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Originally published as JCO Early Release 10.1200/JCO.2006.07.9665 on September 25 2006 © 2006 American Society of Clinical Oncology. Multicenter Phase II Study of Bortezomib in Patients With Relapsed or Refractory Mantle Cell Lymphoma
From the University of Rochester, James P. Wilmot Cancer Center, Rochester; Weill Medical College of Cornell University/New York Presbyterian Hospital; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Wisconsin, Madison, WI; H. Lee Moffitt Cancer Center, Tampa, FL; Indiana University Medical Center, Indianapolis, IN; University of California Los Angeles School of Medicine, Los Angeles; City of Hope National Medical Center, Duarte, CA; Oregon Health and Science University, Portland, OR; Winship Cancer Institute, Emory University, Atlanta, GA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Millennium Pharmaceuticals Inc, Cambridge, MA; and the Cancer Center at Hackensack University Medical Center, Hackensack, NJ Address reprint requests to Richard I. Fisher, MD, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642; e-mail: Richard_Fisher{at}urmc.rochester.edu
PURPOSE: Evaluate response rate, duration of response (DOR), time-to-progression (TTP), overall survival (OS), and safety of bortezomib treatment in patients with relapsed or refractory mantle cell lymphoma (MCL). PATIENTS AND METHODS: Bortezomib 1.3 mg/m2 was administered on days 1, 4, 8, and 11 of a 21-day cycle, for up to 17 cycles. Response and progression were determined using International Workshop Response Criteria, both using data from independent radiology review and by the investigators. Primary efficacy analyses were based on data from independent radiology review. RESULTS: In total, 155 patients were treated. Median number of prior therapies was one (range, one to three). Response rate in 141 assessable patients was 33% including 8% complete response (CR)/unconfirmed CR. Median DOR was 9.2 months. Median TTP was 6.2 months. Results by investigator assessments were similar. Median OS has not been reached after a median follow-up of 13.4 months. The safety profile of bortezomib was similar to previous experience in relapsed multiple myeloma. The most common adverse events grade 3 or higher were peripheral neuropathy (13%), fatigue (12%), and thrombocytopenia (11%). Death from causes that were considered to be treatment related was reported for 3% of patients. CONCLUSION: These results confirm the activity of bortezomib in relapsed or refractory MCL, with predictable and manageable toxicities. Bortezomib provides significant clinical activity in terms of durable and complete responses, and may therefore represent a new treatment option for this population with usually very poor outcome. Studies of bortezomib-based combinations in MCL are ongoing.
Mantle cell lymphoma (MCL), an aggressive, generally incurable subtype of non-Hodgkin's lymphoma (NHL),1 accounts for approximately 5% to 6% of all NHL cases.1-3 With an estimated 59,000 new cases of NHL diagnosed annually in the US4 and 62,000 in the European Union,5 this represents approximately 3,000 to 4,000 new MCL cases annually in each region. Most patients are male, age older than 60 years, and present with advanced disease.6,7 MCL has one of the poorest prognoses of all NHL subtypes.1,8,9 Despite response rates of up to 97% with first-line standard or high-intensity chemotherapy, with or without stem-cell transplantation,6,10-16 most patients relapse. Median failure-free survival is approximately 8 to 20 months with standard therapies,6,16-19 although longer survival has been reported with high-intensity regimens.11-14,16,18 Median survival is approximately 3 to 4 years with standard treatment.6,7,18-20 After first relapse, prognosis is considered very poor, with median survival of approximately 1 to 2 years.6,18 There is no generally accepted therapeutic approach, treatment options are often limited,1 and chemoresistance is common.21 Therefore, novel therapies are required for relapsed and/or refractory MCL.20,21
MCL is characterized by overexpression of cyclin D1, resulting from the t(11;14)(q13;q32) translocation.1,20-22 Nuclear factor- This study was designed to confirm the activity of bortezomib in an international, multicenter study of patients with relapsed or refractory MCL. The objectives were to evaluate response rate (complete response [CR], unconfirmed CR [CRu], and partial response [PR]) according to International Workshop Response Criteria (IWRC),39 duration of response (DOR), time-to-progression (TTP), and overall survival. The intended primary end point was a formal comparison of TTP with historical controls, which could not be accomplished (see Discussion).
Eligibility Eligibility criteria included: age 18 years or older; pathologically confirmed MCL including overexpression of cyclin D1 or evidence of t(11;14); documented relapse or progression after one to two prior lines of antineoplastic therapy (including an anthracycline or mitoxantrone, and rituximab, each in  1 line); one or more measurable or assessable disease sites; and Karnofsky performance status (KPS) 50% or higher. Toxicities from previous therapy had to have resolved to grade 2 or lower (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE], version 3.0). At screening, patients required: absolute neutrophil count 1,000 cells/µL; platelets 50,000 cells/µL; aspartate transaminase  3x upper limit of normal (ULN); alanine transaminase 3x ULN; total bilirubin 2x ULN; and creatinine 2 mg/dL (or creatinine clearance 50 mL/min). All patients provided written informed consent. Exclusion criteria included: prior bortezomib; prior chemotherapy within 3 weeks, nitrosoureas within 6 weeks, therapeutic antibodies within 4 weeks, radio- or toxin immunoconjugates within 10 weeks, radiation therapy within 3 weeks, or major surgery within 2 weeks, of day 1, cycle 1. Patients diagnosed with or treated for a malignancy other than MCL within 5 years before day 1, cycle 1 were excluded, except patients having complete resection of basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy, or definitively treated, low-risk prostate cancer.
Supportive therapy for MCL ongoing at baseline was allowed; platelet and RBC transfusions were permitted. Concomitant corticosteroid therapy was prohibited, except prednisone
Study Design
Efficacy and Safety Assessments Disease response (CR, CRu, PR, stable disease, PD) was assessed according to the IWRC.39 Scans were examined by an independent radiologist to ensure consistency across study sites. Adverse events (AEs) were monitored throughout, and toxicities assessed by NCI CTCAE version 3.0. At the end of treatment visit, 28 days after last bortezomib dose or earlier if patients required alternative antineoplastic therapy, disease response was assessed if there was no prior evidence of PD. Patients discontinuing for reasons other than PD received short-term follow-up every 6 weeks until week 18, then every 12 weeks until PD or use of alternative antineoplastic therapy. All patients received long-term follow-up every 3 months to assess survival. Dosing was held or modified for grade 3 or higher neutropenia with fever, grade 4 neutropenia lasting longer than 7 days, platelets less than 10,000 cells/µL, or any grade 3 or higher nonhematologic toxicity that was considered to be bortezomib related.
Statistical Analysis Patient populations included the all-treated population (ATP; patients who received any amount of bortezomib), response population for final analysis (RP-Final; ATP patients who had measurable disease at screening and at least one postbaseline tumor assessment), and refractory population (ATP patients who had not responded to their last line of therapy or responded with TTP of < 6 months). Safety and efficacy data (except response) were analyzed for ATP; response and DOR were analyzed for RP-Final; and all efficacy parameters were analyzed for the refractory population. Response, date of response, and PD were determined using a computer algorithm that applied the IWRC with a minor modification to correlate more closely with application of these criteria in clinical practice, and used tumor measurements from independent radiology review of patient scans. The IWRC modification was incorporated when it became clear that small changes in nodes smaller than 1 cm in size were assessed as PD by algorithm but not by investigator. The definition of PD, which required 50% or higher increase in the product of the longest perpendicular dimensions of any previously identified, measurable site of lymphoma, or 50% or higher increase in the longest dimension of any previously identified site of lymphoma that was larger than 1 cm in the longest transverse dimension (ie, measurable at baseline), was modified to specify that the lesion should be larger than 1 cm in both perpendicular dimensions at the time of PD and that the absolute increase in either dimension, or in the longest dimension, respectively, should be at least 0.5 cm. This better reflects the recently updated IWRC.40 Response and disease progression were derived using this algorithm, and assessed by investigators using the IWRC. Kaplan-Meier methods were used to estimate distribution of DOR, TTP, and survival. Additional nonprotocol-specified analyses included DOR, TTP, and survival assessment by response status, and assessment of response, DOR, and TTP for patient subgroups based on time since diagnosis of MCL, number of prior lines of therapy, and prior high-intensity chemotherapy (defined as stem-cell transplantation, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine [Hyper-CVAD]; ifosfamide, carboplatin, and etoposide [ICE]; etoposide, methylprednisolone, high-dose cytarabine, and cisplatin [ESHAP]; or dexamethasone, high-dose cytarabine, and cisplatin [DHAP]; all with/without rituximab).
Patient Characteristics and Disposition In total, 155 patients were enrolled and received 1 or more doses of bortezomib. Baseline characteristics are presented in Table 1; median number of prior therapies was one. At data cut off, 100 patients remained on the study (12 on treatment, 16 on short-term follow-up, and 72 on long-term follow-up). Of 55 who discontinued from the study, 52 had died, two were lost to follow-up, and one withdrew consent. Treatment was discontinued by 130 of 155 patients (84%). Reasons included lack of efficacy (72; 46%), AEs (41; 26%), patient decision (7; 5%), and other reasons (10; 6%).
The median number of treatment cycles was four in all patients and eight in responding patients; 59% of patients received four or more cycles, 31% received eight or more. The median total bortezomib dose was 20.7 mg/m2 (range, 1.3 to 87.5); median percentage of expected bortezomib received during time on therapy was 90.4%.
Efficacy
In the refractory population (n = 58; 50 did not respond to last prior therapy, eight responded with TTP < 6 months), among 51 patients assessable for response, the response rate by algorithm was 31% (6% CR/CRu). Median DOR was 4.9 months (based on six events). For all 58 patients, median TTP was 3.8 months, median survival was 14.4 months, and 1-year survival probability was 54%. Bortezomib showed efficacy in all patient subgroups. Response rate was lower in patients diagnosed fewer than 3 years before study entry (25%) compared with 3 years or longer (50%), although DOR (9.4 v 9.2 months) and TTP (6.2 v 6.1 month) were similar. DOR was lower in patients with more than one prior line of therapy (6.1 months) compared with one prior line (9.4 months), although response rate (38% v 30%) and TTP (5.4 v 6.5 months) were similar. Response rate (27% v 37%) and TTP (4.2 v 6.7 months) were lower in patients who had prior high intensity therapy versus those who did not, although DOR was similar (9.2 v 9.4 months).
Safety
Twelve patients died within 28 days after their last dose of bortezomib. The SAEs reported as leading to death were disease progression (six patients), sepsis (three patients; in association with cardiac arrest in one patient, and with fungal pneumonia, pulmonary alveolar hemorrhage and multiorgan failure in one patient), respiratory failure (two patients), and intestinal obstruction (one patient); these included grade 5 (fatal) AEs in five patients (3%; three disease progression, one respiratory failure, one intestinal obstruction). The cause of death was considered related to bortezomib in five patients, three deaths due to sepsis, and one death due to respiratory failure; one patient died unwitnessed in the setting of PD, and the investigator could not rule out a potential contribution of bortezomib.
This study represents the largest prospective study to date in patients with relapsed MCL. In a population typical of the relapsed MCL population, the results demonstrate that bortezomib is effective, with a 33% response rate, including 8% CR/CRu. The median DORs in all responding patients (9.2 months) and patients achieving CR/CRu (13.5 months) are considerable given the median expected survival of 1 to 2 years after initial relapse, suggesting important clinical benefit. Similarly, median TTP was 10.6 months among responders, 14.6 months in patients achieving CR/CRu, and 6.2 months in all patients. These data are supported by similar results from phase I and II studies of single-agent bortezomib in relapsed MCL.34-38,41
After a median follow-up of 13.4 months, median survival has not been reached. Notably, bortezomib was active in patients with aggressive (diagnosed < 3 years before study entry) and less aggressive (diagnosed As described, the intended primary end point was a formal comparison of TTP with historical controls; however, an appropriate cohort of sufficient size could not be identified. Critical data on disease-assessment intervals, response criteria, and prior therapies in three academic research databases of MCL patients were absent. Consequently, only 15 of 258 patients were considered valid comparators, preventing the planned analysis. A comprehensive literature review was conducted of studies of single-agent therapies in relapsed MCL.42-49 None of these studies, of rituximab,42,47,48 fludarabine,45,46 gemcitabine,44 and the investigational agent flavopiridol,43 involved patients with a comparable extent of prior therapies to that required in our study. Nonetheless, our 33% response rate compares favorably with 33%, 37%, and 28% with rituximab,42,47,48 17% and 31% with fludarabine,45,46 27% with gemcitabine,44 and 11% with flavopiridol.43 The patients in a recent temsirolimus study49 were more comparable with those in our study; however, sample size was small (N = 34) and of the 38% response rate, CR/CRu rate was only 3%.49 Our median DOR of 9.2 months compares favorably with 3.3 months with flavopiridol,43 4 to 8 months with fludarabine,46 6.9 months with temsirolimus,49 and 6 to 14 months with rituximab.47,48 Similarly, our median TTP of 6.2 months is comparable with TTP/time to treatment failure of 3.0 months with flavopiridol,43 6.1 months with fludarabine,45 and 6.5 months with temsirolimus,49 and our overall survival compared with 12 months median overall survival with temsirolimus.49 The safety profile of bortezomib was predictable and manageable, and similar to that in relapsed or refractory MM.50-52 The incidence of peripheral neuropathy was higher compared with the Assessment of Proteasome Inhibition for Extending Remissions phase III study in MM,51 perhaps due to inherent differences between the diseases or differences in prior therapy. Baseline neuropathy data were not collected. However, an examination of peripheral neuropathy in two MM studies found no correlation between overall incidence and baseline neuropathy or type of prior therapy, though severe neuropathy was more frequent in the presence of baseline neuropathy.53 Hematologic AEs were less frequent in this study than in MM studies,50-52 which may reflect more significant disease-related bone marrow suppression in MM than MCL. Patients with positive baseline bone marrow evaluation experienced grade 3/4 hematologic AEs more frequently than bone-marrow–negative patients. Thrombocytopenia and neutropenia were cyclical and transient, as in MM studies.54,55 In conclusion, the results of this study confirm the activity of bortezomib, including CRs and durable responses, in relapsed/refractory MCL, with a manageable toxicity profile. Activity compares favorably with other studies of single-agent therapies in this setting. Bortezomib may therefore represent an important new treatment option for this population with usually poor outcome. Based on preclinical findings of additive/synergistic activity in lymphoma, studies are also investigating combinations of bortezomib with standard therapeutic agents in patients with untreated, relapsed, and refractory MCL, with promising early results.56-58
The PINNACLE Study Group Said Baidas, MD, Georgetown University Medical Center, Washington, DC; Nancy Bartlett, MD, Washington University School of Medicine, St Louis, MO; Robert Belt, MD, Kansas City Cancer Center, Kansas City, KC; Jesus Berdeja, MD, Loma Linda University Medical Center, Loma Linda, CA; Steven H. Bernstein, MD, University of Rochester, James P. Wilmot Cancer Center, Rochester, NY; Myron Czuczman, MD, Roswell Park Cancer Institute, Buffalo, NY; Sven de Vos, MD, University of California, Los Angeles School of Medicine, Los Angeles, CA; Benjamin Djulbegovic, MD, PhD, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Martin Dreyling, MD, University Clinic of Munich–Grosshadern, Munich, Germany; Elliot Epner, MD, Oregon Health and Science University, Portland, OR; Richard Fisher, MD, University of Rochester, James P. Wilmot Cancer Center, Rochester, NY; Andres Forero, MD, University of Alabama at Birmingham, Birmingham, AL; Andre Goy, MD, Hackensack University Medical Center, Hackensack, NJ; Stephanie Gregory, MD, Rush-Presbyterian St Lukes Medical Center, Chicago, IL; Michael Grossbard, MD, St Luke's–Roosevelt Hospital, New York, NY; John Hainsworth, MD, Sarah Cannon Cancer Center, Nashville, TN; Sandra Horning, MD, Stanford Cancer Center, Stanford, CA; David Hurd, MD, Wake Forest University Health Sciences, Winston-Salem, NC; David Irwin, MD, Alta Bates Comprehensive Cancer Center, Berkeley, CA; Brad Kahl, MD, University Hospital –Madison, Madison, WI; Lawrence Kaplan, MD, University of California San Francisco, San Francisco, CA; Alan Keller, MD, Cancer Care Associates, Tulsa, OK; Amrita Krishnan, MD, City of Hope National Medical Center, Duarte, CA; John Leonard, MD, Weill Medical College of Cornell University/New York Presbyterian Hospital, New York, NY; John Lister, MD, Western Pennsylvania Hospital, Pittsburgh, PA; Sagar Lonial, MD, Emory University Winship Cancer Institute, Atlanta, GA; James W. Lynch, MD FACP, Florida VA Hospital, Gainesville, FL; Romeo Mandanas, MD, Cancer Care Associates, Oklahoma City, OK; David Morgan, MD, Vanderbilt University Medical Center, Nashville, TN; Martin Oken, MD, North Memorial Hospital Hubert Humphrey Cancer Center, Robbinsdale, MN; Michael Robertson, MD, Indiana University Medical Center, Indianapolis, IN; Jorge Romaguera, MD, University of Texas MD Anderson Cancer Center, Houston, TX; Simon Rule, MD, Plymouth Hospitals NHS Trust, Derriford Hospital, Plymouth, UK; Mansoor Saleh, MD, Georgia Cancer Specialists, Tucker, GA; Edward Stadtmauer, MD, University of Pennsylvania Cancer Center, Philadelphia, PA; James Wooldridge, MD, University of Iowa Cancer Center, Iowa City, IA.
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 Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
We thank Steve Hill and Rosemary Washbrook for their assistance in drafting the manuscript. Steve Hill is a medical writer and Rosemary Washbrook is a medical editor with Gardiner-Caldwell London.
published online ahead of print at www.jco.org on September 25, 2006. Supported by Millennium Pharmaceuticals Inc and Johnson & Johnson Pharmaceutical Research & Development LLC. Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 13-17, 2005 and the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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ABSTRACT
INTRODUCTION
B (NF-
= .025; 95% power; undesirable response rate, 25%; desirable response rate, 40%). Data cut off for this analysis was selected to allow 6 months or longer follow-up after first bortezomib dose in every patient, determined to be adequate for TTP and DOR evaluation. 
