Originally published as JCO Early Release 10.1200/JCO.2005.13.466 on June 27 2005

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Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma

Thomas E. Witzig, Susan M. Geyer, Irene Ghobrial, David J. Inwards, Rafael Fonseca, Paul Kurtin, Stephen M. Ansell, Ronnie Luyun, Patrick J. Flynn, Roscoe F. Morton, Shaker R. Dakhil, Howard Gross, Scott H. Kaufmann

From the Mayo Clinic College of Medicine and Mayo Foundation, Rochester, MN; Scottsdale CCOP, Scottsdale, AZ; Carle Cancer Center CCOP, Urbana, IL; Metro-Minnesota Community Clinical Oncology Program, St Louis Park, MN; Iowa Oncology Research Association CCOP, Des Moines, IA; Wichita Community Clinical Oncology Program, Wichita, KS; and Hematology & Oncology of Dayton Inc, Dayton, OH

Address reprint requests to Thomas E. Witzig, MD, Mayo Clinic, Stabile 628, 200 First St SW, Rochester, MN 55905; e-mail: witzig{at}mayo.edu.

	ABSTRACT

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

 
PURPOSE: Mantle cell lymphoma (MCL) is characterized by a t(11;14) resulting in overexpression of cyclin D1 messenger RNA. This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL.

PATIENTS AND METHODS: Patients with relapsed or refractory MCL were eligible to receive temsirolimus 250 mg intravenously every week as a single agent. Patients with a tumor response after six cycles were eligible to continue drug for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance.

RESULTS: Thirty-five patients were enrolled and were assessable for toxicity; one patient had MCL by histology but was cyclin D1 negative and was ineligible for efficacy. The median age was 70 years (range, 38 to 89 years), 91% were stage 4, and 69% had two or more extranodal sites. Patients had received a median of three prior therapies (range, one to 11), and 54% were refractory to the last treatment. The overall response rate was 38% (13 of 34 patients; 90% CI, 24% to 54%) with one complete response (3%) and 12 partial responses (35%). The median time-to-progression in all patients was 6.5 months (95% CI, 2.9 to 8.3 months), and the duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). Hematologic toxicities were the most common, with 71% (25 of 35 patients) having grade 3 and 11% (four of 35 patients) having grade 4 toxicities observed. Thrombocytopenia was the most frequent cause of dose reductions but was of short duration, typically resolving within 1 week.

CONCLUSIONS: Single-agent temsirolimus has substantial antitumor activity in relapsed MCL. This study demonstrates that agents that selectively target cellular pathways dysregulated in MCL cells can produce therapeutic benefit. Further studies of this agent in MCL and other lymphoid malignancies are warranted.

	INTRODUCTION

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

 
Mantle cell lymphoma (MCL) is an incurable, aggressive B-cell non-Hodgkin's lymphoma (NHL) that represents approximately 8% of cases of NHL. The disease usually presents in an advanced stage (III or IV), and involvement of extranodal sites such as the gut, bone marrow, and peripheral blood are common. There is a male predominance, and most patients are older adults. The characteristic tumor cell immunophenotype is CD20+, CD10–, CD5+, and CD23–, with monoclonal light chain expression on the cell surface. MCL is a unique subtype in that the tumor cells have a t(11;14)(q13;q32) chromosomal translocation that juxtaposes the cyclin D1 gene on chromosome 11 to the immunoglobulin heavy chain enhancer region on chromosome 14.^1-3 The transcription enhancers on 14q32, now linked to the cyclin D1 gene, result in the characteristic overexpression of cyclin D1 in the MCL tumor cells.

There is currently no standard therapy for newly diagnosed or relapsed MCL. Many regimens have been demonstrated to be highly active in producing responses,^4-17 but relapse typically occurs, and patients usually die of their disease, with a median survival of 3 to 4 years. It is clear that new treatments are needed for MCL.

Even though cyclin D1 mRNA is constitutively expressed in MCL, it is potentially subject to translational regulation by a pathway (Fig 1) involving the mammalian target of rapamycin (mTOR).^18,19 Activated receptor tyrosine kinases and activated ras proteins enhance the catalytic activity of the lipid kinase phosphatidylinositol-3 kinase (PI3K), which converts phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphoate (PIP3). PIP3 activates the protein kinase phosphoinositide-dependent kinase 1 (PDK1), which, along with a second kinase such as integrin-linked kinase (ILK), contributes two phosphorylations required for maximal Akt activity. Akt then phosphorylates a number of substrates, including tuberous sclerosis (TSC) protein 2 (TSC2), which in its unphosphorylated state is complexed with TSC protein 1 (TSC1) and acts as a GTPase activating protein that diminishes activation of the small guanine nucleotide binding protein Rheb. When the TSC1/TSC2 complex is inactivated by Akt, Rheb remains in a GTP-bound state that activates mTOR, a protein kinase that regulates mRNA translation by phosphorylating two critical substrates, eukaryotic initiation factor (eIF) 4E (eIF4E) binding protein (4E-BP1) and p70S6 kinase.^20,21 Previous studies have shown that eIF4E is a component of a helicase complex that binds to the cap structure at the 5' end of mRNAs and enhances the ability of ribosome-eIF complexes to scan the mRNA in search of a translation initiation site.²² The ability of eIF4E to bind to and participate in this helicase complex is inhibited when 4E-BP1 is bound. This inhibitory interaction is possible only when 4E-BP1 is unphosphorylated and is abrogated when 4E-BP1 is sequentially phosphorylated by mTOR and other kinases.^22,23 At the same time, mTOR-mediated phosphorylation activates p70S6K, enabling its phosphorylation of ribosomal protein S6 and possibly other substrates, thereby enhancing the translation of messages with 5' terminal oligopyrimidine tracts.^18,22 Collectively, these events markedly enhance translation of a small but important group of messages, including those encoding c-myc, ornithine decarboxylase, and cyclin D1, as well as ribosomal proteins themselves.^18,22,24,25

View larger version (17K): [in this window] [in a new window]   Fig 1. Current understanding of the mammalian target of rapamycin (mTOR) pathway and mechanism of action of rapamycin. In this diagram, arrows pointing downward or curved arrows pointing to the right indicate activation, whereas curved arrows pointing leftward or lines ending in crossbars indicate inhibition. The phosphorylation of S6 was studied before and after temsirolimus on clinical samples from patients in this study (see Fig 4). PI3K, phosphatidylinositol-3 kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphoate; PDK1, phosphoinositide-dependent kinase 1; ILK, integrin-linked kinase; TSC, tuberous sclerosis; 4E-BP1, eIF4E binding protein; eIF4E, eukaryotic initiation factor 4E.

View larger version (44K): [in this window] [in a new window]   Fig 4. Effect of treatment on downstream phosphorylations in vitro and in vivo. (A) MO258 cells were treated for 24 hours with diluent (0.1% ethanol, lane 1) or, 0.1, 0.3, 1, or 3 nmol/L rapamycin (lanes 2 to 5). Dotted line indicates location at which irrelevant lanes have been spliced from the blots. (B, C) Circulating mantle cells from two patients were subjected to immunoblotting for phosphorylated S6 or, as a loading control, HSP90. Lane 1, pretreatment; lanes 2 to 5, post-treatment. In B, S6 phosphorylation was inhibited after a single dose of temsirolimus; the d38 sample showed S6 phosphorylation and the d89 sample inhibition. In C, the signal for S6 phosphorylation, albeit weaker at baseline, is not abolished by temsirolimus treatment.

Temsirolimus (also known as CCI-779), a dihydroester of rapamycin that is suitable for intravenous use, is currently undergoing testing in solid tumor patients as a potential antineoplastic agent.^28-31 In view of the role of cyclin D1 in MCL, we conducted a phase II trial of single-agent temsirolimus for patients with relapsed MCL to learn if therapy that specifically targeted this pathway could result in tumor responses.

	PATIENTS AND METHODS

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

 
A single-stage phase II study with an interim analysis was conducted to assess the proportion of previously treated MCL patients who achieved a partial response (PR) or better after treatment with temsirolimus. This study was conducted through the North Central Cancer Treatment Group (NCCTG) cooperative group and was approved by the institutional review boards of each treatment site. Patients were eligible for this trial if they had previously received therapy and had relapsed or were refractory to their last treatment. There was no limit on the number of prior therapies. Central pathology review confirmed the diagnosis of MCL based on morphology and phenotype. In addition, all tumors were positive for cyclin D1 by immunohistochemistry or demonstrated t(11;14)(q13;q32)/immunoglubulin H fusion by fluorescence in situ hybridization. Patients were required to have measurable disease with a lymph node or tumor mass 2 cm or malignant lymphocytosis with an absolute lymphocyte count 5,000; a life expectancy of 3 months; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; absolute neutrophil count (ANC) 1,000; platelets 75,000; hemoglobin 8 g/dL; serum creatinine 2x the upper limit of normal (ULN); serum bilirubin 1.5 ULN; serum cholesterol 350 mg/dL; and triglycerides 400 mg/dL. Patients could not have had CNS involvement or HIV infection.

Patients were treated with a flat dose of 250 mg of temsirolimus diluted in 250 mL of normal saline and delivered intravenously (IV) over 30 minutes. Patients were pretreated with diphenhydramine 25 to 50 mg IV. Treatment was weekly, and 4 weeks was considered to be one cycle. A CBC was performed each week, and the full dose of temsirolimus was delivered if the platelet count was 50,000 and the ANC 1,000, and if there were no grade 3 or 4 nonhematologic toxicities (National Cancer Institute Common Toxicity Criteria, version 2). Patients who did not meet the retreatment criteria had the dose held until recovery, followed by a stepwise dose modification to 175, 125, 75, or 50 mg. Patients were not to receive prophylactic WBC growth factors to maintain dosing but could receive them at physician discretion if neutropenia developed. Erythropoietin treatment for anemia was also permitted.

Patients were restaged after one cycle and every three cycles thereafter or at physician discretion. Responses were categorized using the International Workshop Criteria.³² Patients who progressed anytime or those patients with stable disease after six cycles went off study. Patients who had a complete remission (CR) or PR at 6 months were to receive two cycles after CR or for a total of 12 months if there was a PR and they were then observed without further therapy.

Statistical Design
This trial was designed to test the null hypothesis that the true overall response rate (ORR) was at most 5%. The smallest ORR that would indicate that this regimen was worth further study in this relapsed MCL patient population was 20%. The design was generated based on the parameters and assumptions of a two-stage Simon min max design, but where accrual was not suspended for the interim analysis. This study design required a maximum of 32 assessable patients, where the interim analysis was performed after 18 patients had been accrued and followed up for at least 24 weeks for response. An additional three patients were accrued to this cohort (for a maximum of 35 patients overall) to account for the possibilities of ineligibility, withdrawal from study before drug administration, or major violations. However, only the first 32 assessable patients were used to evaluate the decision criteria for this design. At least one response in the first 18 assessable patients needed to be observed in the interim analysis to continue accrual. At the time of the final analyses, a total of four or more responses were required to indicate that this regimen warrants further evaluation in this patient population. The proportion of responses was calculated, and the 90% exact binomial CI for the true ORR was calculated (with all eligible patients accrued), assuming that the number of responses was binomially distributed.

Duration of response (DR) was defined as the time from the date of documented response to the date of progression. Patients who went off treatment due to other reasons (eg, adverse reactions, refusal of further treatment) were censored at that time. Time to progression (TTP) was defined as the time from registration to the date of progression. Patients who died without disease progression were censored at the date of their last evaluation. If a patient died without documentation of disease progression, the patient was considered to have had disease progression at the time of death unless there was sufficient documented evidence to conclude that progression did not occur before death. Time to discontinuation of active treatment was defined as the time from registration to the date the decision was made to take the patient off active treatment. Patients who were still receiving treatment at the time of these analyses were censored at the date of their last evaluation. Overall survival (OS) was defined as the time from registration to death resulting from any cause. The distributions of these time-to-event end points were each estimated using the Kaplan-Meier method.³³

Tissue Culture and Exposure to Rapamycin in Vitro
The MO2058 human line, which was established from a patient with prolymphocytic leukemia and which contains the t(11;14)(q13;q32) translocation associated with Cyclin D1 activation,³⁴ was propagated at 37°C in RPMI 1640 medium containing 10% heat-inactivated fetal bovine serum, 2 mmol/L L-glutamine, 100 units/mL penicillin G, and 100 µg/mL streptomycin. To establish conditions for detecting an effect of rapamycin on downstream signaling of mTOR, cells were treated with various rapamycin (Sigma, St Louis, MO) concentrations for 24 hours, washed three times with ice-cold serum-free RPMI 1640 10 mmol/L HEPES (pH 7.4), solubilized in buffered 6M guanidine hydrochloride under reducing conditions, and prepared for electrophoresis, as previously described.³⁵

To determine whether mTOR signaling was inhibited in MCL tumor cells in situ, circulating mantle cells were purified from the peripheral blood of eight patients at four to five time points, which typically included: before therapy, 24 hours after administration of dose 1, 48 hours after dose 1, before dose 5, and before dose 12. At each time point, 1 to 2 x 10⁶ CD19⁺ cells were purified by magnetic bead selection, washed and solubilized under strongly denaturing conditions as describe above. Further characterization of an additional aliquot of these cells by flow cytometry confirmed that they were typically > 90% CD19⁺.

Immunoblotting
Aliquots containing protein from 5 x 10⁵ immunopurified B cells were subjected to electropheresis on sodium dodecyl sulfate (SDS)-polyacrylamide gels containing 5% to 12% acrylamide, transferred to nitrocellulose, and probed under previously described conditions³⁶ with polyclonal antibodies that recognize the following antigens: phospho-Ser^235/236 ribosomal protein S6, S6, phospho-Thr³⁸⁹ p70S6K and p70S6K (all from Cell Signaling Technology, Beverly, MA). Antigen-antibody complexes were detected using peroxidase-coupled secondary antibodies (KPL, Gaithersburg, MD) and enhanced chemiluminescence reagents (Amersham Pharmacia Biotech, Piscataway, NJ) as described.³⁶ Blots were reprobed with antibody to heat shock protein 90 (David Toft, Mayo Clinic, Rochester, MN) as a loading control.

	RESULTS

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Patient Characteristics
A total of 35 patients were enrolled onto this trial by the NCCTG sites from April 2002 to October 2003. One patient was declared ineligible after pathology review indicated that although the histology was consistent with MCL, the cyclin D1 stain was negative. The patients tended to be older adults with a median age of 70 years (range, 38 to 89 years). Most patients (91%) had stage IV disease and were heavily pretreated with a median number of three prior therapies (mean, four therapies; range, one to 11 therapies). The majority of patients had failed to improve on rituximab, an alkylator agent such as cyclophosphamide, and an anthracycline such as doxorubicin. More than half of the patients had received a purine nucleoside analogue. Twenty-nine percent of patients (10 of 35) had an elevated lactate dehydrogenase at baseline. Additional baseline characteristics of these patients are presented in Table 1.

View larger version (100K): [in this window] [in a new window]   Fig 2. Computed tomography scans from two patients who had marked tumor response after one cycle (four doses) of temsirolimus (CCI779). (A) Patient with a large perigastric lymphomatous mass; (B) patient with bulky paratracheal and left axillary adenopathy.

Dose reductions were necessary in all but four patients. Overall, nine patients were able to receive 250 mg weekly for at least the first cycle of treatment, with a median of 2.5 cycles at this full dose (range, 1 to 8 cycles); the other patients required dose reductions in the first cycle. Of the six patients who received more than one cycle at the full dose level, two eventually required a dose reduction in subsequent cycles. Across all patients, the median dose received per month on study was 525 mg, with 564 mg in responding patients and 525 mg in nonresponders.

The median time to progression (Fig 3) was 6.5 months (95% CI, 2.9 to 8.3 months). The median overall survival was 12 months (95% CI, 6.7 months to not yet reached). The median duration of response for the 13 responders was 6.9 months (95% CI, 5.2 to 12.4 months). The median follow-up on living patients was 11 months (range, 6.7 to 24.6+). Overall, 30 patients have had disease progression, and 22 patients have died. No patients have had documented death without disease progression.

View larger version (11K): [in this window] [in a new window]   Fig 3. Time to progression after temsirolimus in all 34 patients.

Pharmacodynamics
To develop an assay for mTOR inhibition that could be applied in clinical MCL samples, we initially treated MO258 cells with varying concentrations of rapamycin in vitro and probed whole cell lysates for phosphorylation of substrates downstream of mTOR using commercially available antiphosphoepitope antibodies. Blotting for phospho–4E-BP1 in this cell line and others proved difficult (data not shown). In contrast, as reported by others,^37,38 we observed that phospho-S6 (Fig 4A) and, with somewhat more difficulty, phospho-p70S6 kinase could be demonstrated. Moreover, inhibition of S6 phosphorylation was readily detectable at 0.1 nmol/L rapamycin and essentially complete at 1 nmol/L (Fig 4A).

When this assay was applied to MCL samples from the blood of patients receiving temsirolimus, phosphorylation of S6 was more readily detectable than phosphorylation of p70S6K. Examination of serial samples revealed two distinct patterns. First, as illustrated in Figure 4B for one patient, S6 phosphorylation was inhibited after temsirolimus treatment in three patients (compare, lanes 2 and 3 with lane 1). Of these three patients, one responded to therapy, one was stable, and one progressed without ever responding. In contrast, as illustrated in Figure 4C for one patient, there was no evidence that S6 phosphorylation was inhibited in circulating MCL cells from two other patients. One of these patients had a PR; the other progressed on therapy.

	DISCUSSION

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The treatment of MCL has remained problematic despite the availability of standard chemotherapy, stem-cell transplantation, and monoclonal antibody therapy with rituximab. Each of these modalities can produce tumor responses in MCL, but the disease typically recurs and requires additional therapy. There is no treatment regimen that can be considered the definitive treatment of choice at this time for patients with new, untreated MCL. Most patients are treated with combinations of rituximab and chemotherapy—often HyperCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone),¹⁷ R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab),¹⁶ or a purine nucleoside analogue and rituximab. Patients who are eligible for high-dose therapy with stem-cell support are increasingly transplanted in first remission.^39,40 Mantle-cell lymphoma remains a difficult disease to treat once it has relapsed, and patients are typically treated with multiple regimens because of the short time to progression between treatments. An improved understanding of the biology of MCL and the availability of new classes of chemotherapy agents led us to hypothesize that drugs that target the machinery that controls cyclin D1 expression might have antitumor activity in MCL. In the study reported herein, temsirolimus was tested as a single agent in a cohort of heavily pretreated patients with MCL to learn if inhibition of mTOR would produce tumor responses. The study demonstrated an ORR of 38% (13 of 34 patients), with a median duration of response of 6.9 months and a median TTP for all patients of 6.5 months. Tumor responses tended to occur rapidly, with most patients demonstrating a response by 3 months. Only two of the 13 responders had their initial response documented beyond 3 months.

Consistent with previous studies showing that temsirolimus can cause thrombocytopenia,⁴¹ this toxicity was the most common side effect in the present trial. Several features of the trial design may have predisposed patients to this side effect. First, patients could enter the protocol with grade 1 thrombocytopenia ( 75,000) and could receive 100% of the temsirolimus dose if the platelet count was 50,000 (grade 2). Second, the patients enrolled on this study were heavily pretreated. Third, most patients had marrow infiltrated with MCL cells, reducing marrow reserve.

Because of the inability to obtain serial biopsies, we studied serial samples of circulating mantle cells from five patients for evidence of mTOR inhibition after temsirolimus. Inhibition of S6 phosphorylation was observed in some sets of serial samples (Fig 4B) but not others (Fig 4C). Because the signal for S6 phosphorylation in many of these samples was close to the limit of detection, we did not attempt to quantitate the present results. While this study was in progress, Peralba et al³⁸ reported that the extent of inhibition of p70^S6 kinase activity in circulating mononuclear-cells correlated with the time to progression of renal cell carcinoma patients receiving temsirolimus. In contrast, Neshat et al³⁷ reported inhibition of S6 phosphorylation in prostate cancer xenografts regardless of whether the xenografts responded to rapamycin or not. Further studies with additional sets of serial MCL samples or circulating normal mononuclear cells obtained from either the peripheral blood or accessible lymph nodes will be required to better determine whether temsirolimus-induced changes in S6 phosphorylation predict response to therapy. Additional factors that might affect response to temsirolimus therapy have also recently been described, including PTEN loss,³⁷ which activates signaling through this pathway (Fig 1), p53 mutational status,⁴² and changes affecting the apoptotic machinery.⁴³ These measurements may better distinguish responders from nonresponders. Because assays of these biologic properties were not built into the present trial when it was designed, future studies will need to determine how important these factors are in determining response to temsirolimus in MCL.

Two additional issues also require further exploration. First, the mechanism of action of rapamycins (Fig 1) and the observed ability of these agents to inhibit the translation of myc mRNA^22,27 suggest that temsirolimus could be active in other types of lymphomas. In addition, the optimal dose of single-agent temsirolimus for hematologic malignancies remains to be determined.³¹ Early studies of temsirolimus were performed predominantly in patients with solid tumors. In a phase I study of temsirolimus in 16 patients with advanced solid tumors, Raymond et al⁴¹ tested doses ranging from 7.5 to 220 mg/m² as a weekly 30-minute infusion. Temsirolimus was well tolerated over that dose range with the most frequent side effects being dermatologic toxicity and mucositis; thrombocytopenia and hyperlipidemia were also observed. Dosing on body-surface area did not provide any advantage over a flat dose (ie, not weight-based) schema. In a subsequent large phase II study of 111 patients with relapsed renal cell carcinoma, patients were randomly assigned to temsirolimus 25, 75, or 250 mg IV weekly.⁴⁴ The ORR was 7% (one CR; seven PR), and minor responses were seen in 26% of patients; the median TTP and OS were 5.8 and 15 months, respectively. The most common reason for dose reductions were thrombocytopenia (20%), mucositis (16%), hypertriglyceridemia (5%), and neutropenia (1%). Nineteen percent of patients (21 of 111) discontinued treatment due to drug-related adverse events, with the most common cause being rash in five patients. Patients at the higher dose levels had more dose reductions and were more likely to go off-study for adverse events; therefore, the authors recommended the 25-mg dose for future trials.⁴⁴

In the present study, which started with 250 mg weekly, patients often experienced side effects that necessitated dose reductions. In contrast to the other studies discussed above, patients with MCL on temsirolimus did not have significant problems with rash or mucositis. The study was amended to allow multiple dose reductions to as low as 50 mg weekly. Twelve patients in our study discontinued treatment for reasons other than tumor progression; therefore, we postulate that lower doses could result in a higher ORR. We are currently studying the 25-mg dose level in a new cohort of patients with relapsed MCL. This issue is important not only to clarify the appropriate dose of temsirolimus as monotherapy for MCL, but also to establish a dose to take forward in trials of combinations of temsirolimus with other agents.

The single-agent response rate found with temsirolimus is similar to that found with other new agents. A recent study by Ghielmini et al⁴⁵ treated 88 patients with four standard doses of rituximab, and the ORR at week 12 was 27%, with 2% CR. Others have demonstrated a somewhat higher ORR (33% to 38%), with rituximab for MCL patients.^6,10 Bortezomib is another novel agent that has recently demonstrated antitumor activity in MCL.⁴⁶ The ORR to bortezomib in 29 patients with relapsed MCL was 41%,⁴⁶ a rate similar to the 38% found in our trial of temsirolimus and lower than the 50% ORR found in the smaller study of bortezomib reported by O'Conner et al.⁴⁷ The key finding of all of these studies is that each has modest single-agent activity with acceptable toxicity. This should enable each of these drugs to be tested in combination with each other and with conventional agents, with the aim of prolonging the survival of patients with MCL.

	Authors' Disclosures of Potential Conflicts of Interest

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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 devises 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 Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Thomas E. Witzig Wyeth Pharmaceuticals (A) Wyeth Pharmaceuticals-United States Food and Drug Administration phone call

Dollar amount codes: (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	NOTES

 
Supported in part by Public Health Service grants CA-25224, CA-37404, CA-15083, CA-63826, CA-35195, CA-35267, CA-35101, CS-35431, CA-35090, CA-35113, CA-35415, CA-60276, CA-35448, and CA-63848, and grant CA97274 from the National Cancer Institute, Department of Heath and Human Services, Bethesda, MD.

This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic. Additional participating institutions include Medcenter One Health Systems, Bismarck, ND (Edward Wos, MD); Illinois Oncology Research Association CCOP, Peoria, IL (John W. Kugler, MD); Toledo Community Hospital Oncology Program CCOP, Toledo, OH (Paul L. Schaefer, MD); Scottsdale CCOP, Scottsdale, AZ (Tom R. Fitch, MD); Geisinger Clinic & Medical Center CCOP, Danville, PA (Albert Bernath, MD); and Ann Arbor Regional CCOP, Ann Arbor, MI (Philip J. Stella, MD).

Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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

 
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Submitted January 24, 2005; accepted April 7, 2005.

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