Phase II Clinical Experience With the Novel Proteasome Inhibitor Bortezomib in Patients With Indolent Non-Hodgkin's Lymphoma and Mantle Cell
http://www.100md.com
《临床肿瘤学》
the Memorial Sloan-Kettering Cancer Center, Department of Medicine, Division of Hematologic Oncology, Lymphoma and Developmental Chemotherapy Services, Departments of Rehabilitation Medicine and Radiology, New York, NY
Millennium Pharmaceutical, Cambridge, MA
Drug Development Branch, National Cancer Institute, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/μL (500/μL if documented bone marrow involvement); and platelet count more than 50,000/μL.
RESULTS: Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7).
CONCLUSION: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.
INTRODUCTION
The ubiquitin-proteasome pathway plays a critical role in regulating cell cycle control.4 For example, cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors (p21, p27kip1) are temporally degraded during the cell cycle by the ubiquitin-proteasome pathway. Both p21 and p27 can induce cell cycle arrest by inhibiting cdk.11 The ordered degradation of these proteins is required for progression through cell cycle and mitosis. Another target of the ubiquitin-proteasome pathway is the tumor suppressor p53, which acts as a negative regulator of cell growth. p53 is required for the transcription of a number of genes involved in cell cycle control and DNA synthesis, and also plays an important function in apoptosis induced by cellular damage, including ionizing radiation.11
In addition to the regulation of cell cycle control, the ubiquitin-proteasome pathway plays an important role in modulating the important transcription factor NF-{kappa}B. NF-{kappa}B is responsible for the activation of several genes that contribute to the malignant phenotype, including genes that promote cell proliferation, cytokine release, antiapoptosis, and changes in cell surface adhesion molecules. The activity of NF-{kappa}B is tightly regulated by the ubiquitin-proteasome pathway through the accumulation or degradation of I{kappa}B, which binds to and inactivates NF-{kappa}B.4,12 Cell adhesion molecules (CAMs), such as E-selectin, ICAM-1, and VCAM-1, are proteins regulated by NF-{kappa}B and are involved in tumor metastasis and angiogenesis in vivo.13 As such, tumor cell metastasis may well be prevented through the downregulation of NF-{kappa}B–dependent CAM expression. NF-{kappa}B also controls cell viability by regulating both anti- and proapoptotic proteins in the mitochondrial membrane.14 Several lines of preclinical evidence now suggest that inhibiting NF-{kappa}B activation by stabilizing the I{kappa}B protein can render cells more sensitive to environmental stress and cytotoxic agents, ultimately leading to programmed cell death. In addition, many lines of experimental investigation have shown that inhibition of the proteasome, and perhaps even NF-{kappa}B, sensitizes cells to a host of conventional cytotoxic therapies.1,5,7
Although dysregulation of NF-{kappa}B is common to many malignancies, select lymphoproliferative malignancies are often characterized by pathognomonic molecular lesions, which may render them especially vulnerable to inhibitors of this pathway. Specific lesions include the following examples. First, the constitutive overexpression of cyclin D1 (bcl-1, PRAD1) in mantle-cell lymphoma (MCL) is due to the t(11;14)(q13;q32) translocation, which may also be augmented through the constitutive activation of NF-{kappa}B (and AP-1), which has been shown in cell lines of MCL.15 Second, the constitutive overexpression of the antiapoptotic protein bcl-2 in follicular lymphoma due to the t(14;18)(q32;q21) translocation can be mitigated through the inhibition of the 26S proteasome,16,17 which may be attributed in part to inactivated NF-{kappa}B. Third, the constitutive overexpression of NF-{kappa}B is noted in gene array studies of chemotherapy-refractory diffuse large B-cell neoplasms (ie, ABC or activated B-cell lymphomas).18,19 Fourth, the t(1:14)(p22:q32) translocation leading to expression of the bcl-10 gene in mucosa-associated lymphoid tissue lymphomas is believed to involve a caspase recruitment domain–containing protein that activates NF-{kappa}B.20,21
Bortezomib (Velcade, formerly known as PS-341; Millenium Pharmaceuticals, Cambridge, MA) is a dipeptidyl boronic acid inhibitor with high specificity for the 26S proteasome.22 It is the first member of this new class of antitumor agents to be studied in human clinical trials, leading recently to its approval by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. Phase I and II clinical studies have demonstrated that bortezomib is a well-tolerated agent with minimal hematologic toxicity. In addition, it has been shown that bortezomib is capable of producing a dose-related effect on proteasome inhibition when analyzed 1 hour postinfusion, with little interpatient variability.9,10 We present here the first clinical experience of bortezomib in patients with indolent and mantle cell non-Hodgkin's lymphoma (NHL).
PATIENTS AND METHODS
In addition, patients were required to meet the following criteria within 2 days of study drug administration: an absolute neutrophil count ≥ 1,500/μL (if known lymphomatous involvement of the bone marrow, then absolute neutrophil count > 500/mL); a platelet count of ≥ 50,000/μL for the first dose of every cycle, and more than 30,000/μl for doses delivered on days 4, 8, and 11; a total bilirubin ≤ 1.5x upper institutional limit of normal (ULN); an AST and ALT ≤ 2.5x ULN (4x ULN if the patient had liver involvement); and a creatinine ≤ 1.5x ULN. Initially, patients were required to have a platelet count ≥ 100,000/μL, but these criteria were modified downward given the absence of bleeding complications and the realization that many patients were unnecessarily missing doses secondary to the high cutoff value. Patients were excluded if they were pregnant; had evidence of intracranial disease; had major surgery within 4 weeks of study drug administration; had uncontrolled illness including active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, a myocardial infarction, or cerebrovascular accident within 6 months of study enrollment; had known HIV disease; or had a psychiatric illness that would limit compliance with study requirements.
Study Design
This was a single-center, single-agent phase II study of bortezomib in patients with relapsed, refractory, or untreated indolent NHL and MCL. The major objectives of the study were to determine the frequency and duration of complete and partial response for patients with indolent lymphoproliferative disorders treated with bortezomib. The study used a Simon two-stage design. Initially, 18 patients were enrolled onto the first stage. If no more than two patients responded, the trial would have been terminated. If at least three patients responded, then up to 35 patients could be enrolled. These statistics were predicated on the assumption that should 20% of patients respond, the drug will be declared as having promising activity.
Drug Administration
Bortezomib (N-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid; CAS No. 179324-69-7) was supplied to investigators by the Division of Cancer Treatment and Diagnosis, National Cancer Institute. Bortezomib for injection was supplied as a lyophilized powder for reconstitution. Each vial contained 3.5 mg of bortezomib and 35 mg mannitol United States Pharmacopeia. Each vial was reconstituted with 3.5 mL normal (0.9%) saline, such that the reconstituted solution contained bortezomib at a concentration of 1 mg/mL. The pH of the reconstituted solution was between 5 and 6. The drug was injected during 3 to 5 seconds into a side arm of a running intravenous infusion of normal saline at 100 mL/h. At the end of the drug infusion, 10 mL of normal saline was infused to flush the line. There was no upper limit on planned therapy, and patients could continue to receive drug as long as there was evidence of clinical benefit without excess toxicity.
Dose Modification
Patients were treated at a dose of 1.5 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 1-week rest period (one cycle). Treatment was delayed for patients whose peripheral blood counts failed to meet the eligibility criteria for re-treatment, and they were re-treated once their counts recovered. Use of antiemetics, erythropoietin, and filgrastim was allowed if deemed necessary by the treating physician. Their use was dictated by standard institutional guidelines. Although rare, in most patients in whom an antiemetic was required, a single oral dose of granisetron was administered.
In patients who developed a grade 3 or 4 nonhematologic toxicity of any sort or grade 4 neutropenic fever or thrombocytopenia, the dose was reduced to 1.3 mg/m2, and then to 1.1 mg/m2 for a repeat episode of toxicity. Patients who experienced persistent nonhematologic toxicity despite this dose reduction were removed from the study. Treatment was delayed until these toxicities resolved to baseline. Dose reductions were also allowed for patients who developed asthenia, anorexia, or neuropathy of any grade, which in the judgment of the treating physician, was believed to be clinically significant and detrimental to the patients' continued involvement on study.
Response Criteria
Response criteria for patients enrolled onto the study followed the guidelines previously reported by Cheson et al.23 All responses were characterized as either complete remission (CR), unconfirmed complete remission (CRu), partial remission (PR), stable disease (SD), or progression of disease (POD). Response criteria for patients with leukemic forms of NHL, including CLL, followed the National Cancer Institute guidelines previously reported by Cheson et al.24 Response was routinely assessed after every two cycles. For patients removed from the study, a 1-month confirmatory scan was performed, and patients were then restaged every 3 months. There was no upper limit on the amount of bortezomib any patient could receive. In general, patients continued participating in the study until one of the following criteria were met: the patient withdrew consent or the patient experienced unacceptable toxicity. If the patient achieved a PR, therapy continued until maximal benefit; if the patient achieved a CR, the patient continued for two cycles beyond CR.
Nerve Conduction Studies
Electrodiagnostic evaluations, including nerve conduction studies and needle electromyography, were completed on select patients. Motor and sensory nerve conduction and needle electromyographic studies were performed and responses recorded using standardized equipment and techniques. Needle electromyography was performed on selected muscles of the upper and or lower extremity and their corresponding paraspinal muscles. Interpretation of the completed electrodiagnostic studies was done by a board-certified electromyographer.
RESULTS
There was a roughly even distribution in sex (54% male patients), with an unintended bias toward a largely white non-Hispanic population (92%). The median age of 63 years approximates the median age for patients with indolent lymphomas in general. The indolent lymphomas represent a vast diversity of biology and different disease subtypes, most of which are represented in this population. Approximately one third of all patients had follicular lymphoma (38%), including grades 1 to 3. Eleven patients (42%) had MCL, whereas three patients (12%) had SLL and two patients (8%) had marginal zone lymphoma. The median number of all prior therapies was three (range, 0 to 5), whereas the median number of prior cytotoxic chemotherapy regimens was also three (range, 0 to 3). All patients (with the exception of the one patient with no history of prior treatment) had been treated with at least one form of an alkylator-based treatment program, whereas only 15% received a purine analog–based regimen. Three patients had undergone prior peripheral-blood stem cell transplantation, and two had received prior radioimmunotherapy (tositumomab and iodine-131 tositumomab or yttrium-90 ibritumomab tiuxetan). These patients did not seem to exhibit any more toxicity than that of other patients participating in the study, and in fact, two of the five attained major remissions (CRu and PR). Fifteen of the 26 patients received prior rituximab as a single agent, with five of those patients receiving two or more courses of antibody therapy. Nine (35%) patients received prior radiotherapy. Only one patient was registered to the study who had received no prior therapy of any sort.
Dose Modifications
In general, the treatment was well tolerated. For the 26 registered patients, a total of 103 cycles of bortezomib were administered, which included 378 doses of the drug. The average number of cycles and doses received per patient was approximately four and 14.5, respectively. There was no difference in the amount of therapy administered to responders or nonresponders (4.2 v 4.3 cycles/patient and 16.3 v 15 doses per patient for responders and nonresponders, respectively). Thirteen patients (50%) missed at least one dose of drug. Among these patients, the median number of doses missed was four. The most common reason for a missed dose was thrombocytopenia, and the bulk of these missed doses occurred early in the study, when the more stringent platelet count requirements were in place (ie, ≥ 100,000/μL). After the modification to platelet count requirements, there have been no missed doses for thrombocytopenia. Missed doses were also attributed to neurotoxicity in four patients (grade 2 to 3 sensory neuropathy), gastrointestinal toxicity in one patient who had bulky intra-abdominal disease that was shrinking on treatment, rash in two patients, and asthenia in three patients. Dose reductions from 1.5 to 1.3 mg/m2 were noted in 14 patients (54%), largely as the result of thrombocytopenia before the protocol revision. Five patients (19%) had additional dose reductions from 1.3 to 1.1 mg/m2. Twelve of the 25 patients (ie, 46%) tolerated the 1.5 mg/m2 dose without significant toxicity or need for dose reduction.
Toxicity
A summary of the toxicity observed during this study is presented in Table 2. Other than thrombocytopenia, there were no other dose-limiting hematologic toxicities. Of note, grade 3 lymphopenia was seen in 14 patients (60%), suggesting intrinsic sensitivity of the lymphoid lineage to the effects of proteasome inhibition. This was not associated with an increase in opportunistic infections, although two patients developed an outbreak of shingles on study. Seven patients developed grade 3 thrombocytopenia. In general, all cytopenias were short lived, and resolved to baseline during the week off therapy. Electrolyte abnormalities including hyponatremia, which was a dose-limiting toxicity in the original phase I study, were also commonly seen among these patients. Three patients experienced hyponatremia (grade 3 or greater), two patients experienced hypokalemia (grade 3 toxicity), and one patient experienced hyperkalemia (grade 3 toxicity). In addition, several patients experienced an unusual rash, which after biopsy revealed a small-vessel necrotizing vasculitis. The rash typically appeared during cycles 3 and 4, approximately during the third or fourth doses of those cycles. The rash resolved during the week of rest from treatment (week 3), and met National Cancer Institute common toxicity criteria for a grade 1 vasculitis. In all cases, the rash was not associated with any adverse sequelae, nor could we document an associated presence of perinuclear antineutrophil cytoplasmic antibody or cytoplasmic antineutrophil cytoplasmic antibody.
Overall, two patients experienced grade 3 sensory neuropathy; one of these patients progressed into a grade 3 sensorimotor neuropathy. A thorough work-up of her condition at the time, including multiple magnetic resonance imaging studies and lumbar punctures to rule out leptomeningeal disease, and an electromyelogram (EMG), were all consistent with a likely pre-existing underlying neurologic disorder. The EMG analysis revealed complex repetitive discharges in both the paraspinal muscles and tongue. The electrophysiologic studies were interpreted as being most consistent with severe motor and sensory axonal polyneuropathy, although this possibly was not attributable to bortezomib. Electrophysiologic evidence for a widespread denervating process affecting motor nerves at all spinal levels and the tongue was also noted. A sural nerve biopsy confirmed marked axonal loss and axonal degeneration.
Response
Table 3 lists the response data from the 26 registered patients; 24 of those patients were assessable for response. Figure 1 is a histogram of the response as a function of the disease subtype and overall best and worse response. Seven of the nine assessable patients with follicular lymphoma achieved objective remissions of their disease, with one CR and one CRu. In all patients, the remissions were confirmed at 1 month, and in all patients, the bulkiness of the disease did not seem to influence response. One patient in PR is still in active follow-up more than 20 months from the end of treatment with bortezomib. She achieved only a 7-month duration of remission from her prior therapy, which was rituximab. In all, 77% of the patients with follicular lymphoma responded to therapy. Five of 10 assessable patients with MCL also achieved major remissions, with four of those patients still in active follow-up. One of these patients achieved a PR lasting about 6 months with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by rituximab. After four cycles of bortezomib, he achieved a major PR, with more than 80% shrinkage of his disease that lasted approximately 19 months. After his response, the protocol was amended to allow patients to be re-treated who achieved a PR or better lasting at least 6 months. On re-treatment, he attained a second PR that lasted approximately 7 months, and has now begun his third course of therapy. At the time of this report, the patient has achieved more than 26 months of remission from single-agent bortezomib after achieving only 6 months of remission from standard CHOP followed by rituximab.
Interestingly, one patient with MCL, who had a prominent leukemic component to his disease and who was scored as having achieved SD, had a dramatic reduction in his leukemic disease after receiving bortezomib. He received four cycles of therapy in total. His pretreatment bone marrow revealed more than 95% involvement with MCL. After treatment with four cycles of bortezomib, his marrow involvement was reduced to approximately 70%, and the WBC and absolute lymphocyte count returned to normal levels. He voluntarily removed himself from study to pursue a syngeneic transplant.
To date, the collective experience in patients with SLL suggests that this particular subtype of NHL is not responsive to bortezomib. All three patients on our study failed to demonstrate any reduction in their total disease burden. In contrast, both patients with nodal marginal zone lymphoma responded rapidly to bortezomib, and although both patients are still in active follow-up, the duration of their responses to date are approximately 8+ (in a previously untreated patient) and 11+ months.
DISCUSSION
Although proteasome inhibition represents a novel target, it by no means is an approach that results in a singular biologic effect. In fact, inhibition of proteasome function produces a wide panoply of biologic effects that can lead to changes in the balance of pro- and antiapoptotic proteins in the mitochondrial membrane,26,27,28 NF-{kappa}B–influenced gene transcription, CAM expression, cytokine production and signaling, and angiogenesis. Although inhibition of the proteasome clearly facilitates dramatic tumor shrinkage, the precise mechanism responsible for this effect in different subtypes of lymphoma is not at all clear. To date, a significant amount of attention has focused on the activity of NF-{kappa}B, which is known to be overexpressed in several lymphomas, including MCL,15 marginal zone lymphomas, and refractory diffuse large B-cell lymphoma.18,19 One under-recognized mechanism of action that may well transcend different diseases is the effect on antiapoptotic proteins. Several lines of evidence have begun to show that inhibition of the 26S proteasome, and in particular, inhibition of the chymotryptic function specifically within the proteasome, results in relatively rapid cytochrome c release (3 to 6 hours), followed by activation of caspases 8 and 9 (about 12 hours later), and caspases 3 and 7 (about 24 hours later), all leading to bcl-2 phosphorylation and cleavage of bcl-2 and PARP.26-28 Other less selective proteasome inhibitors, such as lactacystin and the calpain inhibitors ALLN and ALLM, for example, have not been shown to induce the same set of reactions with regard to cell death signaling. Perhaps most intriguing are a number of studies that have clearly demonstrated that inhibition of the proteasome is selectively cytocidal against malignant cells compared with normal cells.17
The indolent lymphoproliferative malignancies are a diverse group of incurable diseases. The central philosophy in the management of these diseases revolves around consideration of toxicity and the identification of the least cross-resistant agents possible with each successive need for treatment. Hence, because these lymphomas are not curable with the standard treatments available, there is a growing need to identify non–cross-resistant drugs that are active against the indolent lymphomas, which are also minimally myelosuppressive.
The study presented here provides evidence of significant activity of bortezomib in patients with indolent non-Hodgkin's lymphoma, especially patients with follicular lymphoma, marginal zone lymphoma, and MCL. One intriguing observation from this (albeit small) group of patients is the suggestion that the activity of the drug can vary markedly among the different subtypes of lymphoma. The data presented here suggest that follicular and MCL seem to be among the more sensitive subtypes of NHL responsive to proteasome inhibition, whereas SLL is relatively refractory to the drug. The observations in MCL suggest that this drug has significant activity in about half of those patients enrolled onto this study. MCL is a particularly challenging form of NHL to treat; it is characterized by short durations of remission to chemotherapy with poor long-term survival. Published CR rates to conventional chemotherapy programs range from 9% to more than 90%, with an overall survival that typically ranges from 34 to 45 months; anthracycline-based treatment programs offering slight improvement over regimens not containing anthracycline.29-35 On average, the median time to progression is about 12 to 18 months.34
The observations in MCL recently have been corroborated independently by Goy et al.36 In a similarly designed phase II study in patients with any subtype of B-cell neoplasm, and with no limit on the amount of prior therapy, these investigators treated 22 patients with MCL, of whom 20 were assessable for response. Four of these patients achieved a CR after receiving bortezomib, whereas six achieved a PR, with an overall response rate of 50% in MCL (similar to that reported herein). Of six assessable patients with refractory diffuse large B-cell lymphoma, only one achieved a PR. In a third study being conducted by the National Cancer Institute of Canada in patients with only MCL,37 13 patients with zero to two lines of prior therapy were treated with bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. In that study, the overall response rate was approximately 39%, with one patient achieving a CR of nodal-based disease, although residual bone marrow infiltration was still present. That study recently reported that five of the 13 treated patients developed an unusual volume overload syndrome associated by dyspnea and edema—events that were not appreciated in this study or the study reported by Goy et al.36 Although the numbers are small, collectively, the data to date suggest promising activity of bortezomib in patients with MCL, with all responding patients achieving remission of at least 1 month, and at least one patient to date sustaining more than 26 months of remission from this single agent, compared with only 6 months of remission obtained with conventional CHOP followed by rituximab.
Overall, the drug was well tolerated, even at the somewhat higher dose of 1.5 mg/m2, at which about half the patients tolerated the drug without a dose reduction. Present US Food and Drug Administration indications in multiple myeloma recommend a starting dose of 1.3 mg/m2. The higher dose employed in this study antedated the completion of the Summit Trial and US Food and Drug Administration approval, and was used because data from the phase I experience suggested no major adverse toxicities at this dose level (1.5 mg/m2). There was only one grade 4 toxicity (hyponatremia), known to be associated with bortezomib, and several grade 3 toxicities, the most common of which were lymphopenia and thrombocytopenia. Many patients experienced early low-grade sensory neuropathy which resolved spontaneously during the week of rest, although two patients developed grade 3 sensory neuropathy, one of whom went on to develop a grade 3 sensorimotor neuropathy. The electrophysiologic data from the patient who developed grade 3 sensorimotor neuropathy were felt to be most consistent with a severe motor and sensory axonal polyneuropathy. The marked spontaneous activity encountered on EMG suggests that perhaps another neurologic disorder was coexistent or pre-existent, which may have been exacerbated by the bortezomib treatment. To date, no other patient in the database of patients treated with bortezomib has experienced advanced-grade sensorimotor neuropathy. On the basis of the collective experience in lymphoma, there is a suggestion that the incidence of neuropathy may be less than what has been appreciated during the multiple myeloma studies.
Ongoing objectives will focus on determining the individual response rates in the discrete subtypes of indolent NHL. This phase II study has now been expanded to a multicenter collaboration to expedite accrual to these more specific subtypes of lymphoma. In addition, given the single-agent activity in MCL, a large industry-sponsored phase II study has begun, with goals to accrue more than 150 patients with this disease to establish a larger experience regarding the efficacy of bortezomib in patients with relapsed or refractory MCL. At present, it is unclear if there will be clinically significant differences in response between the 1.5 and 1.3 mg/m2 dose levels. Another major area of development relates to the integration of bortezomib into other more conventional chemotherapy regimens. Phase I and II studies are now underway that will explore the integration of bortezomib into rituximab-CHOP; rituximab-cyclophosphamide, vincristine, and prednisone; and various fludarabine-based treatment programs.
One rational drug combination strategy would be to try to exploit the increase in proapoptotic mitochondrial proteins with bortezomib by lowering antiapoptotic proteins with the bcl-2 antisense oblimersen. Such a strategy could theoretically shift the transmembrane mitochondrial potential in a direction that might sensitize tumor cells to conventional chemotherapy drugs. Recent data have demonstrated that the combination of bortezomib and oblimersen in human lymphoma xenograft model in mice with severe combined immunodeficiency resulted in at least additive benefit against a drug-resistant large-cell lymphoma cell line. Even more intriguing was the observation that pretreatment of the tumors markedly sensitized the cells to cyclophosphamide, leading to cures in those animals treated with the triplet combination.38 These types of treatment strategies will provide the basis for future preclinical and clinical studies that attempt to modulate these novel targets in therapeutically meaningful ways. Until the merits of bortezomib in these diseases are clarified in larger multicenter studies, enrollment onto clinical trials with bortezomib is strongly encouraged.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
O.A.O. thanks Mortimer J. Lacher.
NOTES
Supported under an NCI Phase II grant (UO1 CA 69913). O.A.O. is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award and is supported generously by the Werner and Elaine Dannheisser Fund for Research on the Biology of Aging of the Lymphoma Foundation.
O.A.O. is on the Speakers Bureau for Millenium Pharmaceuticals.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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36. Goy A, Hart S, Pro B, et al:. Report of a phase II study of proteasome inhibitor bortezomib (Velcade) in patients with relapsed or refractory indolent or aggressive lymphoma. Blood 102, 2003 (abstr 627)
37. Assouline S, Belch A, Sehn L, et al: A phase II study of bortezomib in patients with mantle cell lymphoma. Blood 102, 2003 (abstr 3358)
38. O'Connor OA, Srinicasan S, Hernandez F, et al: Oblimersen enhances the antitumor activity of bortezomib in multiple myeloma and non-Hodgkin's lymphoma in preclinical models. Proc Am Soc Hematol 2003 (abstr 628)(Owen A. O'Connor, John Wr)
Millennium Pharmaceutical, Cambridge, MA
Drug Development Branch, National Cancer Institute, Bethesda, MD
ABSTRACT
PATIENTS AND METHODS: Patients with indolent and MCL were eligible. Bortezomib was given at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11. Patients were required to have received no more than three prior chemotherapy regimens, with at least 1 month since the prior treatment, 3 months from prior rituximab, and 7 days from prior corticosteroids; absolute neutrophil count more than 1,500/μL (500/μL if documented bone marrow involvement); and platelet count more than 50,000/μL.
RESULTS: Twenty-six patients were registered, of whom 24 were assessable. Ten patients had follicular lymphoma, 11 had MCL, three had small lymphocytic lymphoma (SLL) or chronic lymphocytic leukemia (CLL), and two had marginal zone lymphoma. The overall response rate was 58%, with one complete remission (CR), one unconfirmed CR (CRu), and four partial remissions (PR) among patients with follicular non-Hodgkin's lymphoma (NHL). All responses were durable, lasting from 3 to 24+ months. One patient with MCL achieved a CRu, four achieved a PR, and four had stable disease. One patient with MCL maintained his remission for 19 months. Both patients with marginal zone lymphoma achieved PR lasting 8+ and 11+ months, respectively. Patients with SLL or CLL have yet to respond. Overall, the drug was well tolerated, with only one grade 4 toxicity (hyponatremia). The most common grade 3 toxicities were lymphopenia (n = 14) and thrombocytopenia (n = 7).
CONCLUSION: These data suggest that bortezomib was well tolerated and has significant single-agent activity in patients with certain subtypes of NHL.
INTRODUCTION
The ubiquitin-proteasome pathway plays a critical role in regulating cell cycle control.4 For example, cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors (p21, p27kip1) are temporally degraded during the cell cycle by the ubiquitin-proteasome pathway. Both p21 and p27 can induce cell cycle arrest by inhibiting cdk.11 The ordered degradation of these proteins is required for progression through cell cycle and mitosis. Another target of the ubiquitin-proteasome pathway is the tumor suppressor p53, which acts as a negative regulator of cell growth. p53 is required for the transcription of a number of genes involved in cell cycle control and DNA synthesis, and also plays an important function in apoptosis induced by cellular damage, including ionizing radiation.11
In addition to the regulation of cell cycle control, the ubiquitin-proteasome pathway plays an important role in modulating the important transcription factor NF-{kappa}B. NF-{kappa}B is responsible for the activation of several genes that contribute to the malignant phenotype, including genes that promote cell proliferation, cytokine release, antiapoptosis, and changes in cell surface adhesion molecules. The activity of NF-{kappa}B is tightly regulated by the ubiquitin-proteasome pathway through the accumulation or degradation of I{kappa}B, which binds to and inactivates NF-{kappa}B.4,12 Cell adhesion molecules (CAMs), such as E-selectin, ICAM-1, and VCAM-1, are proteins regulated by NF-{kappa}B and are involved in tumor metastasis and angiogenesis in vivo.13 As such, tumor cell metastasis may well be prevented through the downregulation of NF-{kappa}B–dependent CAM expression. NF-{kappa}B also controls cell viability by regulating both anti- and proapoptotic proteins in the mitochondrial membrane.14 Several lines of preclinical evidence now suggest that inhibiting NF-{kappa}B activation by stabilizing the I{kappa}B protein can render cells more sensitive to environmental stress and cytotoxic agents, ultimately leading to programmed cell death. In addition, many lines of experimental investigation have shown that inhibition of the proteasome, and perhaps even NF-{kappa}B, sensitizes cells to a host of conventional cytotoxic therapies.1,5,7
Although dysregulation of NF-{kappa}B is common to many malignancies, select lymphoproliferative malignancies are often characterized by pathognomonic molecular lesions, which may render them especially vulnerable to inhibitors of this pathway. Specific lesions include the following examples. First, the constitutive overexpression of cyclin D1 (bcl-1, PRAD1) in mantle-cell lymphoma (MCL) is due to the t(11;14)(q13;q32) translocation, which may also be augmented through the constitutive activation of NF-{kappa}B (and AP-1), which has been shown in cell lines of MCL.15 Second, the constitutive overexpression of the antiapoptotic protein bcl-2 in follicular lymphoma due to the t(14;18)(q32;q21) translocation can be mitigated through the inhibition of the 26S proteasome,16,17 which may be attributed in part to inactivated NF-{kappa}B. Third, the constitutive overexpression of NF-{kappa}B is noted in gene array studies of chemotherapy-refractory diffuse large B-cell neoplasms (ie, ABC or activated B-cell lymphomas).18,19 Fourth, the t(1:14)(p22:q32) translocation leading to expression of the bcl-10 gene in mucosa-associated lymphoid tissue lymphomas is believed to involve a caspase recruitment domain–containing protein that activates NF-{kappa}B.20,21
Bortezomib (Velcade, formerly known as PS-341; Millenium Pharmaceuticals, Cambridge, MA) is a dipeptidyl boronic acid inhibitor with high specificity for the 26S proteasome.22 It is the first member of this new class of antitumor agents to be studied in human clinical trials, leading recently to its approval by the US Food and Drug Administration for the treatment of relapsed or refractory multiple myeloma. Phase I and II clinical studies have demonstrated that bortezomib is a well-tolerated agent with minimal hematologic toxicity. In addition, it has been shown that bortezomib is capable of producing a dose-related effect on proteasome inhibition when analyzed 1 hour postinfusion, with little interpatient variability.9,10 We present here the first clinical experience of bortezomib in patients with indolent and mantle cell non-Hodgkin's lymphoma (NHL).
PATIENTS AND METHODS
In addition, patients were required to meet the following criteria within 2 days of study drug administration: an absolute neutrophil count ≥ 1,500/μL (if known lymphomatous involvement of the bone marrow, then absolute neutrophil count > 500/mL); a platelet count of ≥ 50,000/μL for the first dose of every cycle, and more than 30,000/μl for doses delivered on days 4, 8, and 11; a total bilirubin ≤ 1.5x upper institutional limit of normal (ULN); an AST and ALT ≤ 2.5x ULN (4x ULN if the patient had liver involvement); and a creatinine ≤ 1.5x ULN. Initially, patients were required to have a platelet count ≥ 100,000/μL, but these criteria were modified downward given the absence of bleeding complications and the realization that many patients were unnecessarily missing doses secondary to the high cutoff value. Patients were excluded if they were pregnant; had evidence of intracranial disease; had major surgery within 4 weeks of study drug administration; had uncontrolled illness including active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, a myocardial infarction, or cerebrovascular accident within 6 months of study enrollment; had known HIV disease; or had a psychiatric illness that would limit compliance with study requirements.
Study Design
This was a single-center, single-agent phase II study of bortezomib in patients with relapsed, refractory, or untreated indolent NHL and MCL. The major objectives of the study were to determine the frequency and duration of complete and partial response for patients with indolent lymphoproliferative disorders treated with bortezomib. The study used a Simon two-stage design. Initially, 18 patients were enrolled onto the first stage. If no more than two patients responded, the trial would have been terminated. If at least three patients responded, then up to 35 patients could be enrolled. These statistics were predicated on the assumption that should 20% of patients respond, the drug will be declared as having promising activity.
Drug Administration
Bortezomib (N-pyrazinecarbonyl-L-phenylalanine-L-leucine boronic acid; CAS No. 179324-69-7) was supplied to investigators by the Division of Cancer Treatment and Diagnosis, National Cancer Institute. Bortezomib for injection was supplied as a lyophilized powder for reconstitution. Each vial contained 3.5 mg of bortezomib and 35 mg mannitol United States Pharmacopeia. Each vial was reconstituted with 3.5 mL normal (0.9%) saline, such that the reconstituted solution contained bortezomib at a concentration of 1 mg/mL. The pH of the reconstituted solution was between 5 and 6. The drug was injected during 3 to 5 seconds into a side arm of a running intravenous infusion of normal saline at 100 mL/h. At the end of the drug infusion, 10 mL of normal saline was infused to flush the line. There was no upper limit on planned therapy, and patients could continue to receive drug as long as there was evidence of clinical benefit without excess toxicity.
Dose Modification
Patients were treated at a dose of 1.5 mg/m2 twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 1-week rest period (one cycle). Treatment was delayed for patients whose peripheral blood counts failed to meet the eligibility criteria for re-treatment, and they were re-treated once their counts recovered. Use of antiemetics, erythropoietin, and filgrastim was allowed if deemed necessary by the treating physician. Their use was dictated by standard institutional guidelines. Although rare, in most patients in whom an antiemetic was required, a single oral dose of granisetron was administered.
In patients who developed a grade 3 or 4 nonhematologic toxicity of any sort or grade 4 neutropenic fever or thrombocytopenia, the dose was reduced to 1.3 mg/m2, and then to 1.1 mg/m2 for a repeat episode of toxicity. Patients who experienced persistent nonhematologic toxicity despite this dose reduction were removed from the study. Treatment was delayed until these toxicities resolved to baseline. Dose reductions were also allowed for patients who developed asthenia, anorexia, or neuropathy of any grade, which in the judgment of the treating physician, was believed to be clinically significant and detrimental to the patients' continued involvement on study.
Response Criteria
Response criteria for patients enrolled onto the study followed the guidelines previously reported by Cheson et al.23 All responses were characterized as either complete remission (CR), unconfirmed complete remission (CRu), partial remission (PR), stable disease (SD), or progression of disease (POD). Response criteria for patients with leukemic forms of NHL, including CLL, followed the National Cancer Institute guidelines previously reported by Cheson et al.24 Response was routinely assessed after every two cycles. For patients removed from the study, a 1-month confirmatory scan was performed, and patients were then restaged every 3 months. There was no upper limit on the amount of bortezomib any patient could receive. In general, patients continued participating in the study until one of the following criteria were met: the patient withdrew consent or the patient experienced unacceptable toxicity. If the patient achieved a PR, therapy continued until maximal benefit; if the patient achieved a CR, the patient continued for two cycles beyond CR.
Nerve Conduction Studies
Electrodiagnostic evaluations, including nerve conduction studies and needle electromyography, were completed on select patients. Motor and sensory nerve conduction and needle electromyographic studies were performed and responses recorded using standardized equipment and techniques. Needle electromyography was performed on selected muscles of the upper and or lower extremity and their corresponding paraspinal muscles. Interpretation of the completed electrodiagnostic studies was done by a board-certified electromyographer.
RESULTS
There was a roughly even distribution in sex (54% male patients), with an unintended bias toward a largely white non-Hispanic population (92%). The median age of 63 years approximates the median age for patients with indolent lymphomas in general. The indolent lymphomas represent a vast diversity of biology and different disease subtypes, most of which are represented in this population. Approximately one third of all patients had follicular lymphoma (38%), including grades 1 to 3. Eleven patients (42%) had MCL, whereas three patients (12%) had SLL and two patients (8%) had marginal zone lymphoma. The median number of all prior therapies was three (range, 0 to 5), whereas the median number of prior cytotoxic chemotherapy regimens was also three (range, 0 to 3). All patients (with the exception of the one patient with no history of prior treatment) had been treated with at least one form of an alkylator-based treatment program, whereas only 15% received a purine analog–based regimen. Three patients had undergone prior peripheral-blood stem cell transplantation, and two had received prior radioimmunotherapy (tositumomab and iodine-131 tositumomab or yttrium-90 ibritumomab tiuxetan). These patients did not seem to exhibit any more toxicity than that of other patients participating in the study, and in fact, two of the five attained major remissions (CRu and PR). Fifteen of the 26 patients received prior rituximab as a single agent, with five of those patients receiving two or more courses of antibody therapy. Nine (35%) patients received prior radiotherapy. Only one patient was registered to the study who had received no prior therapy of any sort.
Dose Modifications
In general, the treatment was well tolerated. For the 26 registered patients, a total of 103 cycles of bortezomib were administered, which included 378 doses of the drug. The average number of cycles and doses received per patient was approximately four and 14.5, respectively. There was no difference in the amount of therapy administered to responders or nonresponders (4.2 v 4.3 cycles/patient and 16.3 v 15 doses per patient for responders and nonresponders, respectively). Thirteen patients (50%) missed at least one dose of drug. Among these patients, the median number of doses missed was four. The most common reason for a missed dose was thrombocytopenia, and the bulk of these missed doses occurred early in the study, when the more stringent platelet count requirements were in place (ie, ≥ 100,000/μL). After the modification to platelet count requirements, there have been no missed doses for thrombocytopenia. Missed doses were also attributed to neurotoxicity in four patients (grade 2 to 3 sensory neuropathy), gastrointestinal toxicity in one patient who had bulky intra-abdominal disease that was shrinking on treatment, rash in two patients, and asthenia in three patients. Dose reductions from 1.5 to 1.3 mg/m2 were noted in 14 patients (54%), largely as the result of thrombocytopenia before the protocol revision. Five patients (19%) had additional dose reductions from 1.3 to 1.1 mg/m2. Twelve of the 25 patients (ie, 46%) tolerated the 1.5 mg/m2 dose without significant toxicity or need for dose reduction.
Toxicity
A summary of the toxicity observed during this study is presented in Table 2. Other than thrombocytopenia, there were no other dose-limiting hematologic toxicities. Of note, grade 3 lymphopenia was seen in 14 patients (60%), suggesting intrinsic sensitivity of the lymphoid lineage to the effects of proteasome inhibition. This was not associated with an increase in opportunistic infections, although two patients developed an outbreak of shingles on study. Seven patients developed grade 3 thrombocytopenia. In general, all cytopenias were short lived, and resolved to baseline during the week off therapy. Electrolyte abnormalities including hyponatremia, which was a dose-limiting toxicity in the original phase I study, were also commonly seen among these patients. Three patients experienced hyponatremia (grade 3 or greater), two patients experienced hypokalemia (grade 3 toxicity), and one patient experienced hyperkalemia (grade 3 toxicity). In addition, several patients experienced an unusual rash, which after biopsy revealed a small-vessel necrotizing vasculitis. The rash typically appeared during cycles 3 and 4, approximately during the third or fourth doses of those cycles. The rash resolved during the week of rest from treatment (week 3), and met National Cancer Institute common toxicity criteria for a grade 1 vasculitis. In all cases, the rash was not associated with any adverse sequelae, nor could we document an associated presence of perinuclear antineutrophil cytoplasmic antibody or cytoplasmic antineutrophil cytoplasmic antibody.
Overall, two patients experienced grade 3 sensory neuropathy; one of these patients progressed into a grade 3 sensorimotor neuropathy. A thorough work-up of her condition at the time, including multiple magnetic resonance imaging studies and lumbar punctures to rule out leptomeningeal disease, and an electromyelogram (EMG), were all consistent with a likely pre-existing underlying neurologic disorder. The EMG analysis revealed complex repetitive discharges in both the paraspinal muscles and tongue. The electrophysiologic studies were interpreted as being most consistent with severe motor and sensory axonal polyneuropathy, although this possibly was not attributable to bortezomib. Electrophysiologic evidence for a widespread denervating process affecting motor nerves at all spinal levels and the tongue was also noted. A sural nerve biopsy confirmed marked axonal loss and axonal degeneration.
Response
Table 3 lists the response data from the 26 registered patients; 24 of those patients were assessable for response. Figure 1 is a histogram of the response as a function of the disease subtype and overall best and worse response. Seven of the nine assessable patients with follicular lymphoma achieved objective remissions of their disease, with one CR and one CRu. In all patients, the remissions were confirmed at 1 month, and in all patients, the bulkiness of the disease did not seem to influence response. One patient in PR is still in active follow-up more than 20 months from the end of treatment with bortezomib. She achieved only a 7-month duration of remission from her prior therapy, which was rituximab. In all, 77% of the patients with follicular lymphoma responded to therapy. Five of 10 assessable patients with MCL also achieved major remissions, with four of those patients still in active follow-up. One of these patients achieved a PR lasting about 6 months with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy followed by rituximab. After four cycles of bortezomib, he achieved a major PR, with more than 80% shrinkage of his disease that lasted approximately 19 months. After his response, the protocol was amended to allow patients to be re-treated who achieved a PR or better lasting at least 6 months. On re-treatment, he attained a second PR that lasted approximately 7 months, and has now begun his third course of therapy. At the time of this report, the patient has achieved more than 26 months of remission from single-agent bortezomib after achieving only 6 months of remission from standard CHOP followed by rituximab.
Interestingly, one patient with MCL, who had a prominent leukemic component to his disease and who was scored as having achieved SD, had a dramatic reduction in his leukemic disease after receiving bortezomib. He received four cycles of therapy in total. His pretreatment bone marrow revealed more than 95% involvement with MCL. After treatment with four cycles of bortezomib, his marrow involvement was reduced to approximately 70%, and the WBC and absolute lymphocyte count returned to normal levels. He voluntarily removed himself from study to pursue a syngeneic transplant.
To date, the collective experience in patients with SLL suggests that this particular subtype of NHL is not responsive to bortezomib. All three patients on our study failed to demonstrate any reduction in their total disease burden. In contrast, both patients with nodal marginal zone lymphoma responded rapidly to bortezomib, and although both patients are still in active follow-up, the duration of their responses to date are approximately 8+ (in a previously untreated patient) and 11+ months.
DISCUSSION
Although proteasome inhibition represents a novel target, it by no means is an approach that results in a singular biologic effect. In fact, inhibition of proteasome function produces a wide panoply of biologic effects that can lead to changes in the balance of pro- and antiapoptotic proteins in the mitochondrial membrane,26,27,28 NF-{kappa}B–influenced gene transcription, CAM expression, cytokine production and signaling, and angiogenesis. Although inhibition of the proteasome clearly facilitates dramatic tumor shrinkage, the precise mechanism responsible for this effect in different subtypes of lymphoma is not at all clear. To date, a significant amount of attention has focused on the activity of NF-{kappa}B, which is known to be overexpressed in several lymphomas, including MCL,15 marginal zone lymphomas, and refractory diffuse large B-cell lymphoma.18,19 One under-recognized mechanism of action that may well transcend different diseases is the effect on antiapoptotic proteins. Several lines of evidence have begun to show that inhibition of the 26S proteasome, and in particular, inhibition of the chymotryptic function specifically within the proteasome, results in relatively rapid cytochrome c release (3 to 6 hours), followed by activation of caspases 8 and 9 (about 12 hours later), and caspases 3 and 7 (about 24 hours later), all leading to bcl-2 phosphorylation and cleavage of bcl-2 and PARP.26-28 Other less selective proteasome inhibitors, such as lactacystin and the calpain inhibitors ALLN and ALLM, for example, have not been shown to induce the same set of reactions with regard to cell death signaling. Perhaps most intriguing are a number of studies that have clearly demonstrated that inhibition of the proteasome is selectively cytocidal against malignant cells compared with normal cells.17
The indolent lymphoproliferative malignancies are a diverse group of incurable diseases. The central philosophy in the management of these diseases revolves around consideration of toxicity and the identification of the least cross-resistant agents possible with each successive need for treatment. Hence, because these lymphomas are not curable with the standard treatments available, there is a growing need to identify non–cross-resistant drugs that are active against the indolent lymphomas, which are also minimally myelosuppressive.
The study presented here provides evidence of significant activity of bortezomib in patients with indolent non-Hodgkin's lymphoma, especially patients with follicular lymphoma, marginal zone lymphoma, and MCL. One intriguing observation from this (albeit small) group of patients is the suggestion that the activity of the drug can vary markedly among the different subtypes of lymphoma. The data presented here suggest that follicular and MCL seem to be among the more sensitive subtypes of NHL responsive to proteasome inhibition, whereas SLL is relatively refractory to the drug. The observations in MCL suggest that this drug has significant activity in about half of those patients enrolled onto this study. MCL is a particularly challenging form of NHL to treat; it is characterized by short durations of remission to chemotherapy with poor long-term survival. Published CR rates to conventional chemotherapy programs range from 9% to more than 90%, with an overall survival that typically ranges from 34 to 45 months; anthracycline-based treatment programs offering slight improvement over regimens not containing anthracycline.29-35 On average, the median time to progression is about 12 to 18 months.34
The observations in MCL recently have been corroborated independently by Goy et al.36 In a similarly designed phase II study in patients with any subtype of B-cell neoplasm, and with no limit on the amount of prior therapy, these investigators treated 22 patients with MCL, of whom 20 were assessable for response. Four of these patients achieved a CR after receiving bortezomib, whereas six achieved a PR, with an overall response rate of 50% in MCL (similar to that reported herein). Of six assessable patients with refractory diffuse large B-cell lymphoma, only one achieved a PR. In a third study being conducted by the National Cancer Institute of Canada in patients with only MCL,37 13 patients with zero to two lines of prior therapy were treated with bortezomib at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11. In that study, the overall response rate was approximately 39%, with one patient achieving a CR of nodal-based disease, although residual bone marrow infiltration was still present. That study recently reported that five of the 13 treated patients developed an unusual volume overload syndrome associated by dyspnea and edema—events that were not appreciated in this study or the study reported by Goy et al.36 Although the numbers are small, collectively, the data to date suggest promising activity of bortezomib in patients with MCL, with all responding patients achieving remission of at least 1 month, and at least one patient to date sustaining more than 26 months of remission from this single agent, compared with only 6 months of remission obtained with conventional CHOP followed by rituximab.
Overall, the drug was well tolerated, even at the somewhat higher dose of 1.5 mg/m2, at which about half the patients tolerated the drug without a dose reduction. Present US Food and Drug Administration indications in multiple myeloma recommend a starting dose of 1.3 mg/m2. The higher dose employed in this study antedated the completion of the Summit Trial and US Food and Drug Administration approval, and was used because data from the phase I experience suggested no major adverse toxicities at this dose level (1.5 mg/m2). There was only one grade 4 toxicity (hyponatremia), known to be associated with bortezomib, and several grade 3 toxicities, the most common of which were lymphopenia and thrombocytopenia. Many patients experienced early low-grade sensory neuropathy which resolved spontaneously during the week of rest, although two patients developed grade 3 sensory neuropathy, one of whom went on to develop a grade 3 sensorimotor neuropathy. The electrophysiologic data from the patient who developed grade 3 sensorimotor neuropathy were felt to be most consistent with a severe motor and sensory axonal polyneuropathy. The marked spontaneous activity encountered on EMG suggests that perhaps another neurologic disorder was coexistent or pre-existent, which may have been exacerbated by the bortezomib treatment. To date, no other patient in the database of patients treated with bortezomib has experienced advanced-grade sensorimotor neuropathy. On the basis of the collective experience in lymphoma, there is a suggestion that the incidence of neuropathy may be less than what has been appreciated during the multiple myeloma studies.
Ongoing objectives will focus on determining the individual response rates in the discrete subtypes of indolent NHL. This phase II study has now been expanded to a multicenter collaboration to expedite accrual to these more specific subtypes of lymphoma. In addition, given the single-agent activity in MCL, a large industry-sponsored phase II study has begun, with goals to accrue more than 150 patients with this disease to establish a larger experience regarding the efficacy of bortezomib in patients with relapsed or refractory MCL. At present, it is unclear if there will be clinically significant differences in response between the 1.5 and 1.3 mg/m2 dose levels. Another major area of development relates to the integration of bortezomib into other more conventional chemotherapy regimens. Phase I and II studies are now underway that will explore the integration of bortezomib into rituximab-CHOP; rituximab-cyclophosphamide, vincristine, and prednisone; and various fludarabine-based treatment programs.
One rational drug combination strategy would be to try to exploit the increase in proapoptotic mitochondrial proteins with bortezomib by lowering antiapoptotic proteins with the bcl-2 antisense oblimersen. Such a strategy could theoretically shift the transmembrane mitochondrial potential in a direction that might sensitize tumor cells to conventional chemotherapy drugs. Recent data have demonstrated that the combination of bortezomib and oblimersen in human lymphoma xenograft model in mice with severe combined immunodeficiency resulted in at least additive benefit against a drug-resistant large-cell lymphoma cell line. Even more intriguing was the observation that pretreatment of the tumors markedly sensitized the cells to cyclophosphamide, leading to cures in those animals treated with the triplet combination.38 These types of treatment strategies will provide the basis for future preclinical and clinical studies that attempt to modulate these novel targets in therapeutically meaningful ways. Until the merits of bortezomib in these diseases are clarified in larger multicenter studies, enrollment onto clinical trials with bortezomib is strongly encouraged.
Authors' Disclosures of Potential Conflicts of Interest
Acknowledgment
O.A.O. thanks Mortimer J. Lacher.
NOTES
Supported under an NCI Phase II grant (UO1 CA 69913). O.A.O. is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award and is supported generously by the Werner and Elaine Dannheisser Fund for Research on the Biology of Aging of the Lymphoma Foundation.
O.A.O. is on the Speakers Bureau for Millenium Pharmaceuticals.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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