© 2004 Foundation for Promotion of Cancer Research
Clinical Trials for Malignant Lymphoma in Japan
1 Hematology Division, National Cancer Center Hospital, Tokyo and 2 Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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The results of the clinical trials by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG) and those of the industry-supported trials mainly conducted by the members of JCOG-LSG are summarized. In the treatment of advanced aggressive non-Hodgkin’s lymphoma (NHL), we investigated the efficacy of granulocyte colony-stimulating factor (G-CSF)-supported, dose-intensified strategies. Based on the results of a randomized phase II study (JCOG9505), we conducted a phase III study, JCOG9809, comparing CHOP and biweekly CHOP. However, JCOG9809 was terminated early based on the results of a planned interim analysis, because it was deemed highly unlikely that biweekly CHOP would be superior to standard CHOP. For aggressive ATL, a G-CSF-supported, dose-intensified, multi-agent regimen (JCOG9303; LSG15) showed superior efficacy to our historical controls. To establish a new standard for ATL, we conducted a phase III study, JCOG9801, comparing LSG15 and biweekly CHOP. To develop new agents for lymphoid malignancies, we focused on irinotecan hydrochloride, interferon-
, cladribine and oral fludarabine. Among them, cladribine and oral fludarabine are promising for indolent B-cell malignancies. The Japanese phase I and II studies of rituximab, a chimeric anti-CD20 monoclonal antibody, in relapsed indolent and aggressive B-NHL showed high efficacy with minimal toxicities, which led us to conduct combination studies with chemotherapy for B-NHL. In addition, a phase I study of a radiolabeled anti-CD20 antibody (ibritumomab tiuxetan) was completed in 2003, and a phase II study for indolent B-NHL will be initiated. The multicenter trials by the JCOG-LSG and industry-supported new agent studies will contribute to further improvement in the treatment of malignant lymphoma. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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Most clinical trials for malignant lymphoma in Japan have been conducted in two ways: multicenter trials conducted by cooperative study groups and industry-supported trials for new agent development. In this article we review the present status of the clinical trials conducted by the Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG-LSG) and that of the industry-supported trials mainly conducted by the members of JCOG-LSG.
JCOG is a multicenter cooperative oncology group, supported by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan. JCOG has a common Data Center and the Steering Committee, consisting of a JCOG representative and chairpersons from the Clinical Trial Review Committee, Data and Safety Monitoring Committee, Audit Committee and Education and Training Committee, and each of 13 cancer study groups (1). All JCOG studies should be conducted according to the Good Clinical Practice guidelines, i.e. the study should be ethical and scientific, be approved by the institutional review board of each participating institution, and be conducted after obtaining written informed consent.
JCOG-LSG now consists of 46 institutions throughout Japan, and has conducted 21 multicenter trials, including eight randomized controlled trials for lymphoid malignancies, i.e. advanced aggressive non-Hodgkin’s lymphoma (NHL) (JCOG8101, 9002, 9505, 9809), indolent B-NHL (JCOG0203), adult T-cell leukemia-lymphoma (ATL) (JCOG9801), and multiple myeloma (JCOG9301, 0112).
In this review, treatment strategies of advanced aggressive NHL, ATL and Hodgkin’s lymphoma by the JCOG-LSG are summarized. In addition, the results of new agent studies for lymphoid malignancies conducted in Japan are summarized, focusing on monoclonal antibody studies.
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JCOG TRIALS FOR ADVANCED-STAGE AGGRESSIVE NHL |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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The results of consecutive JCOG trials for advanced aggressive NHL are summarized in Table 1. In 1981, LSG initiated the first randomized controlled study, JCOG8101, which compared VEPA [vincristine (VCR), cyclophosphamide (CPA, EndoxanTM), prednisone (PSL) and doxorubicin (DOX)] and VEPA-M [VEPA plus methotrexate (MTX)] (2,3). One hundred and sixty-three untreated patients with advanced NHL, including 54 patients with ATL, were randomized. The complete response rate (%CR) and 4-year overall survival (OS) of 82 patients treated with VEPA-M were 62 and 37%, respectively, while for 81 patients treated with VEPA the rates were 52 and 27%, respectively. The difference between the two regimens was not significant; however, pretreatment variables predictive for efficacy were interesting. Three factors—leukemic change, poor performance status (PS) and T-cell phenotype—were negatively associated with both %CR and OS. In this study, the prognosis of patients with peripheral T-cell lymphoma (PTCL) other than ATL was comparable with that of B-NHL (2,3).
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In 1987, against advanced aggressive NHL including ATL, JCOG-LSG initiated a phase II study (JCOG8701) of a non-cross resistant, alternating multi-agent chemotherapy of second generation, called LSG4, consisting of three regimens: (i) VEPA-B, i.e. VCR, CPA, PSL, DOX and bleomycin (BLM); (ii) M-FEPA, i.e. MTX, vindesine (VDS), CPA, PSL and DOX; (iii) VEPP-B, i.e. VCR, etoposide (ETP), procarbazine (PCZ), PSL and BLM (4). Between 1987 and 1991, 338 untreated patients were enrolled, and 267 (79%) of them were eligible. Central pathology review revealed 84 patients with T-NHL, including 42 with ATL, 151 with B-NHL and 33 with NHL of undetermined lineage (U-NHL). Overall, %CR was 72% (192/267): 81% (123/151) in B-NHL, 76% (25/33) in U-NHL, 66% (27/41) in PTCL other than ATL and 43% (18/42) in ATL. After the median follow-up of 56 months, estimated overall 5-year OS was 48%: 60% in B-NHL, 45% in U-NHL, 35% in PTCL and 12% in ATL. Unfavorable factors on OS that remained independently significant in Cox analyses were clinical diagnosis of ATL, total number of involved lesions
4, C-reactive protein (CRP)-positivity and Eastern Cooperative Oncology Group PS 2. JCOG8701 led to the following conclusions: (i) T-cell phenotype was an important pretreatment variable for aggressive NHL in Japan, (ii) LSG4 protocol was effective against B-NHL. Since the clinical diagnosis of ATL was an independent unfavorable factor, ATL patients were excluded from subsequent JCOG trials for aggressive NHL. The aim of the subsequent JCOG9002 for aggressive NHL was to investigate survival benefit of dose-intensified multi-agent combination chemotherapy (5). Previously untreated patients with intermediate- or high-grade NHL according to the Working Formulation were eligible. Patients were randomly assigned to either dose-intensified multi-agent combination chemotherapy of the third generation, LSG9 (VEPA-B/FEPP-AB/M-FEPA every 10 weeks; three courses, 28 weeks in total) or the control arm combination chemotherapy of the second generation, modified LSG4 (mLSG4) (VEPA-B/FEPP-B/M-FEPA, every 14 weeks; four courses, 54 weeks in total). Planned dose intensity (DI)/week of DOX and CPA were 1.93- and 1.45-fold higher in LSG9 than in mLSG4, respectively.
Four hundred and forty-seven patients (230 in LSG9; 217 in mLSG4) were enrolled between 1991 and 1995. Pretreatment variables of the enrolled patients were well balanced between the two arms. Five-year OS was 57% for LSG9 and 55% for mLSG4 (P = 0.42). The %CR was 70% for LSG9 and 65% for mLSG4 (P = 0.23). Hematologic and non-hematologic toxicities of both regimens were equivalent and tolerable. Median actual DIs of DOX and CPA were 1.56- and 1.17-fold higher in LSG9 than in mLSG4, respectively. It was concluded that the increase in DI of DOX in multi-agent combination chemotherapy could not improve survival of aggressive NHL patients (5).
While conducting JCOG9002, the significant findings of an intergroup phase III study in the USA comparing CHOP (CPA, DOX, VCR, PSL) and three second- or third-generation regimens revealed that CHOP remains the best available treatment for first-line chemotherapy in advanced aggressive NHL (6). Other randomized controlled studies showed similar results. One potential explanation is that the addition of other myelosuppressive agents in second- or third-generation regimens results in a decrease in the DIs of the key agents for aggressive NHL such as DOX and CPA (7,8). Thus, JCOG-LSG changed the treatment strategy from the multi-agent chemotherapies to the dose-intensification of key agents.
There are two ways to increase the DI of CHOP, namely, dose-escalated and dose-dense strategies. The doses of DOX and CPA could be escalated with the prophylactic use of granulocyte colony-stimulating factor (G-CSF) (9). Another strategy is also possible with G-CSF, by shortening the treatment interval. In addition, the international prognostic index (IPI) was proposed as a predictive model for aggressive NHL, and the use of IPI was recommended for the design of future trials (10). Based on these findings, in 1995, JCOG-LSG initiated three kinds of phase II study according to IPI: JCOG9505 and JCOG9506 for high- and high-intermediate risk groups, and JCOG9508 for low- and low-intermediate risk groups. JCOG9506 is a phase II study of upfront, high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (AHSCT), and JCOG9508 is a large-scale, phase II study of standard-dose CHOP therapy for lower risk patients.
Among them, the final results of JCOG9505 were published (11). The aim of the randomized phase II study, JCOG9505, was to explore a suitable dose-intensified regimen for the subsequent phase III study to compare with standard CHOP. Between 1995 and 1998, 70 patients with high-intermediate risk or high risk aggressive NHL according to IPI were enrolled and randomly assigned to receive either eight cycles of biweekly CHOP (CPA 750 mg/m2, DOX 50 mg/m2, VCR 1.4 mg/m2 and PSL 100 mg for 5 days) every 2 weeks or six cycles of dose-escalated CHOP (CPA 1500 mg/m2, DOX 70 mg/m2, VCR 1.4 mg/m2 and PSL 100 mg for 5 days) every 3 weeks. G-CSF was prophylactically administered. The primary endpoint was %CR.
The %CR was 60% [21/35; 95% confidence interval (CI), 42–76%] with biweekly CHOP and 51% (18/35; 95% CI, 34–69%) with dose-escalated CHOP. The major toxicity was grade 4 neutropenia and was more frequent in the dose-escalated CHOP (86%) than in the biweekly CHOP (50%). Grade 4 thrombocytopenia was also more frequent in the dose-escalated CHOP (20%) than the biweekly CHOP (3%). Non-hematologic toxicities were acceptable in both arms. One treatment-related death (due to cardiac arrhythmia) was observed in a dose-escalated CHOP patient. Progression-free survival (PFS) at 3 years was 43% (95% CI, 27–59%) in the biweekly CHOP arm and 31% (95% CI, 16–47%) in the dose-escalated CHOP arm. Similar %CR and PFS, but lower toxicity, suggested that biweekly CHOP is more promising for further investigations (11).
Based on the results of JCOG9505, in 1999 we initiated a phase III study, JCOG9809 (12). The study design of JCOG9809 is shown in Fig. 1. The primary purpose of JCOG9809 was to determine whether treatment results of aggressive NHL could be improved by shortening intervals of CHOP chemotherapy with the prophylactic use of G-CSF. The primary endpoint was PFS, and the planned accrual was 450. Until December 2002, 323 patients with advanced aggressive NHL were randomized to the standard CHOP arm (CHOP x8, every 3 weeks) and biweekly CHOP arm (CHOP x8, every 2 weeks). Major characteristics of 304 patients enrolled up to August 2002 were as follows: median age, 57 (range, 17–69); stage, 100 patients (33%) in II, 85 (28%) in III, 118 (39%) in IV (one ineligible for stage I); ECOG PS, 159 (52%) for 0, 120 (39%) for 1, 25 (8%) for 2; IPI, 128 (42%) for low risk group, 91 (30%) for the low-intermediate risk group, 62 (20%) for high-intermediate risk group, 23 (8%) for high risk group; histologic subtype according to the Working Formulation, 33 for D, 17 for E, 39 for F, 209 (69%) for G, 5 for H, 1 for J. Major prognostic factors, including the IPI risk group, were well balanced between the two arms.
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The first planned interim analysis for 286 patients on December 18 2002 revealed that the PFS of the biweekly CHOP arm (n = 143) was slightly inferior to that of the standard CHOP arm (n = 143). The median PFS was 34 months in the standard CHOP arm and 24 months in the biweekly CHOP arm, and 2-year PFS was 54% in the standard CHOP arm and 51% in the biweekly CHOP arm. The hazard ratio of PFS between the arms was 1.10 (95% CI, 0.76–1.57). Two-year OS was 74% in the standard CHOP arm and 75% in the biweekly CHOP arm. Although there was one treatment-related death in the biweekly CHOP arm, toxicities of both regimens were equivalent and tolerable. According to the recommendations by the Data and Safety Monitoring Committee, JCOG9809 was terminated early, because it was deemed highly unlikely that the biweekly CHOP arm would be superior to the standard CHOP arm in PFS. It was concluded that a dose-dense strategy by interval shortening of CHOP chemotherapy was unable to prolong PFS in patients with aggressive NHL (12).
While we pursued the dose-intensified CHOP strategies, a chimeric anti-CD20 monoclonal antibody, rituximab, was clinically developed for the treatment of B-NHL (13–16). Rituximab as a single agent was found to be effective not only for indolent B-NHL but also for aggressive B-NHL (17,18). More importantly, a phase III study comparing rituximab plus CHOP (R-CHOP) and CHOP for untreated elderly patients with diffuse large B-cell lymphoma (DCBCL) revealed that the efficacy of R-CHOP is superior to CHOP (19). Based on these findings, JCOG-LSG is currently planning future trials of rituximab-containing combination chemotherapy with the aim of improving the efficacy of R-CHOP further against aggressive B-NHL.
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JCOG TRIALS AGAINST ADULT T-CELL LEUKEMIA-LYMPHOMA (ATL) |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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ATL is defined as a peripheral T-cell malignancy caused by an RNA retrovirus, human T-cell leukemia virus type I. Acute-type ATL has characteristic clinical and laboratory findings, including flower cells in peripheral blood, hypercalcemia and frequent organ involvement such as the skin, gastro-intestinal tract, lung and central nervous system. Four clinical subtypes such as acute-, lymphoma-, chronic- and smoldering-type have been recognized (20).
The main results of the JCOG trials for ATL are summarized in Table 2. In the phase III trial, JCOG8101, which compared VEPA versus VEPA-M against advanced NHL including ATL between 1981 and 1983, the %CR of VEPA-M for ATL (37%) was higher than that of VEPA (17%) (P = 0.09) (2,3). However, the %CR was significantly lower for ATL than for B-NHL and PTCL other than ATL (P < 0.001). The median survival time (MST) of 54 patients with ATL treated with VEPA or VEPA-M was only 7.5 months, and the estimated 4-year OS was only 8%.
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In the subsequent phase II study (JCOG8701) of a multi-agent combination chemotherapy, the %CR for ATL patients (43%, 18/42) was improved from 28% (15/54) in JCOG8101; however, the %CR was significantly lower in ATL than in B-NHL and PTCL (P < 0.01) (4). Patients with ATL showed the most unfavorable prognosis with an MST of 8 months and a 5-year OS of 12%. A multivariate analysis demonstrated that the clinical diagnosis of ATL was the most significant unfavorable prognostic factor (4).
The disappointing results against ATL with conventional chemotherapies have led to the search for new active agents. Deoxycoformycin (DCF), an inhibitor of adenosine deaminase, was reported to be effective in a number of lymphoid malignancies. Based on the promising results of some single-institute studies, multicenter phase I and II studies of DCF were conducted against ATL in Japan (21,22). The phase II study revealed a response rate of 32% (10/31) in relapsed or refractory ATL, using the weekly intravenous administration of 5 mg/m2. These encouraging results prompted us to conduct a DCF-containing combination phase II trial (JCOG9109) as an initial chemotherapy for ATL (23). Between 1991 and 1993, 62 untreated patients with ATL (34 acute, 21 lymphoma and seven chronic types) were enrolled. VCR 1 mg/m2 intravenously (IV) on days 1 and 8, DOX 40 mg/m2 IV on day 1, ETP 100 mg/m2 IV on days 1–3, PSL 40 mg/m2 per os on days 1 and 2 and DCF 5 mg/m2 IV on days 8, 15 and 22 were administered every 28 days for 10 cycles unless disease progression occurred. Among the 61 patients evaluable for toxicity, four patients (7%) died of fatal infections such as sepsis and cytomegalovirus pneumonia. In the 60 eligible patients, there were 17 CRs (28%) and 14 PRs [overall response rate (ORR) 52%]. The MST was 7.4 months, and the estimated 2-year OS was 17%, findings that were identical to those of the 42 patients with ATL who were treated in JCOG8701. It was concluded that the prognosis of patients with ATL remained poor even when treated with a DCF-containing combination chemotherapy (23).
In 1994, JCOG-LSG initiated a new multi-agent combination phase II trial (JCOG9303; LSG15): an eight-drug regimen consisting of VCR, CPA, DOX, PSL, ranimustine (MCNU), VDS, ETP and carboplatin (CBDCA), for untreated ATL (24). The elevation of relative DI was attempted with the prophylactic use of G-CSF. In addition, non-cross-resistant agents such as MCNU and CBDCA were incorporated to overcome the multidrug resistance of ATL cells. Ninety-six untreated patients with aggressive ATL were enrolled: 58 patients with acute type, 28 with lymphoma type and 10 with unfavorable chronic type. Eighty-one percent of the 93 eligible patients responded (75/93), with 33 patients obtaining CR (35%) and 42 PR (45%). The OS of 93 eligible patients at 2 years was 31%. The MST was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years. A trend towards better OS for lymphoma-type patients (MST, 20 months) compared with acute-type patients (MST, 11 months) was recognized (hazard ratio, 1.65). Grade 4 hematologic toxicities of neutropenia and thrombocytopenia were observed in 65% and 53% of the patients, respectively, but grade 4 non-hematologic toxicity was observed in only one patient. It was concluded that the LSG15 is feasible and improved the clinical outcome of patients with ATL (24). To confirm whether the LSG15 is a new standard for the treatment of aggressive ATL, JCOG-LSG has conducted a phase III study, JCOG9801, comparing the LSG15 with biweekly CHOP (Fig. 2). Patient enrollment into this phase III study was completed in October 2003.
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JCOG TRIALS AGAINST HODGKIN’S LYMPHOMA |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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Since Hodgkin’s lymphoma is not common in Japan, JCOG-LSG has conducted consecutive phase II studies to confirm the applicability of the commonly used or standard combination chemotherapy regimens, which were established in Western countries, to Japanese patients with Hodgkin’s lymphoma. The main results of JCOG trials for Hodgkin’s lymphoma are summarized in Table 3.
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Between 1989 and 1993, JCOG-LSG conducted a phase II study (JCOG8905) of alternating combination chemotherapy C-MOPP (CPA, VCR, PCZ, PSL) and ABVd [DOX, BLM, vinblastine (VLB), dacarbazine (DTIC)] for clinical stages II–IV Hodgkin’s lymphoma (25). [Note that CPA was substituted for mechlorethamine (in MOPP), since the latter was not commercially available in Japan.] A two-thirds dose (250 mg/m2) of DTIC was used, because a full dose (375 mg/m2) of DTIC was intolerable owing to severe emesis at that time. The full chemotherapy schedule for both regimens was five courses each. Patients with bulky disease were given involved-field radiotherapy (30 Gy) after completion of chemotherapy. Seventy-nine untreated patients were enrolled. For 67 eligible patients, the ORR was 93% with 84% CR. Five-year OS was 85%, and 4-year PFS was 73%. Grade 4 toxicity consisted of leukopenia in 28% of patients, but there were no treatment-related death. It was concluded that the C-MOPP/ABVd regimen is one of the effective regimens for Japanese patients with advanced Hodgkin’s lymphoma (25).
In 1992, Canellos et al. reported the significant results of a phase III study conducted by Cancer and Leukemia Group B (CALGB) which compared MOPP (mechlorethamine, VCR, PCZ, PSL), ABVD or MOPP alternating with ABVD (26). Thereafter, ABVD was regarded as a standard therapy for advanced Hodgkin’s lymphoma because of high efficacy and low short-term and long-term toxicities. Based on the results of the CALGB study (26) and our own preceding JCOG8905 (25), JCOG-LSG conducted a phase II study (JCOG9305) to investigate the efficacy and toxicity of ABVd therapy in Japanese patients with advanced Hodgkin’s lymphoma (27). Between 1993 and 1997, a total of 128 patients with advanced-stage Hodgkin’s lymphoma were enrolled and received ABVd with six or eight courses. Bulky tumors were irradiated after chemotherapy at 30–40 Gy. The CR was 78% (100/128; 95% CI, 70–85%). Major toxicity was grade 4 neutropenia (45%). Non-hematologic toxicities were acceptable; the most frequent toxicity of grade 3 was nausea/vomiting (11%), and grade 4 toxicity was observed in only one patient who developed ileus. OS and PFS at 5 years were 89% (95% CI, 83–95%) and 75% (95% CI, 67–83%), respectively. It was concluded that ABVd therapy is effective in Japanese patients with advanced-stage Hodgkin’s lymphoma (27).
In ABVD or ABVd therapy, gastrointestinal toxicity and phlebitis are frequent adverse events associated with DTIC; however, the evidence of efficacy of DTIC for Hodgkin’s lymphoma is insufficient compared with the three other agents. To explore a less toxic and equally effective regimen, JCOG-LSG conducted a multicenter phase II study (JCOG9705) of ‘ABV’ deleting DTIC followed by involved-field radiotherapy (28). The primary endpoint was %CR. Between 1998 and 2000, 72 patients were enrolled and received six or eight courses of ‘ABV’ with increased dose of DOX (DOX 30 mg/m2, days 1 and 15; BLM 9 mg/m2, day 1 and 15; VLB 6 mg/m2, day 1 and 15). Residual tumors of PR cases and bulky tumors were irradiated after chemotherapy. The first planned interim analysis revealed that 2-year PFS (51%; 95% CI, 39–63%) was significantly inferior to the 80% of our historical control, JCOG9305 (ABVd), although %CR (71%; 95% CI, 58–82%) was equal. According to the recommendations by the Data and Safety Monitoring Committee, patient enrollment was interrupted. In conclusion, the early results of JCOG9705 suggested that the efficacy of ABV with increased dose of DOX and deleted DTIC was inferior to ABVd. It is also suggested that DTIC is a key agent in ABVD therapy (28).
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DEVELOPMENT OF NEW ANTICANCER AGENTS FOR NHL AND ATL |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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Irinotecan Hydrochloride (CPT-11)
CPT-11 is a semisynthetic analog of camptothecin with inhibitory activity against topoisomerase I. CPT-11 has definitive activity against various kinds of solid tumors. Multicenter phase II studies of CPT-11 were conducted against relapsed or refractory NHL in Japan (29–31). The pivotal study revealed nine CRs and 17 PRs (ORR 38%, 26/69), using a weekly intravenous administration of 40 mg/m2/day for 3 consecutive days (30). In that study, five (38%) of 13 patients with ATL showed a response to CPT-11 (one CR and four PRs) (31).
To develop a new effective chemotherapy regimen against NHL and ATL, we conducted two kinds of phase I/II study of CPT-11 in combination with CBDCA or ETP for relapsed or refractory NHL (32,33). However, in both studies, dose-escalation was halted because of hematologic toxicity in combination with CBDCA and hepatotoxicity in combination with ETP.
Daiichi Pharmaceutical Co. Ltd, Tokyo, Japan, supported the trials of CPT-11.
Interferon-
Based on the preliminary documentation of the efficacy of interferon- against ATL, two kinds of phase I/II trial of high-dose interferon- (intravenous and subcutaneous administrations) were conducted in Japan; however, the results were not impressive (unpublished data). In 1995, Gill et al. in the USA reported that 11 of 19 patients with acute- or lymphoma-type ATL achieved major responses (five CRs and six PRs) by the combination therapy of interferon- and zidovudine (34). The efficacy of this combination was also observed in a French study; the major objective responses were obtained in all five ATL patients (35). Although the results of this combination were encouraging, the OS of previously untreated ATL patients was relatively short (4.8 months) (4,36) compared with those in the chemotherapy trials by the JCOG-LSG (7–13 months) (2–4,23,24). Furthermore, the %CR associated with the use of interferon- and zidovudine in previously untreated patients (25%, 3/12) was not superior to the %CR in those treated with the JCOG-LSG chemotherapy protocols (28–42%). In 2001, White et al. reported the results of this combination in 18 patients with ATL mostly pretreated with radioimmunotherapy and only three of them (17%) showed objective responses (37).
The clinical trials of interferon- in Japan were supported by Sumitomo Pharmaceuticals, Osaka, Japan.
Cladribine (2-chlorodeoxyadenosine, 2-CdA)
Cladribine is a chlorinated purine analog resistant to adenosine deaminase. Cladribine was found to be effective against hairy cell leukemia (HCL), B-chronic lymphocytic leukemia, indolent B-NHL and cutaneous T-cell lymphoma. In a Japanese phase I study of cladribine, one relapsed patient with ATL achieved PR (38). A multicenter phase II study of cladribine against relapsed or refractory ATL was conducted in Japan (39). Cladribine was administered as 0.09 mg/kg/day by 7-day continuous intravenous infusion every 28 days up to three courses. However, since the interim analysis revealed that only one of the 15 eligible patients showed PR (ORR 7%; 90%, CI 0–28%), the phase II study for ATL was terminated.
Cladribine was also evaluated for relapsed or refractory indolent NHL in Japan (40). Between 1996 and 1999, 45 previously treated patients with indolent NHL were enrolled, of which 43 were eligible. The median number of prior chemotherapy regimens was 2 (range, 1–14). Central pathology review revealed that 34 patients had follicular, three mantle cell lymphoma (MCL), three marginal zone B-cell lymphoma, two mycosis fungoides and one macroglobulinemia. The median number of administered cycles of cladribine was 3 (range, 1–6). The ORR was 58% (25/43; 95% CI, 45–71%) with 14% CR (6/43; 95% CI, 6–26%). The median time to progression (TTP) in 25 responders was 9 months (range, 1–31+). Neutropenia and thrombocytopenia of grade 3 were observed in 53% (24/45) and 38% (17/45), respectively. Prolonged (180 days) neutropenia and/or thrombocytopenia of grade 3 were observed in 27% (12/45), and they persisted up to 419+ days. Five patients (11%) developed infections of grade 3, including two treatment-related deaths (systemic herpes simplex virus infection and pulmonary aspergillosis). Other non-hematologic toxicities were acceptable. Four patients developed myelodysplastic syndrome after the completion of cladribine treatments. It was concluded that cladribine is an active agent in the treatment of refractory or relapsed indolent NHL with durable major responses. Toxicity was acceptable, but prolonged myelosuppression and myelodysplastic syndrome should be carefully monitored (40). In the phase II study for HCL, we obtained a high response rate (70%, 7/10). In 2002, cladribine was approved for HCL and indolent B-NHL in Japan.
Janssen Pharma Co. Ltd, Tokyo, Japan, supported the clinical trials of cladribine.
Fludarabine Phosphate
Fludarabine, another purine analog, is presently being evaluated for indolent B-NHL in Japan. Intravenous (IV) fludarabine demonstrated marked efficacy for indolent B-NHL; however, 5-day IV administration is inconvenient in an outpatient setting. The primary objective of a Japanese phase I study of oral fludarabine was to investigate its tolerability, efficacy and pharmacokinetic profile in relapsed or refractory patients with indolent B-NHL (41). Twelve relapsed patients, including 10 with follicular lymphoma and two with MCL, were enrolled. Their median age was 57, and the median number of prior regimens was two. They received 30, 40 or 50 mg/m2/day for 5 consecutive days every 4 weeks, for a total of one to three cycles (three patients for 30 mg/m2/day; six patients for 40 mg/m2/day; three patients for 50 mg/m2/day). One of the six patients treated at 40 mg/m2/day developed grade 4 hyperuricemia, and one of the three patients treated at 50 mg/m2/day developed grade 4 febrile neutropenia. Another patient treated at 50 mg/m2/day required G-CSF due to grade 4 neutropenia. In total, grade 3 toxicities were leukopenia (50%), neutropenia (50%), lymphopenia (83%) and hyperuricemia (8%). All the encountered toxicities were reversible. According to the international workshop criteria, the ORR was 67% (8/12) (1/3 for 30 mg/m2/day; 4/6 for 40 mg/m2/day; 3/3 for 50 mg/m2/day). Based on area under the curve (AUC) values of the fifth day, the mean systemic bioavailability of 63% (78% for 30 mg/m2/day; 58% for 40 mg/m2/day; 56% for 50 mg/m2/day) obtained in Japanese patients was similar to that in Caucasians. It was concluded that oral fludarabine is safe and effective for relapsed patients with indolent B-NHL. To assess the efficacy and toxicity of oral fludarabine in relapsed indolent B-NHL further, we are currently conducting a pivotal phase II study using the dose of 40 mg/m2/day.
Nihon Schering K.K., Osaka, Japan, supported the clinical trials of fludarabine phosphate.
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DEVELOPMENT OF MONOCLONAL ANTIBODY THERAPIES FOR B-NHL1 |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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Rituximab
Rituximab is a chimeric monoclonal antibody, with mouse variable and human constant regions, that recognizes the CD20 antigen (42).
Feasibility and Pharmacokinetic Study of Rituximab
The feasibility of rituximab administration in Japanese patients with relapsed B-NHL was evaluated at 250 mg/m2 and 375 mg/m2 per infusion under the administration schedule of four consecutive weekly infusions (14). Four patients received the rituximab 250 mg/m2 infusion and eight the 375 mg/m2 infusion. The majority of patients (8/11) had lymphoma with follicular histology. All encountered non-hematologic toxicities were of grade 2 or less. The commonly observed toxicities of rituximab were fever (6/11), chills/rigor (4/11), rash/urticaria (3/11), pruritus (3/11) and perspiration (3/11). Of 11 eligible patients, seven developed hematologic toxicities, but none was grade 4. Peripheral blood B cells decreased to 0–2% of the total lymphocyte counts within 48 h after the first infusion. There were no significant changes in T-cell counts, or in serum immunoglobulin and complement C3 levels. Human anti-murine antibody (HAMA) and human anti-chimeric antibody (HACA) were not detected.
Of the three patients who received rituximab 250 mg/m2, two achieved objective responses (one CR and one PR). In the eight patients who received rituximab 375 mg/m2, five achieved objective responses (one CR and four PRs).
The mean values [± standard deviation] of the trapezoidal AUC and maximum concentration (Cmax) in the 375 mg/m2 dose group were 118 237 ± 53 412 µg/ml h and 92.1 ± 34.3 µg/ml, respectively, which were higher than those in the 250 mg/m2 dose group (91 343 ± 70 267 µg/ml h and 64.3 ± 21.4 µg/ml). The serum elimination half-life (T1/2) was 445.4 ± 361.4 h (18.6 ± 15.8 days). The mean peak and trough levels of rituximab at each infusion increased in parallel with the course of infusion. The serum levels of rituximab were detectable at 3 months after the final infusion in most patients. It was concluded that the dose of four, once weekly 375 mg/m2 IV infusions of rituximab was safe and effective in Japanese patients with relapsed or refractory B-NHL (14).
Single-agent Phase II Study in Relapsed Indolent B-NHL and MCL
Ninety patients with indolent B-NHL or MCL who had relapsed or were resistant to prior conventional chemotherapy were enrolled and divided into two groups: group I comprised patients with indolent B-NHL and group II patients with MCL (16). A central pathology review was performed for biopsy specimens from 86 (96%) of the 90 patients enrolled in the study, according to the Revised European–American Lymphoma (REAL) Classification. Immunohistochemical analyses were conducted using anti-CD20, anti-CD3, anti-bcl-2 and anti-cyclin-D1 antibodies. Follicular lymphoma accounted for 83% in group I-enrolled patients.
The most commonly observed non-hematologic toxicities were infusion-related symptoms such as fever, chills/rigor, nausea/vomiting, rash, pruritus, perspiration, asthenia, headache, pain and urticaria, which mainly did not exceed grade 2. These symptoms generally occurred during the first infusion and decreased with subsequent infusions. All non-hematologic toxicities were reversible. Grade 3 or 4 hematologic toxicities were observed in 23 patients (26%). Five patients (6%) developed grade 4 neutropenia, two (2%) developed grade 3 thrombocytopenia and one (1%) grade 4 thrombocytopenia. Seven episodes of infection were noted within 6 months after rituximab administration, of which five were grade 1. All patients except two exhibited a marked decrease in peripheral blood CD19+ and CD20+ cells after the first rituximab infusion. The decrease in B cells continued for at least 3 months, but showed a gradual recovery up to 6 months or thereafter. Of the 90 patients who received rituximab infusion, four developed HACA. In three patients, the HACA levels were below the quantifiable limit (3.9 ng/ml) by the enzyme-linked immunosorbent assay (ELISA), while in one patient the HACA levels were 398 ± 53 ng/ml.
The ORR in 61 eligible patients in group I (indolent B-NHL) was 61% (95% CI, 47–73%), including 14 patients (23%) who achieved CR and 23 patients (38%) who achieved PR. The ORR in the 13 eligible patients in group II (MCL) was 46% (95% CI, 19–75%), and all six responders achieved PR. The median PFS interval in groups I and II was 245 and 111 days, respectively.
Pretreatment factors affecting ORR and PFS were analyzed in 77 patients whose histopathology was centrally confirmed as indolent B-NHL or MCL. The ORR was significantly affected by the number of prior chemotherapy regimens (P = 0.02). Multivariate analysis demonstrated that MCL, extranodal disease, and number of prior chemotherapy regimens were unfavorable factors affecting PFS (all P < 0.05). The PFS intervals of patients with higher serum rituximab levels (70 µg/ml) immediately before the third infusion were longer than other patients (P < 0.05).
In summary, rituximab is a highly effective agent in relapsed indolent B-NHL and MCL with acceptable toxicities. Rituximab is more effective in the treatment of relapsed indolent B-NHL than of MCL, and in patients without extranodal disease or with a history of having received only one prior chemotherapy regimen. Several prognostic factors and serum rituximab levels are useful in predicting the efficacy of rituximab monotherapy (16).
Subsequent Clinical Trials of Rituximab in Japan
In 1999, two multicenter phase II studies were initiated in Japan: a single-agent phase II study in recurrent aggressive B-NHL (18), and a randomized phase II study of rituximab in combination with CHOP, comparing concurrent and sequential administration in previously untreated advanced-stage indolent B-NHL (43).
In the single-agent phase II study of rituximab for recurrent aggressive B-NHL, a total of 68 patients with REAL types II-3, 9, 10 and 11 were enrolled and treated with rituximab 375 mg/m2, weekly for 8 consecutive weeks (18). A central pathology review disclosed that 57 patients (84%) were eligible. The Independent Computed Tomography Review Committee confirmed that ORR was 35% (24/68) in enrolled patients and 37% (21/57) in eligible patients. The median PFS of the 53 evaluable patients was 52 days, whereas the time to progression of the 21 eligible responders was 245 days. The encountered toxicities of rituximab were transient and most were of grade 1 or 2. Serum samples were collected for pharmacokinetic analysis in 12 patients. There was a steady increase in the peak and trough rituximab levels at all time points during the eight consecutive weekly treatments. It was concluded that rituximab monotherapy with eight consecutive weekly infusions showed significant anti-lymphoma activity in aggressive B-NHL with acceptable toxicities (18).
After the approval of rituximab in Japan in 2001, three kinds of new trials incorporating rituximab were initiated or are currently in preparation. One is a phase II/III study of rituximab in combination with CHOP and biweekly CHOP for untreated advanced-stage, indolent B-NHL (JCOG0203). In the biweekly CHOP arm, an augmenting effect of antibody-dependent cell-mediated cytotoxicity (ADCC) of rituximab is expected. Another study in preparation is a phase II study of HDC with AHSCT for untreated MCL, which expects to show an in vivo purging effect of rituximab. The third study in preparation is a phase II/III study of rituximab in combination with CHOP for untreated diffuse large B-cell lymphoma, comparing weekly and tri-weekly administrations of rituximab. A schematic representation of the clinical trials of rituximab in Japan is shown in Fig. 3.
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Zenyaku Kogyo Co., Ltd, Tokyo, Japan, supported the clinical trials of rituximab.
Ibritumomab Tiuxetan (ZevalinTM)
Ibritumomab is a murine anti-CD20 monoclonal antibody that was engineered to form rituximab. Tiuxetan is a MX-DTPA linker chelator that is attached to ibritumomab to form ibritumomab tiuxetan (ZevalinTM). The ibritumomab tiuxetan is radiolabeled with either 111In (111In-Zevalin) for dosimetry studies or with 90Y (90Y-Zevalin) for therapy of B-NHL (44). In 2002, a feasibility study of ibritumomab tiuxetan was initiated in Japan, and patient enrollment was completed in August 2003. We are planning a subsequent pivotal phase II study.
Nihon Schering K.K., Osaka, Japan, supported the clinical trials of fludarabine phosphate.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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The present status of the JCOG-LSG trials and industry-supported new agent studies for malignant lymphoma mainly conducted by the members of the JCOG-LSG are summarized. JCOG-LSG has conducted 21 multicenter trials, focusing on aggressive NHL and ATL. In the treatment of advanced aggressive NHL, we investigated the efficacy of G-CSF-supported dose-intensified strategies. Based on the results of a randomized phase II study (JCOG9505), we conducted a phase III study, JCOG9809, comparing CHOP and biweekly CHOP. However, JCOG9809 was terminated early based on the results of a planned interim analysis, because it was deemed highly unlikely that biweekly CHOP would be superior to standard CHOP. For aggressive ATL, a dose-intensified, multi-agent regimen (JCOG9303; LSG15) showed superior efficacy to our historical controls. To establish a new standard for ATL, we have conducted a phase III study, JCOG9801, comparing the LSG15 and biweekly CHOP. New agent development for malignant lymphoma in Japan has been focused on irinotecan, DCF, cladribine, oral fludarabine and rituximab, and encouraging results have been obtained. The multicenter trials by the JCOG-LSG and industry-supported new agent studies will contribute to the further improvement in the treatment of malignant lymphoma.
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Acknowledgments |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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JCOG studies are supported by Grants-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare of Japan. We are grateful to Drs K. Tajima and H. Fukuda, JCOG Statistical/Data Center, for data management and analyses of JCOG trials. We are greatly appreciative of all members of the JCOG-LSG, in particular, Dr Masanori Shimoyama, a previous chairman of the JCOG-LSG. In addition, we thank all the members who participated in the industry-supported multicenter trials.
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FOOTNOTES |
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+ For reprints and all correspondence: Kensei Tobinai, Hematology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: ktobinai{at}ncc.go.jp
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REFERENCES |
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TOPABSTRACTINTRODUCTIONJCOG TRIALS FOR ADVANCED-STAGE...JCOG TRIALS AGAINST ADULT...JCOG TRIALS AGAINST...DEVELOPMENT OF NEW ANTICANCER...DEVELOPMENT OF MONOCLONAL...CONCLUSIONSAcknowledgmentsREFERENCES |
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39 Tobinai K, Uike N, Saburi Y, Chou T, Etoh T, Masuda M, et al. Phase II study of cladribine (2-chlorodeoxyadenosine) in relapsed or refractory adult T-cell leukemia-lymphoma. Int J Hematol 2003;77:512–7.[ISI][Medline]
40 Tobinai K, Kobayashi Y, Morishima Y, Ogura M, Uike N, Chou T, et al. Prolonged cytopenia and myelodysplastic syndrome after cladribine treatment in relapsed patients with indolent non-Hodgkin’s lymphoma: results of Japanese phase II study. Proc Am Soc Clin Oncol 2001;20:228b (Abstract).
41 Tobinai K, Watanabe T, Hotta T, Ogawa Y, Sasaki Y, Minami H, et al. Phase I study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin’s lymphoma. Proc Am Soc Clin Oncol 2003;22:599a (Abstract).
42 Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435–45.
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44 Witzig TE, White CA, Wiseman GA, Gordon LI, Emmanouilides C, Raubitschek A, et al. Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:3793–803.
Received March 8, 2004; accepted April 6, 2004
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