1 Hematology and Clinical Laboratory Divisions, National Cancer Center Hospital, Tokyo; 2 Hematology and Oncology Division, National Cancer Center Hospital East, Kashiwa; 3 Third Department of Internal Medicine, Kyoto Prefectural University of Medicine, Kyoto; 4 Department of Hematology and Chemotherapy and Department of Pathology, Aichi Cancer Center Hospital, Nagoya; 5 First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya; 6 Department of Hematology and Rheumatology, Tokai University School of Medicine, Isehara; 7 Department of Internal Medicine, Sapporo National Hospital, Sapporo; 8 Department of Internal Medicine, Nagoya National Hospital, Nagoya; 9 Department of Hematology/Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka; 10 Department of Pathology, Institute of Medical Science and Biostatistical Sciences, School of Health Science and Nursing Biostatistics, University of Tokyo, Tokyo, Japan
Received 7 November 2003; revised 15 January 2004; accepted 16 January 2004
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ABSTRACT |
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To evaluate the efficacy and feasibility of rituximab monotherapy in Japanese patients with relapsed or refractory aggressive B-cell lymphoma.
Patients and methods:
Sixty-eight patients were treated with rituximab at 375 mg/m2 by eight consecutive weekly infusions. Pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS) and the relationship between pharmacokinetic parameters and efficacy were analyzed.
Results:
The ORRs of 68 enrolled patients and 57 eligible patients were 35% [95% confidence interval (CI) 24% to 48%] and 37% (95% CI 25% to 51%), respectively. Median PFS of 53 evaluable patients was 52 days, whereas time to progression of 21 eligible responders was 245 days. Mild to moderate infusion-related toxicities were observed frequently at the first infusion, but all of them were reversible. Elevated lactate dehydrogenase (LDH) and refractoriness to prior chemotherapy were unfavorable factors affecting ORR and PFS (P <0.01). Serum trough levels of rituximab and area under the concentrationtime curve for responders were higher than for non-responders (P <0.05).
Conclusions:
Eight consecutive weekly infusions of rituximab have significant anti-lymphoma activity for relapsed or refractory aggressive B-cell lymphoma. Several pretreatment variables and serum rituximab levels are useful for predicting its efficacy.
Key words: aggressive B-cell lymphoma, pharmacokinetics, prognostic factor, rituximab
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Introduction |
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Rituximab, a mouse-human chimeric anti-CD20 monoclonal antibody, was the first monoclonal antibody approved for the treatment of malignant neoplasms by the Food and Drug Administration in the United States, and its efficacy against indolent B-cell lymphoma has been established [79]. Its efficacy against aggressive B-cell lymphoma has also been demonstrated by Coiffier et al. in their monotherapy study and combination study with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) comparing CHOP alone in Europe [10, 11]. In the USA, Vose et al. reported promising results of a phase II study of CHOP combined with rituximab [12]. However, the efficacy of rituximab monotherapy against aggressive B-cell lymphoma, especially for relapsed or chemotherapy-refractory patients, has not been extensively studied.
Previously, we conducted multicenter phase I and II studies of rituximab in Japan [9, 13]. In a pivotal phase II study, by employing a dose of 4 weekly infusions at 375 mg/m2 in relapsed indolent B-cell lymphoma and mantle cell lymphoma (MCL), we confirmed its remarkable efficacy [9]. Being encouraged by the high efficacy and acceptable toxicity profiles of rituximab in our previous studies, we planned to investigate the potential use of this chimeric antibody for the treatment of Japanese patients with recurrent or chemotherapy-refractory aggressive B-cell lymphoma. In the present multicenter phase II study, we evaluated the efficacy and toxicity of rituximab at the dose of 375 mg/m2 by eight consecutive weekly infusions. We also analyzed pretreatment variables affecting overall response rate (ORR) and progression-free survival (PFS). In addition, the relationship between pharmacokinetic (PK) parameters and efficacy was analyzed.
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Patients and methods |
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Eligibility criteria
Patients were enrolled from 22 institutions (see Acknowledgements for a list of participating investigators and institutions) from July 1999 to December 2000. Study subjects consisted of patients with aggressive B-cell lymphoma who had relapsed or were refractory to conventional chemotherapy. The pathology of the lymphoma was to be consistent with MCL, DLBCL, Burkitts lymphoma or high-grade B-cell lymphoma Burkitt-like according to the REAL classification [3]. Transformed lymphomas from indolent B-cell lymphoma were allowed to be included. The expression of CD20 antigen on the lymphoma cells was confirmed either by immunohistochemical analysis or by flow cytometry using B1 [16] or L26 [17] anti-CD20 antibody. Eligible patients had to have at least one measurable lesion, which had to be 2 cm in the greatest diameter if the patient had only one measurable lesion. The last chemotherapy cycle had to have been completed at least 2 weeks prior to study entry and have had no influence on the evaluation of rituximab efficacy and organ function. Patients were between 20 and 74 years of age and with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of
2 [18]. All patients were expected to survive for >2 months. Patients had to have no other malignancies, serious illness or infection, and had to have adequate organ functions; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <4 x upper limit of normal (ULN), total bilirubin <2 x ULN, serum creatinine <1.5 x ULN and PaO2
65 mmHg. Absolute neutrophil count was
1200/µl and platelet count
75 000/µl.
Patients meeting any one of the following criteria were excluded from the study: a history of treatment with a murine, chimeric or humanized monoclonal antibody; >1000/µl lymphoma cells in peripheral blood (PB); symptomatic central nervous system (CNS) involvement or a history of CNS involvement of lymphoma; seropositive for hepatitis B virus surface antigen, hepatitis C virus antibody or human immunodeficiency virus (HIV) antibody; pregnancy or potential pregnancy; and HIV-related lymphoma. Patients who had received hematopoietic cytokines, such as granulocyte colony-stimulating factor (G-CSF), within 1 week before enrolment were also excluded. All patients were required to stay in hospital for 2 days after the first infusion of rituximab.
Each patient signed an informed consent form at the time of study entry. The study was approved by the institutional review board of each institution.
Central review of pathology
Biopsy specimens from all enrolled patients were reclassified by a central pathology review committee according to the REAL classification. Thin-layer preparations on glass slides of lymphoma tissues obtained at the initial diagnosis and/or at relapse were collected following the patients entry onto the study. These specimens were stained with hematoxylineosin. In addition, immunohistochemical staining was also conducted using anti-CD20 (L26), anti-CD3, anti-CD10 and anti-cyclin D1 antibodies [19, 20]. Hematoxylineosin and immunohistochemically stained preparations were examined by the central pathology review committee composed of the following three hematopathologists: Y. Matsuno, S. Nakamura and S. Mori. The diagnosis by the central pathology review committee was regarded as the final one in cases where there was a discrepancy between the diagnoses of each institution and the committee.
Rituximab administration and premedication
Rituximab (IDEC-C2B8) manufactured by Genentech, Inc. (San Francisco, CA, USA) was supplied by Zenyaku Kogyo, Co. Ltd (Tokyo, Japan) as a liquid preparation containing 10 mg/ml rituximab in a 10-ml vial, which was stored at 28°C until use. The dosage and schedule of rituximab in this study was 375 mg/m2 and eight consecutive weekly infusions, respectively. Rituximab and pre-medication were given to patients as previously described [9]. Standard supportive care was provided, with the exception of corticosteroids which might affect the evaluation of tumor response. Rituximab infusion was to be discontinued if grade 3 or 4 non-hematological toxicities other than fever occurred during infusion. The use of other anticancer agents and radiotherapy was prohibited during the study period. In most patients, the second and subsequent infusions were conducted in an outpatient setting.
Monitoring of patients
In the 2 weeks prior to enrolment, patients underwent pretreatment tumor assessment at all sites where a tumor could be evaluated or measured using routine computed tomography (CT) scans. Gallium-67 (67Ga) scintigraphy and endoscopic examinations were performed if necessary. In patients with leukemic transformation, tumor cell counts in the PB or bone marrow (BM) were examined by either microscopy or flow cytometry. Clinical observations and routine laboratory examinations were carried out before rituximab administration and 2 days after the first infusion, and were repeated weekly during rituximab administration and approximately every month thereafter. B- (CD19- and CD20-positive cells) and T-lymphocytes (CD3-positive cells) counts in PB and determination of serum immunoglobulins were also performed periodically.
Adverse events (AEs) and adverse drug reactions (ADRs)
Any detrimental change in a patients condition was considered to be an AE. All AEs associated with rituximab administration or where the relationship to rituximab was unknown were regarded as ADRs. The ADRs were graded according to toxicity criteria of the Japan Clinical Oncology Group (JCOG) [21], an expanded version of the National Cancer Institutecommon toxicity criteria (version 1.0).
Human anti-chimeric antibody (HACA) and serum rituximab levels
The presence of HACA in serum was monitored immediately before the first rituximab infusion, and 3 and 6 months thereafter using an enzyme-linked immunosorbent assay (ELISA) as described previously [9, 13, 22, 23]. Serum rituximab levels were assayed in 12 patients who signed another informed consent form for participating in this PK study. During weeks 1 and 8 of treatment, serum was collected immediately before starting the infusion and at 10 min, and 24, 48 and 120 h after completion of the infusion. During weeks 2 and 7, the samples were collected immediately before starting the infusion and at 10 min after the completion of each infusion. Additional samples were taken at 1, 4 and 16 weeks after the final infusion. The PK parameters were calculated using the software WinNonlin PK (WinNonlin Standard Japanese Edition, version 1.1; Scientific Consulting, Apex, NC, USA).
Response, progression-free survival (PFS) and time to progression (TTP)
Tumor lesions were observed by physical examination weekly during rituximab administration and by CT scans and physical examination approximately every 4 weeks thereafter. Response was assessed according to protocol-defined World Health Organization (WHO) criteria and the International Workshop NHL response criteria (IWRC) described by Cheson et al. [24], but is reported here as IWRC because those are the current standards. PFS was defined for all patients, including the non-responders, as the interval from the day of the first rituximab infusion to the day on which progression or death due to any cause was observed, while the TTP was defined for all responders as the interval from the day of the first infusion to the day on which progression was observed.
Central review of CT films
CT films of all responders were centrally reviewed by an independent CT review committee consisting of the following three radiologists: T. Terauchi (National Cancer Center Hospital, Tokyo), S. Nawano (National Cancer Center Hospital East, Kashiwa) and M. Matsusako (St Lukes International Hospital, Tokyo). When there was a discrepancy between the tumor-size evaluations by each institution and by the committee, the evaluation by the central review committee was regarded as the final evaluation.
Statistical methods
ORR and its 95% confidence interval (CI) were calculated for all eligible patients under F-distribution. Median TTP and PFS as well as the 95% CIs were estimated for all eligible and evaluable patients using the method of Kaplan and Meier [25]. In addition, pretreatment factors affecting the ORR and PFS were analyzed for all eligible and evaluable patients. Factors selected for multivariate analyses were as follows: gender; age (<60 versus 60 years); ECOG PS (0 versus 12); Ann Arbor clinical stage (III versus IIIIV); B-symptom (presence versus absence); pathology (MCL versus all other aggressive B-cell NHL); LDH (normal versus elevated); number of extranodal lesions (01 versus
2); BM involvement; the largest tumor size (<5 cm versus
5 cm); number of relapses (0 versus 12); number of prior chemotherapy treatments (one regimen versus two or three regimens); and response to the last chemotherapy treatment (responder versus non-responder). In univariate analyses, Fishers exact probability test was used for factors affecting ORR, and the log-rank test for those affecting PFS. In the multivariate analyses, a logistic regression model [stepwise procedure with entry and stay probability (P) levels
0.25 and
0.15, respectively] was used for factors affecting ORR, and Coxs proportional hazard regression model (stepwise procedure with entry and stay P levels
0.25 and
0.15, respectively) for those affecting PFS [26]. The relationship between PK parameters and response was analyzed by Students t-test. All statistical analyses were performed using SAS software (version 6.12; SAS Institute, Cary, NC, USA).
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Results |
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Early termination of rituximab treatment
Rituximab treatment was discontinued early in the course of the treatment period because of disease progression in 22 patients (33%). One patient who turned out not to meet the eligibility criteria during rituximab treatment was withdrawn early from the study. No patient developed grade 3 non-hematological toxicity requiring the discontinuation of rituximab treatment. Thus 44 of 67 patients (66%) completed the planned rituximab treatment.
ORR, PFS and TTP
Fifty-seven eligible patients were evaluated for response to rituximab on a protocol-compatible (PC) basis, whereas 68 patients were evaluated on an intention-to-treat (ITT) basis. As shown in Table 2, the ORRs on the basis of PC and ITT were 37% (21/57; 95% CI 2551%) and 35% (24/68; 95% CI 2448%), respectively.
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Median PFS and the 95% CI were estimated by the KaplanMeier method for all eligible patients on the basis of PC and for all enrolled patients on the basis of ITT. However, unevaluable patients (use of steroid or anti-cancer agents, four patients; early withdrawal from the study, two patients; and inadequate measurement of tumor lesion, two patients) were excluded from the estimation of PFS. Median PFSs for all eligible and evaluable patients (n = 53) and for all enrolled and evaluable patients (n = 60) were 52 days (95% CI 33111 days) and 61 days (95% CI 41156 days), respectively, as shown in Figure 1. The median TTP of 21 eligible responders was 245 days (95% CI 176435 days; Figure 1).
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Hematological toxicities
Twenty-nine patients (43%) developed hematological toxicities, as shown in Table 3. Grade 4 toxicities were observed in four patients (6%), including one case of leukopenia (2%) and four of neutropenia (6%). Out of the four patients, three had a history of receiving autologous peripheral blood stem cell transplantation. While one patient required G-CSF, the remaining three recovered without any medical intervention.
Abnormal laboratory findings
As also shown in Table 3, 20 patients (30%) had abnormal laboratory values for which a relationship to rituximab was not clearly ruled out. Elevation of hepatic enzymes (AST, ALT or ALP) and/or total bilirubin was observed in 10 patients (15%). Out of the 10, one patient, who had developed a flu-like syndrome, asthenia and jaundice 5 days after the final rituximab infusion, demonstrated grade 4 AST and ALT elevations along with grade 3 total bilirubin elevation. He was diagnosed as having developed acute hepatitis and was hospitalized. The patient had a history of TT virus infection and the TT virus-DNA [28, 29] was detected at the time of the event, while hepatitis B virus surface, core and envelope antigens were all negative; antibodies to hepatitis A and C virus were also negative. The patient recovered 32 days after the onset of the syndrome with conservative management. In addition to routine laboratory testing, examination of serum C-reactive protein (CRP) was performed for all 67 patients. Elevation (1.0 mg/dl) of CRP values was observed in 14 patients (21%). All non-hematological toxicities, including abnormal laboratory findings, were reversible.
Infection
Within 6 months after the initiation of rituximab administration, 37 episodes of infection or suspected infection (events for which antibiotic, anti-fungal and/or anti-viral agents were prescribed) were reported in 28 patients, including one patient who developed a grade 3 upper-respiratory tract infection and the patient described above who developed acute TT virus-positive hepatitis.
Early death
Two patients died within 30 days following the last rituximab infusion. They showed rapid lymphoma progression during rituximab treatment and were withdrawn early from the study. They both received salvage chemotherapy 5 or 7 days after withdrawal and developed grade 4 neutropenia and septic shock leading to death 14 days and 15 days after the initiation of the chemotherapy, respectively.
PB T- and B-cell counts, and serum immunoglobulins
All 67 patients receiving rituximab exhibited a marked decrease in CD19- and CD20-positive cells after the first rituximab infusion (data not shown). On the other hand, no change was observed in CD3-positive cells. Changes in the mean percentage ± standard deviation (SD) of CD19- and CD20-positive cells in the PB from immediately before the first rituximab infusion until 2 days thereafter were 8.5 ± 9.4% to 0.5 ± 0.3% and 9.4 ± 10% to 0.4 ± 0.7%, respectively. There was little change in serum immunoglobulin levels (IgG, IgA and IgM) for 12 months (data not shown).
HACA development
The number of patients whose sera were tested for HACA at 3 and 6 months or thereafter were 40 and 25, respectively. HACA was not detected in these patients.
Factors affecting ORR and PFS
Univariate and multivariate analyses of pretreatment factors affecting ORR and PFS were performed in 53 patients who were eligible and evaluable. As shown in Table 4, elevated LDH and primary chemorefractoriness were found to be unfavorable factors significantly affecting ORR and PFS in the univariate and multivariate analyses. In the univariate analysis, PFS in patients in the low/low-intermediate risk group according to IPI was longer than that in patients in the high-intermediate/high risk group (P = 0.034). PFS in patients with a history of AHSCT was also longer than that in patients without it (P = 0.045).
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Discussion |
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The schedule of administration of rituximab in our study was similar to that of arm A of the European study. The ORR obtained in the present study was 35% on the basis of ITT. The seemingly higher ORR in the present study may be ascribed to the difference in the patient pathological demography. The ORR in DLBCL in the present study was 34% (17/50), which was similar to that of the European study (37%, 11/30). The median TTP of responders in the present study was 245 days, which was also comparable with that observed in the European study (246 days+; n = 17). There was little difference in the toxicity profiles between the two studies, while the incidence of non-hematological toxicity was higher in the present study. The high incidence of toxicities in the present study may partially have resulted from the relatively frequent performance of examinations.
One patient developed grade 4 elevations of AST (2564 IU/l) and ALT (3176 IU/l) concomitantly with grade 3 elevation of total bilirubin after completion of the planned infusion, and was diagnosed with acute hepatitis in the present study. Virus testing revealed that hepatitis viruses A, B and C were negative, but TT virus-DNA was present in his serum. TT virus has been reported to be a novel virus associated with elevation of hepatic transaminase in patients with post-transfusion as well as acute and chronic non-A to G hepatitis [28, 29]. Neither hepatomegaly nor space-occupying lesion was observed on CT films in this patient. Pretreatment transaminase levels were all within normal ranges. Moreover, the acute hepatitis resolved without particular treatment, suggesting that TT virus might have been causative for the hepatitis.
The incidence of grade 4 hematological toxicity was 6%, which was very similar to that in the European study (arm A, 6%; arm B, 8%) [10]. Out of four patients who developed grade 4 neutropenia, three had a history of receiving AHSCT. The remaining patient had a history of three regimens of prior chemotherapy. One of the four patients developed a grade 3 respiratory infection 12 weeks after completion of the final rituximab infusion. The neutrophil count at that time was 10/µl. He was effectively treated with G-CSF and antibiotics. This patient also developed grade 2 herpes zoster concomitantly with grade 4 neutropenia 20 weeks after completion of the final rituximab infusion.
According to the International Non-Hodgkins Lymphoma Prognostic Factors Project, age >60 years, ECOG PS of 24, clinical stage IIIIV, elevated LDH and extranodal involvement of two or more organs were significant factors unfavorably affecting OS [27]. In the present study, elevated LDH and primary refractoriness to prior chemotherapy were unfavorable factors affecting both ORR and PFS, while other factors as listed in IPI were not unfavorable. However, when we compared the median PFS of the low/low-intermediate subgroup with that of the high-intermediate/high subgroup, there was a significant difference, suggesting that IPI is an important predictor of efficacy of rituximab monotherapy. Tsai et al. reported that rituximab has significant activity in intermediate-grade B-cell lymphoma that has relapsed after AHSCT [30]. Similar results were obtained in the present study.
The trough levels and AUCs of rituximab were significantly higher in the responders than in the non-responders. Berinstein et al. reported, based on their analyses of the pivotal study in the USA, that there was a correlation between response and serum rituximab level [31]. In our previous study of indolent B-cell lymphoma, patients with higher serum rituximab levels had longer PFS [9]. These results suggest that PK-guided treatment may be worthy of future investigations to further improve the efficacy of rituximab.
In conclusion, rituximab monotherapy is effective in relapsed or refractory patients with aggressive B-cell lymphoma with acceptable toxicity. Several pretreatment variables, including refractoriness to prior chemotherapy, elevated LDH and higher IPI score, and serum rituximab level are useful for predicting the efficacy of rituximab. Further investigations on rituximab-incorporating combination chemotherapy are warranted for improving the outcome in untreated and relapsed or refractory patients with B-cell lymphoma.
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Acknowledgements |
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Participating institutions and principal investigators of the IDEC-C2B8 Study Group are as follows: Sapporo National Hospital (K. Aikawa, Y. Nakata), Sapporo Hokuyu Hospital (M. Kasai, Y. Kiyama), Tochigi Cancer Center (Y. Kano, M. Akutsu), International Medical Center of Japan (T. Miwa, N. Takesako), National Cancer Center Hospital East (K. Itoh, T. Igarashi, K. Ishizawa), National Cancer Center Hospital (K. Tobinai, Y. Kobayashi, T. Watanabe), Tokyo Medical University (K. Ohyashiki, T. Tauchi), Tokai University School of Medicine (T. Hotta, T. Sasao), Hamamatsu University School of Medicine (K. Ohnishi), Aichi Cancer Center Hospital (Y. Morishima, M. Ogura, Y. Kagami), Nagoya University School of Medicine (T. Kinoshita, T. Murate, H. Nagai), Nagoya National Hospital (K. Tsushita, H. Ohashi), Fujita Health University School of Medicine (M. Hirano, M. Okamoto), Mie University School of Medicine (S. Kageyama, M. Yamaguchi), Kyoto Prefectural University of Medicine (M. Taniwaki), Kyoto University School of Medicine (H. Ohno, T. Ishikawa), Shiga Medical Center for Adults (T. Suzuki), Center for Cardiovascular Diseases and Cancer, Osaka (A. Hiraoka, T. Karasuno), Hyogo Medical Center for Adults (T. Murayama), Hiroshima University School of Medicine (A. Sakai), National Kyushu Cancer Center (N. Uike), Nagasaki University School of Medicine (T. Maeda, K. Tsukasaki).
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FOOTNOTES |
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