatment of neoplastic disease. Ann N Y Acad Sci. 1958;68: 899-914. Lowenbraun S, DeVita VT, Serpick AA. Combination chemotherapy with nitrogen mustard, vincristine, procarbazine, and prednisone in lymphosarcoma and reticulum cell sarcoma. Cancer. 1970; 25:1018-1025. Jacobs EM, Peters FC, Luce JK, Zippin C, Wood DA. Mechlorethamine HCl and cyclophosphamide in the treatment of Hodgkin’s disease and the lymphomas. JAMA. 1968;203:392-398. Lenhard RE Jr, Owens AH Jr. Recent advances in chemotherapy of lymphoma. Johns Hopkins Med J. 1967;121:136-140.

22. 23. 24.

25. 26. 27. 28.

29.

30. 31. 32.

33.

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Bonadonna G, De Lena M, Lattuada A, Milani F, Monfardini S, Beretta G. Combination chemotherapy and radiotherapy in nonHodgkin’s lymphomata. Br J Cancer. 1975;31(suppl 2):481-488. Rubin P. Comment: the non-Hodgkin’s lymphomas. JAMA. 1973; 223:175-178. Carbone PP. Management of patients with non-Hodgkin’s lymphoma. Arch Intern Med. 1973;131:455-459. Stefanato CM, Reyes-Mugica M. Masked Hodgkin’s disease: the pruriginous disguise [letter]. Pediatr Hematol Oncol. 1996;13:293294. Duggan DB, Petroni GR, Johnson JL, et al. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin’s disease: report of an intergroup trial. J Clin Oncol. 2003;21:607-614. Gertz MA, Garton JP, Greipp PR, Witzig TE, Kyle RA. A phase II study of high-dose methylprednisolone in refractory or relapsed multiple myeloma. Leukemia. 1995;9:2115-2118. Norfolk DR, Child JA. Pulsed high dose oral prednisolone in relapsed or refractory multiple myeloma. Hematol Oncol. 1989;7:6168. Herishanu Y, Lishner M, Kitay-Cohen Y. The role of glucocorticoids in the treatment of fulminant hepatitis induced by dacarbazine. Anticancer Drugs. 2002;13:177-179. Grillo-Lopez AJ, Hedrick E, Rashford M, Benyunes M. Rituximab: ongoing and future clinical development. Semin Oncol. 2002;29(1, suppl 2):105-112. Yedibela S, Reck T, Niedobitek G, et al. Anti-CD20 monoclonal antibody treatment of Epstein-Barr virus-induced intrahepatic lymphoproliferative disorder following liver transplantation. Transpl Int. 2003;16:197-201. Crosbie OM, Crown JP, Nolan NP, Murray R, Hegarty JE. Resolution of paraneoplastic bile duct paucity following successful treatment of Hodgkin’s disease. Hepatology. 1997;26:5-8. Takauchi K, Kono H, Ito T, Zaima K, Okumoto S. A case of primary hepatic lymphoma successfully treated by THP-COP therapy [in Japanese]. Nippon Ronen Igakkai Zasshi. 2003;40:65-68. Benjamin RS, Wiernik PH, Bachur NR. Adriamycin chemotherapy—efficacy, safety, and pharmacologic basis of an intermittent single high-dose schedule. Cancer. 1974;33:19-27. Van den Berg HW, Desai ZR, Wilson R, Kennedy G, Bridges JM, Shanks RG. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol. 1982;8:215-219. Dobbs NA, Twelves CJ, Gregory W, Cruickshanka C, Richards MA, Rubens RD. Epirubicin in patients with liver dysfunction: development and evaluation of a novel dose modification scheme. Eur J Cancer. 2003;39:580-586. Juma FD. Effect of liver failure on the pharmacokinetics of cyclophosphamide. Eur J Clin Pharmacol. 1984;26:591-593. Donelli MG, Zucchetti M, Munzone E, D’Incalci M, Crosignani A. Pharmacokinetics of anticancer agents in patients with impaired liver function. Eur J Cancer. 1998;34:33-46. Skrabs C, Muller C, Agis H, Mannhalter C, Jager U. Treatment of HBV-carrying lymphoma patients with rituximab and CHOP: a diagnostic and therapeutic challenge [letter]. Leukemia. 2002;16: 1884-1886. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab [letter]. N Engl J Med. 2001;344:68-69.

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