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Originally published as JCO Early Release 10.1200/JCO.2005.04.6789 on April 10 2006 © 2006 American Society of Clinical Oncology. Bortezomib Therapy in Patients With Relapsed or Refractory Lymphoma: Potential Correlation of In Vitro Sensitivity and Tumor Necrosis Factor Alpha Response With Clinical Activity
From the Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital; Cancer Research UK Translational Oncology Laboratory, Barts and The London, Queen Mary's Medical School, London; Cancer Research UK Clinical Centre, Southampton General Hospital, Southampton; Cancer Research UK Department of Medical Oncology, Christie Hospital, Manchester, United Kingdom; and Millennium Pharmaceuticals Inc, Cambridge, MA. Address reprint requests to T. Andrew Lister, MD, FRCP, FRCPath, Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, W Smithfield, London, EC1A 7BE, United Kingdom; e-mail: andrew.lister{at}cancer.org.uk
PURPOSE: To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures.
PATIENTS AND METHODS: Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-
RESULTS: Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-
CONCLUSION: Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-
The non-Hodgkin's lymphomas (NHLs) are a heterogenous group of lymphoid malignancies that showed an increasing incidence until the 1990s and pose a number of treatment dilemmas.1 Chemotherapy and radiotherapy are initially effective, but relapse is common, and patients die of chemoresistant disease.2,3 Patients with mantle cell lymphoma (MCL) have a particularly poor outcome, with a median survival of approximately 3 years.4,5 Therefore, new therapies are required, and therapies with novel mechanisms of action are particularly desirable.
Constitutive nuclear factor-kappa B (NF-
This was a multicenter, single-arm, phase II study with the primary end point of efficacy defined as response rate. Biologic activity examining plasma cytokine levels and in vitro activity of bortezomib were also measured. Permission to conduct the clinical study and laboratory analyses was obtained from individual institutional review boards and research ethics committees, and all patients provided written, informed consent before study entry.
Patient Eligibility
Patients were excluded if they had received cytotoxic chemotherapy or radiotherapy to the index lesion within the previous 4 weeks and antibody therapy within the previous 8 weeks; had
Treatment
Evaluation of Toxicity and Dose Modification
Response Evaluation
In Vitro Activity of Bortezomib in Patient Samples
Cytokine Analysis
Statistical Analysis
Patient Characteristics Fifty-one patients were enrolled. Two patients were treated as protocol exceptions, with platelet counts of less than 30 x 109/L as a result of bone marrow involvement. Clinical characteristics are listed in Table 1. Patients were heavily pretreated, having received a median of four prior therapies. Three patients withdrew from the study; two withdrew after three doses of the first cycle, and one withdrew after one dose of the second cycle; all of these patients withdrew because of lack of symptomatic improvement. Therefore, 48 patients were assessable for response, and 51 patients were assessable for toxicity.
Treatment Forty-two patients (84%) received two or more cycles of bortezomib. Six patients discontinued therapy during the first or second cycle of therapy as a result of clinical progression. In total, 193 cycles of therapy were administered, with a median of four cycles per patient (range, one to eight cycles).
Toxicity Treatment was reasonably tolerated, and toxicity was manageable (Table 2). The most common toxicity was thrombocytopenia, which was grade 3 or 4 in 22 patients (43%). There were no bleeding complications, and the platelet count almost always recovered in time for the next treatment cycle. Grade 4 neutropenia was seen in three patients with bone marrow involvement, two of whom were neutropenic before treatment. Fourteen patients (27%) experienced grade 2 peripheral sensory disturbance or neuropathic pain, primarily involving the lower limbs. Three patients developed grade 3 or 4 neuropathy; in one patient, a painful grade 3 sensory neuropathy developed rapidly during the fourth cycle of treatment and required discontinuation of therapy. An electromyelogram revealed severe sensory axonal polyneuropathy. Five patients developed an autonomic neuropathy, which was grade 3 in one patient and preceded development of a grade 3 painful neuropathy of the feet. The median onset of neurologic adverse effects requiring dose omission or reduction occurred during cycle 4 of treatment. In the majority of patients, it resolved after 3 to 6 months; however, two patients were left with symptoms 1 year after completing therapy. Other toxicity included cumulative fatigue (grade 3 or 4 in 10 patients, 20%); grade 3 rash, resulting in discontinuation of treatment in one patient; and grade 3 breathlessness without cardiac failure in one patient. Respiratory function tests revealed a reduced carbon monoxide transfer factor (diffusing capacity), and the symptoms resolved on dose reduction.
Dose Delay and Modification Nineteen patients had at least one dose omission, and dose delay was required in seven patients. Fourteen patients (25%) required dose reduction from 1.3 mg/m2 as a result of neuropathy (n = 6), thrombocytopenia (n = 2), neuropathy and fatigue (n = 1), fatigue (n = 2), neutropenia (n = 1), transaminitis (n = 1), and hypotension (n = 1). Three patients required further dose reduction to 0.7 mg/m2 as a result of ongoing neuropathy (n = 2) and thrombocytopenia (n = 1). Four responding patients stopped treatment as a result of the following toxicities: grade 3 sensory neuropathy after four cycles (n = 1), symptomatic postural hypotension after six cycles (n = 1), and grade 2 neuropathy and fatigue after five and six cycles, respectively (n = 2).
Response to Treatment
Investigation of the Effect of Bortezomib on Lymphoma Primary Cultures Effect of bortezomib and doxorubicin on cell viability in primary cultures. In vitro sensitivity was determined in 17 primary culture samples (nine MCLs and eight FLs), eight of which were from patients entered onto this phase II study. The median percent B cells (CD19+) before and after the 72-hour culture period was 73% (range, 45% to 89%) and 78% (range, 63% to 85%), respectively. A dose-dependent reduction in cell viability in response to bortezomib was observed, with median EC50 values of 209 nmol/L in MCL and 1,311 nmol/L in FL (P = .07; Fig 1A). There was no correlation between the prior number of therapies and in vitro response to bortezomib.
Primary culture cells were markedly less sensitive to doxorubicin than bortezomib, and activity was comparable in MCL and FL samples (median EC50, 5,200 v 8,000 nmol/L; P = .29; Fig 1B). Four samples (two MCLs and two FLs) showed little decrease in viability with doxorubicin, such that EC50 concentration could not be calculated in these samples. Correlation of in vitro bortezomib sensitivity with clinical activity. For the eight samples described earlier from patients treated on this clinical study (six MCLs and two FLs), EC50 values for in vitro bortezomib activity correlated with clinical response in all patients (EC50, 115 to 179 nmol/L v 377 to 2,516 nmol/L in responding and nonresponding patients, respectively; P = .03; Fig 2). Three patients with an EC50 of less than 120 nmol/L achieved a PR, whereas one patient with an intermediate sensitivity (179 nmol/L) achieved a PR after four cycles, but after a dose delay and two dose reductions, this patient experienced progression at the end of therapy. All four patients with an in vitro EC50 of more than 377 nmol/L experienced progression on therapy.
Effect of Bortezomib on Plasma Cytokines Plasma cytokines were measured in 17 patients with MCL, all of whom were in the clinical trial and six of whom responded to therapy. Before therapy, TNF-  was detectable in all patients, with a median value of 22.9 pg/mL (range, 0.96 to 148 pg/mL), and median IL-6 was 11.5 pg/mL (range 1.7 to 151 pg/mL). There was no significant difference between pretreatment levels of either cytokine in responding and nonresponding patients (Fig 3).
Plasma cytokine levels measured at 1, 2, 4, and 24 hours after the first dose of bortezomib in 14 patients showed no consistent changes. TNF- initially changed little after bortezomib administration, whereas IL-6 levels increased in several patients before returning to near baseline levels by 24 hours (data not shown). Prolonged treatment with bortezomib resulted in a progressive reduction in TNF- in all six patients who responded to therapy, with a median reduction of 98% (to < 1 pg/mL in four patients) at the radiologic assessment after four cycles of therapy. In contrast, there was only a 38% reduction in TNF- in six nonresponders who remained on therapy for four cycles of treatment (P = .07; Fig 3). One responder experienced progression clinically at the end of the eighth cycle of therapy, with a corresponding increase in plasma TNF-. Bortezomib therapy did not have a consistent effect on IL-6.
This multicenter phase II trial has combined both clinical and laboratory end points in the evaluation of a novel therapy for lymphoma. In the clinical trial, bortezomib demonstrated the most encouraging efficacy in patients with MCL, with responses also observed in FL, WM, and HD. These results are in keeping with other recently published studies and preliminary analyses (Table 4) demonstrating that MCL seems most sensitive to the effects of bortezomib, with the highest overall response rate and complete response/unconfirmed complete response rate.21,26,27 Comparison of the data with other studies in MCL and FL suggests that the superficially less impressive responses observed in this study may be accounted for by the lower dose of bortezomib used and a more heavily pretreated patient population.
Two of five assessable patients with WM achieved a greater than 50% reduction in M band, but there was no change in bone marrow infiltration, and bortezomib was not of clinical benefit to these patients. However, bortezomib does demonstrate evidence of activity in this disease, and our results are in keeping with other preliminary results.28,31 A response was also observed in one of five patients with HD, but combined data from this study and the other studies examining the effect of bortezomib in HD as well as DLBCL suggest that it is unlikely that bortezomib will benefit such heavily pretreated patients as a single agent, despite evidence for a role of NF-  B in mediating HD and activated B-cell like type DLBCL cell survival.12,14,21,29 Its role in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab chemotherapy is currently being assessed in a phase II study in patients with DLBCL. The toxicities were modest and generally manageable. The most common grade 3 to 4 toxicity was thrombocytopenia, which occurred in 43% of patients at day 11 of therapy. The incidence of peripheral neuropathy was similar to that reported by others, with grade 2 toxicity experienced in 14 patients (28%) and grade 3 toxicity experienced in three patients (6%) and with an autonomic component in five patients. There is insufficient evidence to state that the incidence of neuropathy is lower in lymphoma, and all patients receiving bortezomib should be closely monitored for the development of symptoms.21 Other significant toxicities included cumulative fatigue, which was comparable to other recent reports, and grade 3 breathlessness in one patient that improved on dose reduction. The major laboratory end point of this study was the determination of in vitro sensitivity to bortezomib in patients who went on to receive the drug in the context of a phase II clinical trial, thus generating in vitro and in vivo sensitivity data in the same patient. Although the number of trial patients in whom this was possible is small, the results are intriguing in that the in vitro sensitivity predicted the clinical response to the drug in all patients. Additionally, a difference in in vitro sensitivity was demonstrated between MCL and FL samples. This was not a function of the culture system because sensitivity to doxorubicin was comparable between both subsets of lymphoma. The primary samples studied were obtained from clearly involved lymph nodes by excisional biopsy or from circulating blast cells (n = 6, requiring leukapheresis in four samples), with median percent CD19+ cells before and after culture of 73% and 78%, respectively, which suggests that the majority of cells cultured were lymphoma cells. This assay has now been reported in other drug development studies, although not alongside clinical data with the same drug.30 It is noteworthy that normal lymphocytes are less sensitive to proteasome inhibition than chronic lymphatic leukemia–derived lymphocytes, suggesting that low in vitro EC50 values, reflecting sensitivity to bortezomib, are not a result of normal cell contamination.32 These in vitro data provide further evidence of a differential sensitivity between MCL and FL in line with that observed in the clinical trials. Because the time to response also seems to differ (median of 5 weeks of treatment in MCL compared with a median of 11 weeks of treatment in FL), it is likely that bortezomib induces cell death by different mechanisms in these lymphomas.25
Patients with NHL with high pretreatment TNF- In conclusion, bortezomib demonstrates most encouraging efficacy in patients with MCL, although evidence of efficacy in FL, HD, and WM is also demonstrated. MCL primary cultures demonstrate greater sensitivity to bortezomib than FL, which substantiates clinical findings and suggests that the mechanism by which proteasome inhibition results in cell death may be different in these illnesses. It remains to be determined what the role of bortezomib is in the treatment of lymphomas and with which other agents it may most effectively be combined.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C)
We thank the patients who agreed to participate in this clinical trial, all the doctors and nurses who cared for them, and Cancer Research UK for continued support.
Supported by Cancer Research UK and Millennium Pharmaceuticals Inc, Cambridge, MA. Presented in part at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 3-7, 2004; and 9th International Conference on Malignant Lymphoma, Lugano, Switzerland, June 8-11, 2005. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Clin Cancer Res 9:1145-1154, 2003 19. 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 20. O'Connor OA, Wright J, Moskowitz C, et al: Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol 23:676-684, 2005 21. Goy A, Younes A, McLaughlin P, et al: Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. J Clin Oncol 23:667-675, 2005 22. Weber D, Treon SP, Emmanouilides C, et al: Uniform response criteria in Waldenstrom's macroglobulinemia: Consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol 30:127-131, 2003[CrossRef][Medline] 23. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2, creatinine clearance of more than 30 mL/min, bidimensionally measurable disease by computed tomography, life expectancy of 3 months, hemoglobin more than 8.0 g/dL, neutrophils more than 1.0 x 109/L (> 0.5 x 109/L if bone marrow involvement), and platelets more than 30 x 109/L within 14 days before enrollment. A measurable immunoglobulin M paraprotein was required for patients with WM. There was no limit on the number of previous cytotoxic regimens including myeloablative therapy or immunotherapy. 
grade 2 peripheral neuropathy, a cardiac event within 6 months, active infection, known HIV positivity, or other primary malignancy (other than squamous or basal cell skin cancer or cervical cancer in situ) diagnosed within 5 years; or were pregnant or breastfeeding. 
