Originally published as JCO Early Release 10.1200/JCO.2005.03.108 on December 21 2004

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Phase II Study of Proteasome Inhibitor Bortezomib in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

From 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; and Millennium Pharmaceuticals, Inc, Cambridge, MA

Address reprint requests to Andre Goy, MD, Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 459, Houston, TX 77030; e-mail: ahgoy{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: Evaluate efficacy and toxicity of bortezomib in patients with relapsed or refractory B-cell non-Hodgkin's lymphoma.

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 Waldenström'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

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The incidence of non-Hodgkin's lymphoma (NHL) has increased over the last three decades to represent about 55,000 new cases a year in the United States.¹ Although the majority of patients with NHL respond to initial therapy, a large number eventually relapse. NHL encompasses multiple entities with distinct clinical features and outcomes. Among these entities, follicular lymphoma (FL) remains incurable with conventional chemotherapy,² and mantle-cell lymphoma (MCL) has a poor outcome, with a median failure-free survival of 12 to 16 months after anthracycline-based therapy.^3,4 Although both the response rate (RR) and complete remission rate obtained with R-HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), alternating with methotrexate and cytarabine (M-A) in MCL are higher than those obtained with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, patients older than 65 years showed a high relapse rate and a significantly worse failure-free survival than patients younger than 65 years.⁵ Overall, despite high-dose chemotherapy and progress in supportive care, the mortality from NHL has continued to increase,⁶ and therefore, there is a necessity to explore new therapies. We report here the efficacy of bortezomib (VELCADE, formerly known as PS-341; Millennium Pharmaceuticals Inc, Cambridge, MA) in patients with relapsed or refractory B-cell NHL. Bortezomib is a novel small molecule, which is a potent selective and reversible inhibitor of the proteasome.^7,8 Proteasome inhibition results in the disruption of a variety of pathways and checkpoints leading to cellular apoptosis.^9-11 The efficacy of bortezomib in multiple myeloma (MM) led to its approval by the US Food and Drug Administration for the treatment of MM patients who have failed at least two prior therapies.¹² Bortezomib has also shown activity in vitro against a variety of lymphoma cell lines including MCL-derived¹³ and diffuse large-cell lymphoma (DLCL)-derived cell lines.⁷ Of interest, in vitro treatment of MCL cells by bortezomib led to cell growth inhibition and rapid induction of apoptosis¹⁴ and was associated with stabilization of nuclear factor-kappa B inhibitor and reduced nuclear factor-kappa B binding to its promoter.¹³ Bortezomib also exhibited activity against MCL tumors in a severe combined immunodeficiency mouse xenograft model.¹⁵ Preclinical studies also showed that continuous inhibition of the proteasome led to cumulative toxicity.⁷ Moreover, after bortezomib injection, proteasome inhibition is detectable within 1 hour and returns to baseline within 48 hours. This observation led to the original schedule using bortezomib every 72 hours in the first clinical trials to prevent cumulative toxicity.^7,8 A phase I study of bortezomib in patients with refractory hematologic malignancies¹⁶ showed remarkable responses in patients with plasma cell dyscrasia. These results were confirmed by the SUMMIT¹⁷ and CREST¹⁸ phase II trials in MM. In addition, the same phase I study showed activity in NHL; two patients, one with relapsed MCL and one with relapsed FL, achieved a partial remission; one patient with Waldenström's macroglobulinemia (WM) showed a 79% decrease in bone marrow involvement.¹⁶The preclinical results and clinical observations provided the rationale for this phase II trial of bortezomib for the treatment of patients with relapsed or refractory B-cell NHL.

	PATIENTS AND METHODS

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Eligibility
The study was conducted under a protocol approved by the institutional review board of The University of Texas M.D. Anderson Cancer Center. All patients provided written informed consent. Patients at least 16 years of age with relapsed or refractory B-cell NHL were eligible for the study. There was no limitation in the number of prior systemic cytotoxic regimens or immunotherapy. Patients who experienced treatment failure with prior high-dose therapy followed by autologous stem-cell transplantation (ASCT) were also eligible. Patients could not have received any anticancer therapy for at least 3 weeks before enrollment. Patients had to have measurable disease. Eligibility criteria also included Zubrod performance status 3 and a minimum life expectancy of 12 weeks. Patients with peripheral neuropathy grade 3 within 14 days before enrollment were not eligible for study. Hematologic parameters required for study entry were platelet count 50,000/µL and an absolute neutrophil count (ANC) 1,500/µL. In patients with either extensive bone marrow involvement by lymphoma or splenomegaly, platelets 30,000/µL and ANC 1,000/µL were also acceptable. Other laboratory criteria before entry included serum ALT levels no higher than 2.5 x the upper limit of normal, serum total bilirubin concentration 2 mg/dL, and creatinine less than 2 mg/dL. All patients agreed to use contraception, and a negative serum pregnancy test was required before enrollment in women of child-bearing potential. Patients with CNS involvement by lymphoma were not eligible. Patients with HIV-1 or other active infection or serious intercurrent illness were excluded. Patients with prior malignancy other than basal cell carcinoma of the skin or in situ cervical carcinoma were also excluded.

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/m^{2 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

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Patients Characteristics
A total of 60 patients were enrolled between June 2002 and June 2004. Clinical characteristics were available for all patients and are listed in Table 1. According to protocol design, patients were enrolled by histology onto two arms, arm A for MCL patients (33 patients, 55%) and arm B for other B-cell NHL patients (27 patients, 45%), which included 12 patients with DLCL (20%), five with FL (8%), three with transformed FL (5%), four with small lymphocytic lymphoma (SLL; 6%), two with WM (3%), and one with marginal zone lymphoma (1%). Arm A included 26 males and seven females, with a median age of 61 years (range, 45 to 78 years). Arm B included 18 males and nine females, with a median age of 60 years (range, 38 to 81 years). Our study population was heavily pretreated, as detailed in Table 2. Among patients diagnosed with MCL, the median number of prior therapies was three (range, one to 10 therapies), and among these patients, 81% had received R-HyperCVAD combination, 18% had received radioimmunotherapy with ibritumomab tiuxetan as part of their salvage therapy, and four patients had experienced treatment failure with prior high-dose therapy with ASCT. The median time from diagnosis to the first dose of bortezomib was 35.1 months (range, 8.5 to 118 months), and the median time from their last therapy to the first dose of bortezomib was 8.4 months (range, 1 to 45.3 months). Among the patients diagnosed with other B-cell lymphomas, the median number of prior treatments was four (range, one to 12 treatments), including a variety of anthracycline-based regimens. The median time from diagnosis to the first dose of bortezomib was 55.2 months (range, 8 to 340 months), and the median time from their last therapy to the first dose of bortezomib was 6.2 months (range, 1 to 40.3 months). Four of these patients also had experienced treatment failure with previous high-dose therapy with ASCT.

View larger version (12K): [in this window] [in a new window]   Fig 1. Response duration in patients with mantle-cell lymphoma (MCL). Time in response was measured from start of response until progression, last follow-up, or censor (autologous stem-cell transplantation). Median follow-up was 8.5 months. Four of 12 MCL responders progressed within 2 to 12 months. An estimated 80% (95% CI, 59% to 100%) of patients are still in response at 6 months, and only one of six patients with complete responses relapsed after 7 months.

View larger version (13K): [in this window] [in a new window]   Fig 2. Progression-free survival curve for patients in arm A. Time to progression was measured from entry onto the study until progression or death from lymphoma. In arm A, 18 of 33 patients progressed, two died, and three were censored (autologous stem-cell transplantation). The median time to progression was 3.5 months. The estimate of progression-free survival at 6 months was 42% (95% CI, 27% to 65%).

View larger version (13K): [in this window] [in a new window]   Fig 3. Progression-free survival curve for patients in arm B. Time to progression was measured from entry onto the study until progression or death from lymphoma. In arm B, 14 patients progressed, and one died. The median time to progression was 1.8 months, and the progression-free survival estimate at 6 months was 36% (95% CI, 20% to 64%).

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.

	DISCUSSION

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In this phase II trial, we evaluated the efficacy of the proteasome inhibitor bortezomib in patients with relapsed or refractory B-cell NHL. The overall response rate seen in MCL was 41% (half of the responses were CRs) in a population with extensive prior therapies (median, three prior therapies; range, of one to 10 therapies). Among these patients, 81% of MCL patients experienced treatment failure with R-HyperCVAD combination, and 18% experienced treatment failure with salvage therapy with radioimmmunotherapy. MCL patients responded to bortezomib therapy after a median number of 2.1 cycles, which is similar to what was observed in MM patients.¹⁷ This result is consistent with other ongoing studies, which have shown encouraging activity in MCL patients. A phase II study was conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) using the same dose and schedule but for a total of eight cycles. This trial included patients with indolent lymphoma who had received a maximum of two prior cytotoxic therapies. Consistent with our results, O'Connor et al²² showed objective response in about half of the patients with relapsed MCL. Activity of bortezomib in MCL was also seen in a multicenter Canadian study using a dose of 1.3 mg/m² with the same schedule as our study.²³

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

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The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Employment: Elizabeth Trehu, Millennium Pharmaceuticals, Inc; David Schenkein, Millennium Pharmaceuticals, Inc. Research Funding: Anas Younes, Millennium Pharmaceuticals, Inc. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.

	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

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Submitted March 15, 2004; accepted September 8, 2004.

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