Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, June 1-5, 2007; and at the 10th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 4-7, 2008
Bortezomib demonstrated promising activity in lymphomas. The authors conducted a randomized phase 2 trial of frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with the addition of bortezomib in patients with B-cell lymphoma.
Patients were randomized between 2 schedules of bortezomib, Arm A (Days 1, 4, 8, and 11) and Arm B (Days 1 and 8), combined with 6 cycles of R-CHOP. For the first patients (Step 1), bortezomib was given at a dose of 1 mg/m2 in Arm A and 1.3 mg/m2 in Arm B. For the next patients (Step 2), doses were increased to 1.3 mg/m2 and 1.6 mg/m2 in Arms A and B, respectively. The primary endpoint was the rate of complete response (CR) and unconfirmed CR (CR/CRu) after 6 cycles.
Forty-nine patients were included in the study, and 41 patients (84%) achieved a CR/CRu, ie, 18 of 20 patients (90%) in Arm A and 23 of 29 patients (79%) in Arm B. There were 6 partial responses and 2 patients with progressive disease. Neurologic toxicity occurred in 21 patients (43%) and was grade 2 in 11 patients (7 patients in Step 2) and grade 3 in 10 patients (9 patients in Step 2). Other grade 3 and 4 toxicities included constipation (n = 1), infections (n = 3), and cardiac events (n = 2). Grade 3 and 4 thrombocytopenia and leucopenia occurred in 14% and 41% of cycles, respectively.
The rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) regimen is standard for most patients who have B-cell malignancies that are positive for CD20 (a nonglycosylated phosphoprotein that is expressed on the surface of all mature B-cells). However, in patients who have diffuse large cell lymphomas, progress is needed, because the complete response rate is usually <75%.1 In addition, in low-grade lymphomas, although patients respond well to chemotherapy, the complete response (CR) rate averages only 50%, and there is a continuous pattern of recurrence.2, 3 These data suggest that there is a need to improve this combination therapy with new innovative agents. Bortezomib is the first member of the new class of anticancer agents called proteasome inhibitors to be studied in human clinical trials. Proteasome inhibitors can act through multiple mechanisms to arrest tumor growth, tumor spread, and angiogenesis, and they also direct the induction of apoptosis. In vitro studies have demonstrated a synergistic effect of the combination of bortezomib with doxorubicin.4 Phase 1 and 2 clinical studies demonstrated that bortezomib is a well tolerated agent when used alone with minimal hematologic toxicity. When it was used as a single agent administered twice weekly for 2 weeks at a dose of 1.5 mg/m2 followed by a 1-week rest period, bortezomid exhibited activity in 2 phase 2 studies in patients with indolent lymphomas with overall response rates of 41% and 58%.5, 6
Before running a randomized phase 3 study, it is important to evaluate the efficacy of bortezomib combined with a well established regimen such as the R-CHOP in phase 2 trials. The objective of the current randomized phase 2 study was to evaluate the response rate and toxicity of the R-CHOP regimen combined with 2 schedules of administration of bortezomib in patients with CD20-positive B-cell lymphoma.
MATERIALS AND METHODS
This study was an open-label, randomized, multicenter phase 2 trial. The primary endpoint was the CR and unconfirmed CR (CRu) rate after the end of treatment (CR/CRu rate). Calculation of the sample size was based on the primary CR/CRu endpoint. We anticipated a CR rate of 75% and computed that, by using a triangular test procedure for every 3 consecutive patients, an average sample size of 48 patients would provide 80% power at the overall 5% (2-sided) significance level to detect a CR rate >55% (null hypothesis, 55%; alternative hypothesis, 75%).7 The secondary endpoints were toxicity, overall survival (OS), and event-free survival (EFS).
The protocol was approved by the local ethics committees and the national regulatory agency according to French regulatory laws. The study was posted on the US National Institutes of Health National Clinical Trials (NCT) website (NCT00169468).
Patients with 1 of the following CD20-positive B-cell lymphomas were enrolled in this study: marginal zone lymphoma, lymphocytic lymphoma, follicular lymphoma requiring treatment (including histologic transformation), mantle cell lymphoma, and diffuse large B-cell lymphoma (but without adverse prognostic factors defined by the International Prognostic Index [IPI]). Patients were required to be between ages 18 years and 80 years and had to have an Eastern Cooperative Oncology Group performance status (PS) <3. Exclusion criteria were other types of lymphoma (Burkitt lymphoma, CD20-negative B-cell lymphomas, T-cell lymphomas) and central nervous system involvement. Pathologic review of the biopsy material was performed after inclusion by a panel of expert pathologists.
Treatments and Dose Adaptation
Patients received the CHOP regimen, ie, a combination of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 (up to 2 mg) all on Day 1, and prednisone 40 mg/m2 daily for 5 days administered every 3 weeks (1 cycle). Rituximab was given at a dose of 375 mg/m2 on Day 1 of each CHOP cycle. Patients had to receive 6 cycles of R-CHOP with granulocyte–colony-stimulating factor support.
Patients were randomized between 2 schedules (Arm A and Arm B) of bortezomib administration. Bortezomib was administered as a biweekly schedule on Days 1, 4, 8, and 11 of R-CHOP in Arm A and as a weekly schedule on Days 1 and 8 in Arm B. For the first patients (Step 1), bortezomib was delivered at doses of 1 mg/m2 (total dose per cycle, 4 mg/m2) and 1.3 mg/m2 (total dose per cycle, 2.6 mg/m2) in Arms A and B, respectively. After mid-inclusion (Step 2; ie, in the absence of severe toxicity after the end of treatment in Patients 1 through 24), it was planned to escalate the bortezomib dose up to 1.3 mg/m2 in Arm A and up to 1.6 mg/m2 in Arm B.
In case of hematologic toxicity, bortezomib was withheld for up to 2 weeks until the patient had a hemoglobin value ≥7.5 g/dL, an absolute neutrophil count ≥0.75 × 109/L, and a platelet count ≥50 × 109/L. If the toxicity did not resolve, then the study drug was discontinued. If the toxicity resolved, then bortezomib was restarted at the same dose level if 1 dose was held or at reduced doses if 2 doses were held (either in consecutive cycles or twice in 1 cycle). If the patient received 1.3 mg/m2, 1.5 mg/m2, or 1.6 mg/m2, then the dose was reduced to 1.0 mg/m2. If the patient received 1.0 mg/m2, then the dose was reduced to 0.7 mg/m2. If the patient received 0.7 mg/m2, then bortezomib was stopped.
Patients who experienced grade 2 bortezomib-related neuropathic pain and/or peripheral sensory neuropathy had a 25% dose reduction for the next injection. Bortezomib was stopped when grade 3 or greater peripheral sensory neuropathy was observed. Treatment was withheld for up to 2 weeks with grade 3 or worse other nonhematologic toxicities until they resolved to grade 1 or lower.
Staging and Follow-Up
Initial staging included a computerized tomodensitometry scan of the chest, abdomen, and pelvic areas and a bone marrow biopsy. During treatment, patients were observed before each study drug dose. They were evaluated for possible toxicities that may have occurred after the previous doses. Toxicities were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).
Disease evaluation for response assessments were those recommended in the International Workshop criteria.8 Patients who completed their treatment had a complete clinical examination every 3 months for the first year and then every 6 months for 5 years. A computed tomography scan was obtained twice a year. No routine molecular biology procedures or dynamic imaging methods were used.
Patients were analyzed in an intent-to-treat basis. EFS was defined as the time between randomization and primary treatment failure, recurrence, and either death from any cause or last follow-up. OS was defined as the time between randomization and either last follow-up or death from any cause. Estimates of survival were calculated according to the Kaplan-Meier method. All statistical analyses were performed using Statistical Application System software (SAS, version 9.13; SAS Institute, Cary, NC).
Between January 2005 and April 2006, 49 patients were randomized from 4 participating French centers. In January 2006, according to the triangular-test sequential analysis and dose-limiting toxicity, Arm A was closed at 20 patients, and inclusion continued only in Arm B. Then, in total, 20 patients were assigned to Arm A (13 were treated at Step 1, and 7 were treated at Step 2), and 29 patients were assigned to Arm B (14 were treated at Step 1, and 15 were treated at Step 2).
Patient characteristics at study entry are detailed in Table 1. The median age was 63 years (range, 32-76 years), and 28 patients (57%) were men. PS was altered in 4 patients (8%), 33 patients (67%) had stage IV lymphoma, lactate dehydrogenase serum levels were elevated in 16 patients (33%), and the IPI was >1 in 18 patients (37%). A central review indicated that the pathologic subtypes of lymphoma included were lymphoplasmacytic lymphoma (3 patients), small lymphocyte lymphoma (8 patients), marginal zone lymphoma (8 patients), follicular lymphoma (11 patients), mantle cell lymphoma (3 patients), follicular lymphoma with histologic transformation (5 patients), and diffuse large B-cell lymphoma (11 patients).
Table 1. Patient Characteristics According to Treatment Arm
Two hundred ninety cycles of R-CHOP and 819 injections of bortezomib were administered to the 49 patients. Forty-six of 49 patients received the 6 planned cycles of R-CHOP chemotherapy. The other 3 patients received 4, 5, and 5 cycles of R-CHOP, respectively: chemotherapy was stopped because of lymphoma progression after 4 courses and 5 courses of R-CHOP for the first 2 patients and because of the investigator's decision after 5 cycles without grade 3 toxicity for the other patient.
Five of 20 patients in Arm A (all patients in Step 2) and 7 of 29 patients in Arm B (2 patients in Step 1 and 5 patients in Step 2) received <90% of the scheduled dose of bortezomib. The 2 patients who did not receive >90% of scheduled doses in Arm B during Step 1 did not receive the 6 cycles of R-CHOP or the combined bortezomib infusions (1 because of the investigator's decision and the other because of lymphoma progression). During Step 2, and in both arms, 10 of 23 patients received <90% of the schedule dose of bortezomib, 9 patients because of toxicity and the other patient because of lymphoma progression.
All patients were assessable for toxic effects. No deaths were observed on the study. The most common drug-related, nonhematologic toxicities observed on Arm A (biweekly schedule) were neurologic toxicity (70% of patients), queasiness (40%), stomatitis (35%), infection (30%), constipation (10%), and cardiovascular toxicity (5%). The most common drug-related, nonhematologic toxicities observed on Arm B (weekly schedule) were neurologic toxicity (71% of patients), infection (37%), stomatitis (28%), queasiness (28%), constipation (10%), and cardiovascular toxicity (3%). Grade 3 nonhematologic toxicities are detailed in Table 2. There was no grade 4 nonhematologic toxicity.
Table 2. Frequency of Grade 3 Nonhematologic Toxicities According to Treatment Arm (All Cycles)*
Arm A, Biweekly
Arm B, Weekly
Arms A and B, Entire Population
Step 1 consisted of bortezomib at 1 mg/m2 in and 1.3 mg/m2 in Arms A and B, respectively; for Step 2, doses were increased to 1.3 mg/m2 and 1.6 mg/m2 in Arms A and B, respectively.
There were no grade 4 nonhematologic toxicities reported, and was no grade 3 toxicity for stomatitis, liver, kidney, or lung was reported.
For both arms, the frequency and severity of neurologic toxicity was greater in Step 2 with the highest dose of bortezomib. Grade 2 neurologic toxicity was observed in 11 patients (22%), including 1 of 13 patients in Arm A, Step 1; 3 of 14 patients in Arm B, Step 1; and 7 of 15 patients (47%) in Arm B, Step 2. In addition, grade 3 neurologic toxicity (10 patients; 20%) also was more frequent during Step 2 and occurred in 1 of 14 patients in Arm B, Step 1; in 5 of 7 patients (71%) in Arm A, Step 2; and in 4 of 15 patients (27%) in Arm B, Step 2.
Grade 3 and 4 leucopenia was observed in 41% of cycles (35% of cycles in Arm A; 44% of cycles in Arm B). There was no relation to the bortezomib dose (38% of cycles in Step 1; 43% of cycles in Step 2). Grade 3 and 4 thrombocytopenia occurred in 14% of cycles and only among patients in Arm A (35% of cycles; ie, 27% in Step 1 and 44% in Step 2).
All patients were evaluated for tumor response after 6 cycles of R-CHOP + bortezomib. Forty-one patients achieved a CR/CRu, 6 patients achieved a partial response (PR), and 2 patients progressed on therapy. In Arm A, 18 of 20 patients (90%) achieved a CR/CRu (9 CRs, 9 CRus); and, in Arm B, 23 of 29 patients (79%) patients achieved a CR/CRu (15 CRs, 8 CRus). In Arm A, 2 of 20 patients (10%) achieved a PR; and, in Arm B, 4 of 29 patients (14%) achieved a PR. Two patients progressed on therapy in Arm B. According to the triangular test (Fig. 1), Arm A was stopped when the CR/CRu rate reached 90% and Arm B was stopped when the CR/CRu rate reached 79% (P = .31).
The CR/CRu rate was 73% in small cell lymphomas (14 of 19 patients, including marginal zone, small lymphocytic, and lymphoplasmacytic lymphomas), 82% in follicular lymphomas (9 of 11 patients), and 100% in mantle cell lymphomas (3 of 3 patients). All together, the CR/CRu rate was 79% in 33 patients with indolent lymphoma and 88% in patients with aggressive lymphomas (14 of 16 patients, including those with transformed follicular lymphomas and diffuse large B-cell lymphomas; P = .46).
The median follow-up was 2 years (range, 13-27 months). Among the 47 patients who responded, 36 remained in CR/CRu, 4 retained a PR, and 7 developed recurrent disease. Three patients died, including 2 who failed to respond to R-CHOP + bortezomib and died rapidly died and 1 patient in PR who died after developing recurrent disease. The 2-year EFS and OS estimates were 64% and 83%, respectively (Figs. 2, 3). The 2-year EFS estimate was 44% in patients with indolent lymphomas versus 100% in patients with aggressive lymphomas (P = .02), and the 2-year OS rate was 81% versus 100%, respectively (P = .06).
The current trial demonstrated that the combination of R-CHOP plus bortezomib was able to produce a >75% CR rate in a wide range of B-cell lymphoma subtypes. The 2 treatment arms cannot be compared statistically; however, the biweekly schedule seems to lead to better results than the weekly schedule (CR/CRu rate, 90% vs 79%, respectively).
Bortezomib demonstrated activity in different lymphoma subtypes and received regular approval for the treatment of patients with recurrent mantle cell lymphoma after previous therapy.9 A few early phase 2 studies have been reported in patients with recurrent or refractory lymphoma subtypes other than B-cell lymphoma subtypes,.5, 6, 10 Very limited experience has been reported with bortezomib combined with chemotherapy in patients with lymphoma. In a phase 1 study reported by Orlowski et al,11 patients received bortezomib on Days 1, 4, 8, and 11 of a 3-week cycle at doses ranging from 0.90 mg/m2 to 1.5 mg/m2 along with pegylated liposomal doxorubicin on Day 4 at 30 mg/m2. Six of their patients had lymphoma, and 2 PRs were observed (1 in a patient with mycosis fungoides and 1 in a patient with peripheral T-cell lymphoma).
Recently, Leonard et al also presented a phase 1/2 trial of dose-escalated bortezomib with standard R-CHOP in patients with diffuse large B-cell lymphoma.12 Patients received the same R-CHOP combination as that used in the current study, but bortezomib was given at a dose of 0.7 mg/m2, 1.0 mg/m2, or 1.3 mg/m2 on Days 1 and 4 of each cycle. Thirty-six patients in that study were evaluable: The objective response rate was 100%, and the CR/CRu rate was 75% CR/CRu. The 2-year progression-free survival was estimated at 72%. Peripheral neuropathy occurred in 22 patients (55%) and was grade 1 in 45% of patients, grade 2 in 5% of patients, and grade 3 in 5% of patients.
In the current study, neurologic toxicity was more frequent and severe, particularly on the biweekly schedule, and 5 episodes of grade 3 neuropathy were reported in 7 patients (71%) who received bortezomib 1.3 mg/m2. The 21 episodes of sensitive neurologic toxicity were observed after 3 or 4 cycles of full-dose therapy and resolved within 6 months in most patients. However, 3 patients remained symptomatic and still needed analgesics 12 months after the end of therapy. This observation raises the question of which dose of bortezomib produces the maximum activity in combination with standard R-CHOP. The current results suggest that, for future trials, the biweekly schedule should be used only at 1 mg/m2. In addition, this recommendation is in line with the preliminary report by Kahl et al, who identified a maximum tolerated dose of 1 mg/m2 for vincristine and 1.3 mg/m2 for bortezomid.13
In conclusion, our results indicate that the combination of bortezomib plus R-CHOP is encouraging and may warrant further studies. Toxicity was acceptable when low doses of bortezomib were used, but neurologic toxicity was excessively high when bortezomib was given at doses that were explored in monotherapy during phase 2 trials in lymphomas.
We thank Maryse Berlion for editing the English.
Conflict of Interest Disclosures
Supported in part by research funding from Millennium.