Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma
http://www.100md.com
《临床肿瘤学》
the Departments of Lymphoma and Myeloma, Molecular Pathology, Biostatistics, and Imaging, The University of Texas M.D. Anderson Cancer Center, Houston TX
Hematology Oncology Department, Hygeia Hospital, Athens, Greece
Millennium Pharmaceuticals, Inc, Cambridge, MA
ABSTRACT
PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles.
RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrm's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study.
CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.
INTRODUCTION
PATIENTS AND METHODS
Treatment Protocol
In the phase I study in hematologic malignancies, the responses seen in lymphoma patients were obtained with a dose of 1.38 mg/m2 using a schedule of twice a week for 4 weeks every 6 weeks.16 Additional phase I studies in solid tumors using a 2-weeks-on and 1-week-off schedule showed that the maximum-tolerated dose was between 1.56 mg/m2 19 and 1.65 mg/m2.20 Given these observations, bortezomib was administered in our study at a dose of 1.5 mg/m2 intravenous (IV) bolus push over 3 to 5 seconds on days 1, 4, 8, and 11, followed by a 10-day rest for a 21-day cycle. Doses were repeated if the ANC was ≥ 1,000/μL and the platelet count was ≥ 30,000/μL. Patients were observed for a minimum of 1 hour after administration of bortezomib. The protocol was modified after the first third of patients were enrolled to include prophylactic IV fluids of 250 to 500 mL of normal saline, which was administered before each infusion or before every other infusion of bortezomib based on the clinical impression of the tolerance to bortezomib by the primary physician. Six cycles were administered unless treatment was discontinued because of toxicity or progression of disease (PD) or if the patient wished to discontinue therapy. Support with granulocyte colony-stimulating factor and/or erythropoietin was allowed, but no other chemotherapy or immunotherapy was allowed.
Evaluation of Response and Toxicity
Baseline evaluation included clinical examination, bone marrow aspirate and biopsy, and computed tomography of chest, abdomen and pelvis, and head and neck, if indicated. Patients were restaged every two cycles while on therapy and then every 3 months afterwards until progression. Gallium or positron emission tomography scan tests were repeated in patients with known positive nuclear imaging studies at baseline. Bone marrow biopsy was also repeated as part of the restaging if positive at baseline. Patient response was evaluated according to the criteria of Cheson et al.21 Repeat endoscopies were also performed in patients with documented gastrointestinal tract involvement on study entry. In patients who achieved a complete response (CR) according to the Cheson criteria, if the endoscopy was still positive, they were considered as having a partial response (PR). In patients with no nodal disease but measurable gastrointestinal disease by endoscopy, if all lesions were resolved and multiple random biopsies were negative, the patient was considered as having a CR. In patients with WM, a PR was defined as at least a 50% reduction of monoclonal immunoglobulin M level by serum protein electrophoresis on two occasions at least 6 weeks apart and a more than 50% reduction of tumor infiltrate at all involved sites (bone marrow, lymph nodes, and spleen). A CR was defined as disappearance of abnormal M protein by immunoelectrofixation, resolution of all lymphadenopathy and splenomegaly, less than 20% lymphocytes in bone marrow, and no evidence of monoclonal lymphocytes by immunohistochemistry and/or flow cytometry.
Unless patients had clinical evidence of progression, they were considered assessable for response after completion of at least two courses of therapy, which was the time of their first restaging analysis. At this time, patients who achieved a CR or a PR continued treatment up to a maximum of six cycles. Patients with PD at any time were removed from the study. Patients with evidence of any tumor reduction after two cycles of bortezomib, even if they did not meet PR criteria, were allowed to continue for an additional two cycles before re-evaluation. If after four cycles patients had achieved a CR or a PR, they continued for a maximum of six cycles; otherwise, they were removed from the study. Patients were also removed from the study in case of severe intercurrent illness or occurrence of an unacceptable adverse event. In addition, patients were removed from study if they had a treatment cycle delay or bortezomib interruption for more than 2 weeks or if they missed three of the four bortezomib doses within a given treatment cycle because of toxicity. Patients were also taken off study on patient request, protocol violations, noncompliance, or responsive disease resulting in eligibility for bone marrow transplantation after a minimum of two cycles had been completed. Adverse events were assessed at each visit and graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0) from the first dose until the first follow-up visit after treatment. Treatment was withheld in patients with grade 3 or more nonhematologic toxicity or grade 4 hematologic toxicity until the side effects diminished to grade 1 or better. After resolution, treatment was resumed at a lower dose level. The initial dose was 1.5 mg/m2, and stepwise reductions were to 1.3, 1.1, 0.9, or 0.7 mg/m2; dose reduction below 0.7 mg/m2 was not permitted, and thus, patients were removed from study.
Statistical Methods
On the basis of preclinical data, which showed promising activity in experimental models in MCL in vitro and in SCID mice xenograft models, we designed our study in two arms; arm A comprised only patients with MCL, and arm B comprised patients with other B-cell lymphomas. The primary end point was the overall response rate (ORR) to bortezomib, which was defined as CR plus PR. The secondary end points were time to progression and toxicity. The trial was conducted according to the optimal two-stage design of Simon considering the following two hypotheses: first, an RR less than 10% is of no further interest; and second, an RR ≥ 30% is clinically meaningful. In the initial stage, 12 patients were to be entered onto each arm. If no more than one response (≤ 1 in 12) was observed in each arm, that arm of the trial would be terminated. Otherwise, accrual was to continue to a total of a maximum of 35 patients in each arm. At the end of the trial, if five or fewer responses had occurred among the 35 patients in either diagnostic group, it would be concluded that the regimen is not worthy of further investigations for that group of patients. Patients were observed to assess failure-free survival. Responders to bortezomib could undergo either autologous or allogeneic bone marrow transplantation as part of their salvage chemotherapy, if indicated. These patients were censored at the time of analysis for failure-free survival.
RESULTS
Treatment Outcome
In arm A, among 29 assessable patients, there were 12 responders (Table 3), for an ORR of 41% (95% CI, 24% to 61%) with six CRs (20.5%) and six PRs (20.5%). Among the other patients, there were six patients with stable disease (SD; 20.5%); the remaining 11 patients had PD (38%). In arm B, among 21 assessable patients, the ORR was 19% (95% CI, 5% to 42%), with two PRs (one patient with B-cell DLCL and one with WM), one CR (SLL), and one CR unconfirmed (FL). The patient with SLL was confirmed to be CD5-CD20 positive, cyclin D1 negative, and negative also by fluorescent in situ hybridization analysis for the t(11;14) translocation. Among the other patients, six achieved SD (27%), and the remaining 11 patients had PD (52%). Intent-to-treat analysis was also performed, which confirmed an RR of 39% (95% CI, 22% to 58%) in arm A and 17% (95% CI, 5% to 39%) in arm B.
This population was heavily pretreated, as detailed in Table 4. Among the four patients with MCL who had relapsed after high-dose therapy and ASCT, one achieved a CR, one achieved a PR, one had SD, and one had PD. The other responders in the MCL group had a range of prior therapies of one to seven therapies. Three of the patients who achieved a CR had bulky disease (> 5 cm) at study entry.
The evaluation of duration of response was limited to patients with MCL because only four patients with other B-cell lymphomas responded to bortezomib. This analysis included the 12 MCL patients who achieved a CR or a PR. The duration of response curve is shown in Figure 1. Three patients who had achieved a CR underwent a bone marrow transplantation (one ASCT and two nonmyeloablative allotransplantations); and although they were in CR at the time of transplantation, these patients were censored for response duration analysis at that time. Four of the 12 MCL responders progressed within 2 to 12 months. Five patients had no PD at their last follow-up, with a median follow-up of 9.3 months (range, 1.7 to 24 months). An estimated 80% (95% CI, 59% to 100%) of patients are still in response at 6 months, and the median time to progression for MCL responders has not been reached yet. Among patients who achieved a CR, only one of six relapsed. The response duration for the patient who progressed was 8 months, the other patients have been observed still in CR from 1 month to 19 months. For the patients who achieved a PR, three of six relapsed, with a median response duration of 11.5 months. The minimum response duration among patients who achieved a PR was 2 months, and one patient was observed still in response after 22.8 months. Progression-free survival analyzed separately for each group is shown in Figures 2 and 3. The estimated progression-free survival at 6 months was 42% for patients in arm A (95% CI, 27% to 65%; Fig 2) and 36% for patients in arm B (95% CI, 20% to 64%; Fig 3).
Our study, which was initiated in June 2002, had enrolled 60 patients by June 2004. Because the original trial design specified that at least five responses out of 35 MCL patients were necessary to demonstrate efficacy, the trial has been halted in view of these early promising results so that the next phase of investigation may begin.
Toxicities
Overall, a total of 129 cycles of bortezomib were delivered; 76 cycles were administered in arm A, with a median number of 2.1 cycles per patient (range, one to six cycles), and 53 cycles were administered in arm B, with a median number of two cycles per patient (range, one to six cycles). In arm A, 21 patients received two to five cycles of bortezomib, and two patients completed six cycles. In arm B, 14 patients received two to five cycles, and two patients completed six cycles.
Grade 3 and 4 toxicities are listed in Table 5. The most common nonhematologic grade 3 toxicity was gastrointestinal (12 patients, 20%), including anorexia, nausea, vomiting, diarrhea, constipation, or small bowel obstruction. Other nonhematologic toxicities included fatigue in eight patients (13%), hypotension, dehydration, and dizziness in seven patients (11%), peripheral neuropathy in three patients (5%), and myalgia in three patients (5%). Six patients (10%) developed a maculopapular rash while receiving bortezomib. In four patients, the rash was grade 2, and in two patients, it was grade 3 because of associated pruritus. Biopsies were performed in two patients and showed necrotizing vasculitis. For the hematologic toxicity, six patients had grade 3 neutropenia (10%), and 28 had grade 3 thrombocytopenia (47%); among these patients, 11 had platelet counts between 25,000 and 50,000/μL, and 17 had platelet counts between 25,000/μL and 10,000/μL. Only one patient had platelets less than 10,000/μL, and there was no episode of bleeding. Grade 4 events occurred in nine patients (15%) and included two non-neutropenic infections (one pneumonia and one generalized zoster; 3%). All other grade 4 events (syncope, fatigue, diarrhea, neutropenia, and thrombocytopenia) were seen in only one patient for each toxicity.
Eleven patients (18%) required a dose reduction at least once. Drug-related adverse events led to discontinuation of bortezomib therapy in 13 patients (22%). Discontinuation of bortezomib was attributed to fatigue and hypotension in seven patients (12%), peripheral neuropathy in three patients (5%), and thrombocytopenia in three patients (5%). Three patients died while on study (5%); two died from progression of DLCL within 30 days after the last dose of bortezomib, and one patient died from infection. This patient had extensive mediastinal disease and died of nonneutropenic bacterial pneumonia while receiving the second cycle of bortezomib. An additional patient died of generalized zoster with encephalitis more than 5 weeks after being taken off study for PD.
DISCUSSION
The lower RR seen in the other B-cell NHL group might reflect the fact that these patients received more prior therapies than patients in arm A, with a median number of prior therapies of four (range, one to 12 therapies). This might also explain differences seen with the MSKCC study in which patients had a maximum of three prior therapies. However, we might also have underestimated the responses by not giving further therapy in the absence of any response after two cycles. In both studies, patients with MCL tended to respond within the first two cycles, whereas other types of lymphoma have responded more slowly, as seen with the MSKCC study, which showed significant activity of bortezomib in patients with relapsed FL.24 In our study, a high proportion of patients in arm B experienced PD, especially patients with DLCL. This finding could be explained, in part, by kinetic failure in aggressive relapsed or refractory lymphomas. Further evaluation of the efficacy of bortezomib in aggressive lymphoma is needed both as a single agent in less pretreated patients as well as in combination with other chemotherapy agents. In vitro data suggest a synergy between bortezomib and a variety of cytotoxic agents,25,26 and ongoing studies are currently testing this hypothesis. Two phase I to II studies have shown that the combination of bortezomib with chemotherapy, such as liposomal doxorubicin27 or dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin),28 can be administered safely without significant changes in the toxicity profile. Interestingly, preliminary data for the combination of bortezomib and liposomal doxorubicin27 showed two responses in DLCL patients, including a CR in a peripheral T-cell lymphoma patient and a PR in a B-cell DLCL patient. In the dose-adjusted EPOCH trial,28 77% of the patients were either refractory to induction therapy or to their last therapy, and all patients had received an anthracycline-containing regimen. Among the nine assessable patients in that study, there was one patient with PR, two patients with SD, and six patients with PD. Additional studies will explore the role of bortezomib in combination with other chemotherapy agents, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, or biological agents, such as rituximab or oblimersen (Bcl-2 antisense), both in the context of front-line or salvage therapy. As part of these upcoming studies, it will be important to explore different doses and schedules, including a once a week schedule versus the current schedule of twice a week for 2 weeks every 3 weeks. Besides convenience for patients, scheduling and timing might be critical to obtain the best synergy in the combination studies.
This study also shows that bortezomib can be administered safely to patients with B-cell NHL. However, we might also have underestimated the cumulative toxicity of bortezomib in certain cases because patients who did not respond after two cycles were removed from study. Most adverse events in our study could be managed through standard supportive care. Hypotension appeared more common in elderly patients, and its incidence decreased with routine prophylactic IV fluids. The incidence of neuropathy was much less in our experience than what was reported in MM phase II studies.18,29 This observation could be explained in part by differences in predisposing factors. In MM patients, neuropathy can be related to the underlying disorder in approximately one third of patients and/or to prolonged prior exposure to other neurotoxic agents, such as thalidomide and vinca alkaloids. In addition, in our series, patients received fewer cycles of bortezomib than in the MM trials, in which 39% of patients received up to eight cycles of bortezomib.17 All three cases of grade 3 neuropathy in our study were seen in patients who had received several different regimens including neurotoxic agents, such as vinca alkaloids or taxanes for treatment of their lymphoma. As in the MSKCC experience, a fraction of our patients developed a maculopapular rash that showed necrotizing vasculitis.22 Although the patients who had a rash usually had recurrence of this rash over time, this did not preclude continuation of therapy with bortezomib, and all patients were successfully treated symptomatically with topicals and/or antihistamines. Thrombocytopenia was the most common adverse event, with grade 3 thrombocytopenia observed in 28 patients and grade 4 thrombocytopenia observed in one patient. Thrombocytopenia was also frequent in myeloma patients treated with bortezomib, in whom it was found to be transient, with a nadir at approximately 40% of the baseline platelet count.30 In our study, only one patient had a platelet count of less than 10,000/μL, and there was no episode of bleeding.
In conclusion, the novel proteasome inhibitor bortezomib shows promising activity as well as durable response as a single agent in relapsed or refractory MCL patients. This observation led to the initiation of a national multicenter trial with bortezomib as a single agent in patients with relapsed or refractory MCL. Encouraging responses have also been seen in patients with DLCL, FL, and WM. Laboratory studies suggest synergy between bortezomib and conventional chemotherapy agents or biologic agents in several models. Further studies will explore such combinations, opening new perspectives in the treatment of NHL.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by Millennium Pharmaceuticals Inc, Cambridge, MA.
Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Chiu BC, Weisenburger DD: An update of the epidemiology of non-Hodgkin's lymphoma. Clin Lymphoma 4:161-168, 2003
2. Coiffier B, Thieblemont C, Felman P, et al: Indolent nonfollicular lymphomas: Characteristics, treatment, and outcome. Semin Hematol 36:198-208, 1999
3. Barista I, Romaguera JE, Cabanillas F: Mantle-cell lymphoma. Lancet Oncol 2:141-148, 2001
4. Howard OM, Gribben JG, Neuberg DS, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288-1294, 2002
5. Romaguera JE, Khouri IF, Kantarjian HM, et al: Untreated aggressive mantle cell lymphoma: Results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 39:77-85, 2000
6. Zeeb H, Blettner M: Increasing incidence and mortality of non-Hodgkin lymphomas: An epidemiological review of recent studies on risk factors for non-Hodgkin lymphoma. Med Klin (Munich) 96:87-100, 2001
7. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res 59:2615-2622, 1999
8. Goldberg AL: Protein degradation and protection against misfolded or damaged proteins. Nature 426:895-899, 2003
9. Mack PC, Davies AM, Lara PN, et al: Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. Lung Cancer 41:S89-S96, 2003
10. Mitsiades N, Mitsiades CS, Poulaki V, et al: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374-14379, 2002
11. Hideshima T, Mitsiades C, Akiyama M, et al: Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530-1534, 2003
12. Kane RC, Bross PF, Farrell AT, et al: Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508-513, 2003
13. Pham LV, Tamayo AT, Yoshimura LC, et al: Inhibition of constitutive NF-kappaB activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171:88-95, 2003
14. Bogner C, Ringshausen I, Schneller F, et al: Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. Br J Haematol 122:260-268, 2003
15. Pham L, Tamayo A, Lo P, et al: Anti-tumor activity of the proteasome inhibitor PS-341 in mantle cell lymphoma B cells. Blood 98:1945, 2001 (abstr 1945; suppl)
16. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002
17. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003
18. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004
19. Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-2511, 2002
20. Papandreou CN, Daliani DD, Nix D, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108-2121, 2004
21. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244, 1999
22. O'Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the proteasome inhibitor bortezomib (formerly PS-341) in patients with indolent lymphomas. Proc Am Soc Clin Oncol 22:566, 2003 (abstr 2277)
23. Assouline S, Belch A, Sehn L, et al: A phase II study of bortezomib in patients with mantle cell lymphoma. Blood 107:902a, 2003 (abstr 3358)
24. O'Connor OA: Marked clinical activity of the novel proteasome inhibitor bortezomib in patients with relapsed follicular (RL) and mantle cell lymphoma (MCL). Proc Am Soc Clin Oncol 22:5785, 2004 (abstr 6582)
25. Ma MH, Yang HH, Parker K, et al: The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136-1144, 2003
26. Cusack JC Jr, Liu R, Houston M, et al: Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: Implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61:3535-3540, 2001
27. Orlowski R, Hall M, Voorhees P, et al: Phase I study of the proteasome inhibitor bortezomib (PS-341, Velcade) in combination with pegylated liposomal doxorubicin (Doxil) in patients with refractory hematologic malignancies. Blood 100:105a, 2002 (abstr 388)
28. Dunleavy KM, Janik J, Grant N, et al: Phase I/II study of bortezomib combined with dose adjusted-EPOCH chemotherapy in relapsed or refractory diffuse large B-cell lymphomas. Blood 102:636a, 2003 (abstr 2349)
29. Richardson P: Clinical update: Proteasome inhibitors in hematologic malignancies. Cancer Treat Rev 29:33-39, 2003
30. Lonial S, Waller EK, Richardson PG, et al: Evaluation of the degree of thrombocytopenia and associated risk factors following bortezomib therapy for relapsed multiple myeloma. Blood 102:447a, 2003 (abstr 1632)(Andre Goy, Anas Younes, P)
Hematology Oncology Department, Hygeia Hospital, Athens, Greece
Millennium Pharmaceuticals, Inc, Cambridge, MA
ABSTRACT
PATIENTS AND METHODS: Patients were stratified, based on preclinical data, into arm A (mantle-cell lymphoma) or arm B (other B-cell lymphomas) without limitation in number of prior therapies. Bortezomib was administered as an intravenous push (1.5 mg/m2) on days 1, 4, 8, and 11 every 21 days for a maximum of six cycles.
RESULTS: Sixty patients with a median number of prior therapies of 3.5 (range, one to 12 therapies) were enrolled; 33 patients were in arm A and 27 were in arm B, including 12 diffuse large B-cell lymphomas, five follicular lymphomas (FL), three transformed FLs, four small lymphocytic lymphomas (SLL), two Waldenstrm's macroglobulinemias (WM), and one marginal zone lymphoma. In arm A, 12 of 29 assessable patients responded (six complete responses [CR] and six partial responses [PR]) for an overall response rate (ORR) of 41% (95% CI, 24% to 61%), and a median time to progression not reached yet, with a median follow-up of 9.3 months (range, 1.7 to 24 months). In arm B, four of 21 assessable patients responded (one SLL patient had a CR, one FL patient had a CR unconfirmed, one diffuse large B-cell lymphoma patient had a PR, and one WM patient had a PR) for an ORR of 19% (95% CI, 5% to 42%). Grade 3 toxicity included thrombocytopenia (47%), gastrointestinal (20%), fatigue (13%), neutropenia (10%), and peripheral neuropathy (5%). Grade 4 toxicity occurred in nine patients (15%), and three deaths from progression of disease occurred within 30 days of withdrawal from study.
CONCLUSION: Bortezomib showed promising activity in relapsed mantle-cell lymphoma and encouraging results in other B-cell lymphomas. Future studies will explore bortezomib in combination with other cytotoxic or biologic agents.
INTRODUCTION
PATIENTS AND METHODS
Treatment Protocol
In the phase I study in hematologic malignancies, the responses seen in lymphoma patients were obtained with a dose of 1.38 mg/m2 using a schedule of twice a week for 4 weeks every 6 weeks.16 Additional phase I studies in solid tumors using a 2-weeks-on and 1-week-off schedule showed that the maximum-tolerated dose was between 1.56 mg/m2 19 and 1.65 mg/m2.20 Given these observations, bortezomib was administered in our study at a dose of 1.5 mg/m2 intravenous (IV) bolus push over 3 to 5 seconds on days 1, 4, 8, and 11, followed by a 10-day rest for a 21-day cycle. Doses were repeated if the ANC was ≥ 1,000/μL and the platelet count was ≥ 30,000/μL. Patients were observed for a minimum of 1 hour after administration of bortezomib. The protocol was modified after the first third of patients were enrolled to include prophylactic IV fluids of 250 to 500 mL of normal saline, which was administered before each infusion or before every other infusion of bortezomib based on the clinical impression of the tolerance to bortezomib by the primary physician. Six cycles were administered unless treatment was discontinued because of toxicity or progression of disease (PD) or if the patient wished to discontinue therapy. Support with granulocyte colony-stimulating factor and/or erythropoietin was allowed, but no other chemotherapy or immunotherapy was allowed.
Evaluation of Response and Toxicity
Baseline evaluation included clinical examination, bone marrow aspirate and biopsy, and computed tomography of chest, abdomen and pelvis, and head and neck, if indicated. Patients were restaged every two cycles while on therapy and then every 3 months afterwards until progression. Gallium or positron emission tomography scan tests were repeated in patients with known positive nuclear imaging studies at baseline. Bone marrow biopsy was also repeated as part of the restaging if positive at baseline. Patient response was evaluated according to the criteria of Cheson et al.21 Repeat endoscopies were also performed in patients with documented gastrointestinal tract involvement on study entry. In patients who achieved a complete response (CR) according to the Cheson criteria, if the endoscopy was still positive, they were considered as having a partial response (PR). In patients with no nodal disease but measurable gastrointestinal disease by endoscopy, if all lesions were resolved and multiple random biopsies were negative, the patient was considered as having a CR. In patients with WM, a PR was defined as at least a 50% reduction of monoclonal immunoglobulin M level by serum protein electrophoresis on two occasions at least 6 weeks apart and a more than 50% reduction of tumor infiltrate at all involved sites (bone marrow, lymph nodes, and spleen). A CR was defined as disappearance of abnormal M protein by immunoelectrofixation, resolution of all lymphadenopathy and splenomegaly, less than 20% lymphocytes in bone marrow, and no evidence of monoclonal lymphocytes by immunohistochemistry and/or flow cytometry.
Unless patients had clinical evidence of progression, they were considered assessable for response after completion of at least two courses of therapy, which was the time of their first restaging analysis. At this time, patients who achieved a CR or a PR continued treatment up to a maximum of six cycles. Patients with PD at any time were removed from the study. Patients with evidence of any tumor reduction after two cycles of bortezomib, even if they did not meet PR criteria, were allowed to continue for an additional two cycles before re-evaluation. If after four cycles patients had achieved a CR or a PR, they continued for a maximum of six cycles; otherwise, they were removed from the study. Patients were also removed from the study in case of severe intercurrent illness or occurrence of an unacceptable adverse event. In addition, patients were removed from study if they had a treatment cycle delay or bortezomib interruption for more than 2 weeks or if they missed three of the four bortezomib doses within a given treatment cycle because of toxicity. Patients were also taken off study on patient request, protocol violations, noncompliance, or responsive disease resulting in eligibility for bone marrow transplantation after a minimum of two cycles had been completed. Adverse events were assessed at each visit and graded according to the National Cancer Institute Common Toxicity Criteria (version 2.0) from the first dose until the first follow-up visit after treatment. Treatment was withheld in patients with grade 3 or more nonhematologic toxicity or grade 4 hematologic toxicity until the side effects diminished to grade 1 or better. After resolution, treatment was resumed at a lower dose level. The initial dose was 1.5 mg/m2, and stepwise reductions were to 1.3, 1.1, 0.9, or 0.7 mg/m2; dose reduction below 0.7 mg/m2 was not permitted, and thus, patients were removed from study.
Statistical Methods
On the basis of preclinical data, which showed promising activity in experimental models in MCL in vitro and in SCID mice xenograft models, we designed our study in two arms; arm A comprised only patients with MCL, and arm B comprised patients with other B-cell lymphomas. The primary end point was the overall response rate (ORR) to bortezomib, which was defined as CR plus PR. The secondary end points were time to progression and toxicity. The trial was conducted according to the optimal two-stage design of Simon considering the following two hypotheses: first, an RR less than 10% is of no further interest; and second, an RR ≥ 30% is clinically meaningful. In the initial stage, 12 patients were to be entered onto each arm. If no more than one response (≤ 1 in 12) was observed in each arm, that arm of the trial would be terminated. Otherwise, accrual was to continue to a total of a maximum of 35 patients in each arm. At the end of the trial, if five or fewer responses had occurred among the 35 patients in either diagnostic group, it would be concluded that the regimen is not worthy of further investigations for that group of patients. Patients were observed to assess failure-free survival. Responders to bortezomib could undergo either autologous or allogeneic bone marrow transplantation as part of their salvage chemotherapy, if indicated. These patients were censored at the time of analysis for failure-free survival.
RESULTS
Treatment Outcome
In arm A, among 29 assessable patients, there were 12 responders (Table 3), for an ORR of 41% (95% CI, 24% to 61%) with six CRs (20.5%) and six PRs (20.5%). Among the other patients, there were six patients with stable disease (SD; 20.5%); the remaining 11 patients had PD (38%). In arm B, among 21 assessable patients, the ORR was 19% (95% CI, 5% to 42%), with two PRs (one patient with B-cell DLCL and one with WM), one CR (SLL), and one CR unconfirmed (FL). The patient with SLL was confirmed to be CD5-CD20 positive, cyclin D1 negative, and negative also by fluorescent in situ hybridization analysis for the t(11;14) translocation. Among the other patients, six achieved SD (27%), and the remaining 11 patients had PD (52%). Intent-to-treat analysis was also performed, which confirmed an RR of 39% (95% CI, 22% to 58%) in arm A and 17% (95% CI, 5% to 39%) in arm B.
This population was heavily pretreated, as detailed in Table 4. Among the four patients with MCL who had relapsed after high-dose therapy and ASCT, one achieved a CR, one achieved a PR, one had SD, and one had PD. The other responders in the MCL group had a range of prior therapies of one to seven therapies. Three of the patients who achieved a CR had bulky disease (> 5 cm) at study entry.
The evaluation of duration of response was limited to patients with MCL because only four patients with other B-cell lymphomas responded to bortezomib. This analysis included the 12 MCL patients who achieved a CR or a PR. The duration of response curve is shown in Figure 1. Three patients who had achieved a CR underwent a bone marrow transplantation (one ASCT and two nonmyeloablative allotransplantations); and although they were in CR at the time of transplantation, these patients were censored for response duration analysis at that time. Four of the 12 MCL responders progressed within 2 to 12 months. Five patients had no PD at their last follow-up, with a median follow-up of 9.3 months (range, 1.7 to 24 months). An estimated 80% (95% CI, 59% to 100%) of patients are still in response at 6 months, and the median time to progression for MCL responders has not been reached yet. Among patients who achieved a CR, only one of six relapsed. The response duration for the patient who progressed was 8 months, the other patients have been observed still in CR from 1 month to 19 months. For the patients who achieved a PR, three of six relapsed, with a median response duration of 11.5 months. The minimum response duration among patients who achieved a PR was 2 months, and one patient was observed still in response after 22.8 months. Progression-free survival analyzed separately for each group is shown in Figures 2 and 3. The estimated progression-free survival at 6 months was 42% for patients in arm A (95% CI, 27% to 65%; Fig 2) and 36% for patients in arm B (95% CI, 20% to 64%; Fig 3).
Our study, which was initiated in June 2002, had enrolled 60 patients by June 2004. Because the original trial design specified that at least five responses out of 35 MCL patients were necessary to demonstrate efficacy, the trial has been halted in view of these early promising results so that the next phase of investigation may begin.
Toxicities
Overall, a total of 129 cycles of bortezomib were delivered; 76 cycles were administered in arm A, with a median number of 2.1 cycles per patient (range, one to six cycles), and 53 cycles were administered in arm B, with a median number of two cycles per patient (range, one to six cycles). In arm A, 21 patients received two to five cycles of bortezomib, and two patients completed six cycles. In arm B, 14 patients received two to five cycles, and two patients completed six cycles.
Grade 3 and 4 toxicities are listed in Table 5. The most common nonhematologic grade 3 toxicity was gastrointestinal (12 patients, 20%), including anorexia, nausea, vomiting, diarrhea, constipation, or small bowel obstruction. Other nonhematologic toxicities included fatigue in eight patients (13%), hypotension, dehydration, and dizziness in seven patients (11%), peripheral neuropathy in three patients (5%), and myalgia in three patients (5%). Six patients (10%) developed a maculopapular rash while receiving bortezomib. In four patients, the rash was grade 2, and in two patients, it was grade 3 because of associated pruritus. Biopsies were performed in two patients and showed necrotizing vasculitis. For the hematologic toxicity, six patients had grade 3 neutropenia (10%), and 28 had grade 3 thrombocytopenia (47%); among these patients, 11 had platelet counts between 25,000 and 50,000/μL, and 17 had platelet counts between 25,000/μL and 10,000/μL. Only one patient had platelets less than 10,000/μL, and there was no episode of bleeding. Grade 4 events occurred in nine patients (15%) and included two non-neutropenic infections (one pneumonia and one generalized zoster; 3%). All other grade 4 events (syncope, fatigue, diarrhea, neutropenia, and thrombocytopenia) were seen in only one patient for each toxicity.
Eleven patients (18%) required a dose reduction at least once. Drug-related adverse events led to discontinuation of bortezomib therapy in 13 patients (22%). Discontinuation of bortezomib was attributed to fatigue and hypotension in seven patients (12%), peripheral neuropathy in three patients (5%), and thrombocytopenia in three patients (5%). Three patients died while on study (5%); two died from progression of DLCL within 30 days after the last dose of bortezomib, and one patient died from infection. This patient had extensive mediastinal disease and died of nonneutropenic bacterial pneumonia while receiving the second cycle of bortezomib. An additional patient died of generalized zoster with encephalitis more than 5 weeks after being taken off study for PD.
DISCUSSION
The lower RR seen in the other B-cell NHL group might reflect the fact that these patients received more prior therapies than patients in arm A, with a median number of prior therapies of four (range, one to 12 therapies). This might also explain differences seen with the MSKCC study in which patients had a maximum of three prior therapies. However, we might also have underestimated the responses by not giving further therapy in the absence of any response after two cycles. In both studies, patients with MCL tended to respond within the first two cycles, whereas other types of lymphoma have responded more slowly, as seen with the MSKCC study, which showed significant activity of bortezomib in patients with relapsed FL.24 In our study, a high proportion of patients in arm B experienced PD, especially patients with DLCL. This finding could be explained, in part, by kinetic failure in aggressive relapsed or refractory lymphomas. Further evaluation of the efficacy of bortezomib in aggressive lymphoma is needed both as a single agent in less pretreated patients as well as in combination with other chemotherapy agents. In vitro data suggest a synergy between bortezomib and a variety of cytotoxic agents,25,26 and ongoing studies are currently testing this hypothesis. Two phase I to II studies have shown that the combination of bortezomib with chemotherapy, such as liposomal doxorubicin27 or dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin),28 can be administered safely without significant changes in the toxicity profile. Interestingly, preliminary data for the combination of bortezomib and liposomal doxorubicin27 showed two responses in DLCL patients, including a CR in a peripheral T-cell lymphoma patient and a PR in a B-cell DLCL patient. In the dose-adjusted EPOCH trial,28 77% of the patients were either refractory to induction therapy or to their last therapy, and all patients had received an anthracycline-containing regimen. Among the nine assessable patients in that study, there was one patient with PR, two patients with SD, and six patients with PD. Additional studies will explore the role of bortezomib in combination with other chemotherapy agents, such as cyclophosphamide, doxorubicin, vincristine, and prednisone, or biological agents, such as rituximab or oblimersen (Bcl-2 antisense), both in the context of front-line or salvage therapy. As part of these upcoming studies, it will be important to explore different doses and schedules, including a once a week schedule versus the current schedule of twice a week for 2 weeks every 3 weeks. Besides convenience for patients, scheduling and timing might be critical to obtain the best synergy in the combination studies.
This study also shows that bortezomib can be administered safely to patients with B-cell NHL. However, we might also have underestimated the cumulative toxicity of bortezomib in certain cases because patients who did not respond after two cycles were removed from study. Most adverse events in our study could be managed through standard supportive care. Hypotension appeared more common in elderly patients, and its incidence decreased with routine prophylactic IV fluids. The incidence of neuropathy was much less in our experience than what was reported in MM phase II studies.18,29 This observation could be explained in part by differences in predisposing factors. In MM patients, neuropathy can be related to the underlying disorder in approximately one third of patients and/or to prolonged prior exposure to other neurotoxic agents, such as thalidomide and vinca alkaloids. In addition, in our series, patients received fewer cycles of bortezomib than in the MM trials, in which 39% of patients received up to eight cycles of bortezomib.17 All three cases of grade 3 neuropathy in our study were seen in patients who had received several different regimens including neurotoxic agents, such as vinca alkaloids or taxanes for treatment of their lymphoma. As in the MSKCC experience, a fraction of our patients developed a maculopapular rash that showed necrotizing vasculitis.22 Although the patients who had a rash usually had recurrence of this rash over time, this did not preclude continuation of therapy with bortezomib, and all patients were successfully treated symptomatically with topicals and/or antihistamines. Thrombocytopenia was the most common adverse event, with grade 3 thrombocytopenia observed in 28 patients and grade 4 thrombocytopenia observed in one patient. Thrombocytopenia was also frequent in myeloma patients treated with bortezomib, in whom it was found to be transient, with a nadir at approximately 40% of the baseline platelet count.30 In our study, only one patient had a platelet count of less than 10,000/μL, and there was no episode of bleeding.
In conclusion, the novel proteasome inhibitor bortezomib shows promising activity as well as durable response as a single agent in relapsed or refractory MCL patients. This observation led to the initiation of a national multicenter trial with bortezomib as a single agent in patients with relapsed or refractory MCL. Encouraging responses have also been seen in patients with DLCL, FL, and WM. Laboratory studies suggest synergy between bortezomib and conventional chemotherapy agents or biologic agents in several models. Further studies will explore such combinations, opening new perspectives in the treatment of NHL.
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by Millennium Pharmaceuticals Inc, Cambridge, MA.
Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Chiu BC, Weisenburger DD: An update of the epidemiology of non-Hodgkin's lymphoma. Clin Lymphoma 4:161-168, 2003
2. Coiffier B, Thieblemont C, Felman P, et al: Indolent nonfollicular lymphomas: Characteristics, treatment, and outcome. Semin Hematol 36:198-208, 1999
3. Barista I, Romaguera JE, Cabanillas F: Mantle-cell lymphoma. Lancet Oncol 2:141-148, 2001
4. Howard OM, Gribben JG, Neuberg DS, et al: Rituximab and CHOP induction therapy for newly diagnosed mantle-cell lymphoma: Molecular complete responses are not predictive of progression-free survival. J Clin Oncol 20:1288-1294, 2002
5. Romaguera JE, Khouri IF, Kantarjian HM, et al: Untreated aggressive mantle cell lymphoma: Results with intensive chemotherapy without stem cell transplant in elderly patients. Leuk Lymphoma 39:77-85, 2000
6. Zeeb H, Blettner M: Increasing incidence and mortality of non-Hodgkin lymphomas: An epidemiological review of recent studies on risk factors for non-Hodgkin lymphoma. Med Klin (Munich) 96:87-100, 2001
7. Adams J, Palombella VJ, Sausville EA, et al: Proteasome inhibitors: A novel class of potent and effective antitumor agents. Cancer Res 59:2615-2622, 1999
8. Goldberg AL: Protein degradation and protection against misfolded or damaged proteins. Nature 426:895-899, 2003
9. Mack PC, Davies AM, Lara PN, et al: Integration of the proteasome inhibitor PS-341 (Velcade) into the therapeutic approach to lung cancer. Lung Cancer 41:S89-S96, 2003
10. Mitsiades N, Mitsiades CS, Poulaki V, et al: Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proc Natl Acad Sci U S A 99:14374-14379, 2002
11. Hideshima T, Mitsiades C, Akiyama M, et al: Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood 101:1530-1534, 2003
12. Kane RC, Bross PF, Farrell AT, et al: Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist 8:508-513, 2003
13. Pham LV, Tamayo AT, Yoshimura LC, et al: Inhibition of constitutive NF-kappaB activation in mantle cell lymphoma B cells leads to induction of cell cycle arrest and apoptosis. J Immunol 171:88-95, 2003
14. Bogner C, Ringshausen I, Schneller F, et al: Inhibition of the proteasome induces cell cycle arrest and apoptosis in mantle cell lymphoma cells. Br J Haematol 122:260-268, 2003
15. Pham L, Tamayo A, Lo P, et al: Anti-tumor activity of the proteasome inhibitor PS-341 in mantle cell lymphoma B cells. Blood 98:1945, 2001 (abstr 1945; suppl)
16. Orlowski RZ, Stinchcombe TE, Mitchell BS, et al: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20:4420-4427, 2002
17. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609-2617, 2003
18. Jagannath S, Barlogie B, Berenson J, et al: A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol 127:165-172, 2004
19. Aghajanian C, Soignet S, Dizon DS, et al: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies. Clin Cancer Res 8:2505-2511, 2002
20. Papandreou CN, Daliani DD, Nix D, et al: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108-2121, 2004
21. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas: NCI Sponsored International Working Group. J Clin Oncol 17:1244, 1999
22. O'Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the proteasome inhibitor bortezomib (formerly PS-341) in patients with indolent lymphomas. Proc Am Soc Clin Oncol 22:566, 2003 (abstr 2277)
23. Assouline S, Belch A, Sehn L, et al: A phase II study of bortezomib in patients with mantle cell lymphoma. Blood 107:902a, 2003 (abstr 3358)
24. O'Connor OA: Marked clinical activity of the novel proteasome inhibitor bortezomib in patients with relapsed follicular (RL) and mantle cell lymphoma (MCL). Proc Am Soc Clin Oncol 22:5785, 2004 (abstr 6582)
25. Ma MH, Yang HH, Parker K, et al: The proteasome inhibitor PS-341 markedly enhances sensitivity of multiple myeloma tumor cells to chemotherapeutic agents. Clin Cancer Res 9:1136-1144, 2003
26. Cusack JC Jr, Liu R, Houston M, et al: Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: Implications for systemic nuclear factor-kappaB inhibition. Cancer Res 61:3535-3540, 2001
27. Orlowski R, Hall M, Voorhees P, et al: Phase I study of the proteasome inhibitor bortezomib (PS-341, Velcade) in combination with pegylated liposomal doxorubicin (Doxil) in patients with refractory hematologic malignancies. Blood 100:105a, 2002 (abstr 388)
28. Dunleavy KM, Janik J, Grant N, et al: Phase I/II study of bortezomib combined with dose adjusted-EPOCH chemotherapy in relapsed or refractory diffuse large B-cell lymphomas. Blood 102:636a, 2003 (abstr 2349)
29. Richardson P: Clinical update: Proteasome inhibitors in hematologic malignancies. Cancer Treat Rev 29:33-39, 2003
30. Lonial S, Waller EK, Richardson PG, et al: Evaluation of the degree of thrombocytopenia and associated risk factors following bortezomib therapy for relapsed multiple myeloma. Blood 102:447a, 2003 (abstr 1632)(Andre Goy, Anas Younes, P)