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Br J Haematol. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: Br J Haematol. 2015 November ; 171(4): 539–546. doi:10.1111/bjh.13637.
A Phase II Study of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent non-Hodgkin’s Lymphoma
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Jonathon B. Cohen1,2, Jeffrey M. Switchenko3, Jean L. Koff1, Rajni Sinha1,2, Jonathan L. Kaufman1,2, H. Jean Khoury1,2, Nassoma Bumpers2, Amanda Colbert2, Amanda HutchisonRzepka2, Loretta J. Nastoupil1, Leonard T. Heffner1,2, Amelia Langston1,2, Mary Jo Lechowicz1,2, Sagar Lonial1,2, and Christopher R. Flowers1,2 1Hematology 2Winship
and Medical Oncology, Emory University, Atlanta, Georgia
Cancer Institute, Emory University, Atlanta, Georgia
3Biostatistics
and Bioinformatics, Emory University, Atlanta, Georgia
Summary
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Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit its dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1.6 mg/m2) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1.5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular
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Corresponding Author: Christopher R. Flowers, MD, MS, Director, Lymphoma Program, Associate Professor, Department of Hematology & Medical Oncology, Emory University School of Medicine, 1365 Clifton Road, NE, Atlanta, GA 30322, Phone: 404-778-3942, Fax: 404-778-3366, [email protected]. Author contributions: JC analysed data, wrote the manuscript, and cared for patients on the study. JS analysed data, reviewed and edited the manuscript. JKoff cared for patients on the study, reviewed and edited the manuscript. RS cared for patients on the study, reviewed, and edited the manuscript. JKaufman cared for patients on the study, reviewed and edited the manuscript. HJK cared for patients on the study, reviewed and edited the manuscript. NB cared for patients on the study, reviewed and edited the manuscript. AC maintained patient data, coordinated the care for patients on the study, reviewed and edited the manuscript. A H-R maintained patient data, coordinated the care for patients on the study, reviewed and edited the manuscript. LN cared for patients on the study, reviewed and edited the manuscript. LH cared for patients on the study, reviewed and edited the manuscript. AL cared for patients on the study, reviewed and edited the manuscript. MJL cared for patients on the study, reviewed and edited the manuscript. SL cared for patients on the study, reviewed and edited the manuscript. CRF designed the research study, supervised all aspects of the trial, cared for patients on the study, reviewed and edited the manuscript. ALL authors have approved the final, submitted version of the manuscript.
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(n=20), marginal zone (n=5) and small lymphocytic lymphoma (n=4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48.7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and 2 had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL.
Keywords Non-Hodgkin lymphoma; Bortezomib; Neuropathy; Follicular lymphoma; Indolent Lymphoma
Introduction Author Manuscript Author Manuscript
Although combination chemo-immunotherapy regimens for follicular lymphoma (FL) and other forms of indolent B-cell non-Hodgkin lymphoma (NHL) have varied in the United States(Friedberg, et al 2012), rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) compared favourably to rituximab, cyclophosphamide, vincristine and prednisone (R-CVP) in a recent analysis of the National LymphoCare study, with a 5-year overall survival (OS) of 86% for R-CHOP and 76% for R-CVP.(Nastoupil, et al 2015) In addition, bendamustine and rituximab (BR) demonstrated improved progressionfree survival (PFS) over R-CHOP for untreated patients with FL (median not reached for BR vs 40.9 months for R-CHOP, p=0.0072) in one German study, and another US study indicated that BR was non-inferior to standard therapy with investigators’ choice of RCHOP/R-CVP for patients with indolent NHL.(Flinn, et al 2014, Rummel, et al 2013) Maintenance rituximab following initial therapy also can improve PFS although this does not appear to improve OS.(Salles, et al 2011) However, despite continued improvement in the front-line management of indolent B-cell NHL with chemo-immunotherapy induction regimens, such as BR(Rummel, et al 2013) and R-CHOP(Press, et al 2013) and maintenance rituximab(Salles, et al 2011), nearly all patients relapse and high risk patients respond poorly to initial therapy and have shortened survival.(Nooka, et al 2013) In each of these studies, approximately 20% of patients experienced progression or death within 2 years of first-line therapy.(Casulo, et al 2013, Federico, et al 2013, Press, et al 2013, Rummel, et al 2013, Salles, et al 2011) These consistent findings highlight the existence of a subgroup of patients with “indolent” NHL who experience a disease course with an aggressive biological behaviour that may benefit from alternative approaches to initial therapy, maintenance, or salvage therapy.
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While the single agent response rate in a phase II study of bortezomib in relapsed or refractory indolent NHL is modest, at 13% with a median PFS of 5.1 months,(Di Bella, et al 2010) bortezomib has been successfully administered in combination with rituximab alone, BR and additional chemotherapy combinations in the relapsed/refractory setting.(Baiocchi, et al 2011, Coiffier, et al 2011, Fowler, et al 2011) In addition, bortezomib shows more promising activity as a single agent in both untreated and relapsed/refractory marginal zone lymphoma, with CR rates of up to 43% in untreated marginal zone lymphoma.(Conconi, et
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al 2011, Troch, et al 2009) In the front-line setting, bortezomib-containing combinations are also effective. When combined with R-CVP in a phase II in Canada, the overall response rate (ORR) was 83%, and there were no incidents of grade 4 neurotoxicity.(Sehn, et al 2011) In this study, bortezomib was administered at a dose of 1.3 mg/m2 on days 1 and 8, and vincristine was administered at standard dose. A non-vincristine containing combination of bortezomib, cyclophosphamide and dexamethasone has also been evaluated with bortezomib administered on a weekly schedule at 1.6 mg/m2, with an ORR of 90% and a median time to progression not reached with a limited sample of 12 patients.(Nabhan, et al 2012) Full dose bortezomib and vincristine have been evaluated in the front-line setting, in a 2-arm study in which patients received either weekly bortezomib at 1.6 mg/m2 or twice-weekly dosing at 1.3 mg/m2 combined with R-CHOP administered at standard dose (vincristine dose: 1.4 mg/m2 with cap of 2 mg).(Ribrag, et al 2009) Despite outstanding efficacy with a CR rate ranging from 79–90%, there was a 41% incidence of grade 3 peripheral neuropathy, suggesting that this regimen may be too toxic at the full doses of vincristine and bortezomib.
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Our group has previously reported the results of a phase I study of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CHOP) on a 21-day schedule.(Sinha, et al 2012) In this dose-finding study, the maximum tolerated dose (MTD) for bortezomib was 1.6 mg/m2 on days 1 and 8, with the vincristine dose on day 1 capped at 1.5 mg. Overall, the incidence of grade ≥3 neuropathy was 11%, and the ORR for this phase I study was 100%, including a CR rate of 68%. Based on the demonstrated tolerability and preliminary evidence of efficacy in the phase I study, we now performed a phase II study of VR-CHOP in patients with previously untreated indolent NHL.
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Methods Patients
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This study was open to all patients with untreated indolent NHL meeting modified GELF (Groupe d’Etude des Lymphomes Folliculaires) criteria for treatment.(Brice, et al 1997) In addition, patients with FL with a FL international prognostic index (FLIPI) score ≥ 3 were eligible for enrolment even if they did not meet modified GELF criteria.(Nooka, et al 2013, Solal-Celigny, et al 2004) While prior chemotherapy was not allowed, patients with prior radiation therapy to 1 or 2 sites of disease were eligible to enrol. In addition, subjects were required to have adequate bone marrow, renal, and hepatic function and to have an Eastern cooperative Oncology Group (ECOG) performance status of 0–2. All patients completed the informed consent form and were enrolled in accordance with the Declaration of Helsinki. This study was approved by the Institutional Review Board of Emory University. Treatment Plan Based on our previously reported phase I study, patients were treated at the recommended phase 2 dose for this regimen.(Sinha, et al 2012) This consisted of a 21-day cycle wherein patients received rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2) and vincristine (1.4 mg/m2 with a cap of 1.5 mg) on day 1. In addition, all patients received bortezomib 1.6 mg/m2 intravenously on days 1 and 8, and all patients received
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prednisone 100 mg orally days 1–5. Patients received at least 6 cycles of induction therapy and could receive up to 8 cycles at the discretion of the treating investigator, with the goal being to treat for 2 cycles after best response. At the conclusion of induction, all patients without progressive disease were eligible for maintenance therapy. Patients achieving a CR received rituximab monotherapy (375 mg/m2) every 12 weeks for 2 years, and patients with partial response (PR) or stable disease received rituximab (375 mg/m2) and bortezomib (1.6 mg/m2) administered weekly for 4 weeks every 6 months for up to 2 years.
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Toxicity was assessed for all patients at prescribed time points using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). Given the well-described incidence of neuropathy with both bortezomib and vincristine, an aggressive dosemodification algorithm for patients with neuropathic pain and/or peripheral sensory neuropathy was incorporated into the protocol. In addition, patients completed the Functional Assessment of Cancer Therapy/Gynecological Oncology Group (FACT/GOG) neurotoxicity questionnaire to assist with evaluation of neuropathy and neurological toxicity (Cella, et al 1993). Dose reductions were instituted for all patients with grade 1 neuropathy with pain and higher grade events. Therapy with bortezomib was held for all patients with grade 2 neuropathy with pain or grade 3 neuropathy and therapy was re-introduced at a reduced dose only if the toxicity resolved. Patients with grade 4 neuropathy received no further bortezomib or vincristine. In order to allow patients receiving benefit to continue on study therapy, patients could proceed through up to 3 dose reductions due to toxicity before having to discontinue bortezomib, including reductions to 1.3 mg/m2, 1.0 mg/m2, and 0.7 mg/m2, with patients continuing to receive bortezomib on days 1 and 8 of each cycle. Dose reductions of R-CHOP were not incorporated into the protocol. Statistical Plan
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The primary objective of this phase II study was to determine whether VR-CHOP provides benefit to subjects with previously untreated follicular NHL and other low grade B-cell NHL subtypes, assessed primarily using the CR rate, as determined by international working group criteria.(Cheson, et al 1999) Response was assessed by computerized tomography (CT) after every 2 cycles of induction therapy, one time at least 4 weeks after completing induction (i.e., prior to maintenance), and then every 3 months while on maintenance therapy. At the conclusion of maintenance therapy, patients underwent one post-treatment scan, with further scans completed at the discretion of the treating physician. Positron emission tomography was permitted but only CT measurements were used to determine response. CR rate was determined in an intention-to-treat fashion by dividing the total number of CRs by the total number of patients registered. In addition to the intention-to-treat population, a safety population was identified as all patients receiving at least 1 dose of study therapy. For the primary endpoint, our hypothesis was that VR-CHOP would improve the CR rate from a historical rate of 41% for R-CVP to at least 87%. With a power of 80% to detect this
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improvement and alpha of 0.05, the planned sample size was 30 patients. The estimated CR rate was compared to the historical rate using a one-sided binomial test. Secondary survival endpoints included OS, PFS and duration of CR. For OS and PFS, the time was calculated from the date of first dose of treatment until the date of the event or last follow-up, and duration of CR was calculated from the date of confirmed CR to the date of documented disease progression or death. Median time to event was estimated using the Kaplan-Meier method. Neurological, haematological, and other non-haematological toxicities were reported according to CTCAE version 3.0 and presented in tabular form. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC), and survival curves were generated using R 3.1.1 (http://cran.r-project.org). Significance was assessed at the 0.05 level.
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Results Patient Characteristics
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Thirty patients were initially enrolled on the study. However, one patient was found to have diffuse large B-cell lymphoma when the pathology was re-reviewed at Emory following enrolment and was thus excluded from further analyses. The remaining 29 patients included 16 males (55%) and had a median age of 58 years (range: 31–71). Most patients had follicular lymphoma (n=20, 69%), including 6 with grade 1, 12 with grade 2 and two with grade 3. Among the patients with FL, 70% had a FLIPI ≥ 3 (high risk). In addition, 5 patients had marginal zone lymphoma (17%) and 4 patients had small lymphocytic lymphoma (14%). Most patients had advanced stage disease, including 38% with Stage III and 45% with stage IV disease. Remaining baseline characteristics for enrolled patients are described in Table I. Therapy Received
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Of the 29 eligible patients, one patient discontinued induction therapy after 4 cycles due to thrombocytopenia while 10 patients received 6 cycles and 18 patients received 8 cycles of induction therapy with VR-CHOP. No patient progressed while receiving induction therapy and 25 patients received maintenance therapy, including 19 who received rituximab alone and 6 who received bortezomib and rituximab. The reasons that 4 patients did not receive maintenance therapy were progression (n=1), thrombocytopenia (n=1), refusal (n=1) and loss to follow-up (n=1). As of 1 January 2015, all patients have completed induction and 5 patients remain on maintenance therapy. The remaining patients have discontinued treatment due to completion of maintenance (n=15), grade 3 thrombocytopenia after cycle 4 of induction which precluded further therapy (n=1), progression while on maintenance treatment (n=4), refusal/loss to follow-up before receiving maintenance (n=2) or loss to follow-up after 1 (n=1) and 3 (n=1) cycles of maintenance therapy. See Table II for therapy received and outcomes for treated patients. Response to Therapy All 29 patients were evaluable for response; 19 achieved a CR after induction therapy, resulting in a CR rate of 66%, which was significantly improved over the historical
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comparison of 41% (p=0.007). The PR rate was 34%, resulting in an ORR for this population of 100%. Among the 6 patients who received bortezomib and rituximab as maintenance therapy, 3 converted from a PR to CR. The remaining 3 patients progressed after one maintenance cycle (n=2) or were lost to follow-up after 3 maintenance cycles (n=1). Twenty patients with FL were evaluable for response, and the CR rate for these patients was 75%, with a PR rate of 25% (ORR 100%). Survival Outcomes With a median follow-up of 48.7 months, the 2- and 4-year PFS estimates were both 82.8%. No relapses have occurred between 2 and 4 years. The 2- and 4-year OS estimates were both 92.7% (See Fig 1). Median PFS and OS have not been reached. As of the last available follow-up, 2 patients have died of disease, 4 patients are alive with relapsed disease and 23 patients are alive in continuous remission without documented relapse.
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Adverse Events and Toxicity
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This regimen was generally well tolerated with manageable severity and incidence of peripheral neuropathy, with 2 cases of grade 3 and no cases of grade 4 neuropathy. Grade 1– 2 neuropathy occurred in 20 patients, including 16 patients with grade 1 and four patients with grade 2 neuropathy. Grade 4 neutropenia occurred in 4 patients, and additional grade 3 haematological toxicities included neutropenia (n=10), thrombocytopenia (n=3), anemia (n=1), and febrile neutropenia (n=1). Additional grade 3–4 non-haematological toxicities are identified in Table III and were infrequent. One patient discontinued induction after 4 cycles due to thrombocytopenia and was unable to be retreated. Bortezomib was held during some or all of the maintenance treatments for 4 patients with PR, including 3 cases due to neuropathy (Grade 2 = 2 and Grade 3 = 1) and one case due to grade 3 diarrhoea. There were no identified cardiac toxicities that were felt to be directly related to study therapy aside from tachycardia associated with infection.
Discussion
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As the development of novel therapies for NHL continues, it will be increasingly important to understand their optimal integration into standard therapies, and herein we describe a regimen with manageable toxicity and evidence of efficacy in the front-line setting for indolent NHL. The observed CR rate of 66% compares favourably to historical reports of RCVP (41%), R-CHOP (30%) and BR (40%) in indolent NHL.(Marcus, et al 2005, Rummel, et al 2013) Notably, the percentage of FL patients with FLIPI scores ≥ 3 is greater in this cohort (70%) was greater than that seen in the StiL (Study Group Indolent Lymphoma) study (46% for BR group and 48% for R-CHOP group). Despite the known propensity for indolent NHL to relapse, the achievement of a CR to initial therapy has been associated with improved OS. In a review of 536 patients with untreated FL who received initial therapy across a series of GELA studies in the pre-rituximab era, patients achieving a CR had an improved OS (p< 0.001) as well as an improved survival after first relapse (p=0.025). (Bachy, et al 2010)
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In the current era, in which nearly all patients receive rituximab and in which there are numerous salvage options, CR rate may not be as essential. However, 2-year PFS is also associated with improved long-term outcomes. Casulo et al (2013) reported outcomes of 588 patients in the National Lymphocare Study and found that FL patients with an early progression of disease (i.e., < 2 years after therapy with R-CHOP) had significantly worsened OS at 5 years (50% vs 95%). The 2- and 4- year PFS of 82.8% in the current study compares favourably to prior reports and would suggest a large portion of our sample may experience prolonged OS. Indeed, with the current follow-up, our estimated 4-year OS is 92.7%.
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Integration of bortezomib with additional regimens in other subtypes of NHL has also resulted in excellent response rates and survival, although these regimens have been complicated by the development of peripheral neuropathy. In relapsed DLBCL, the combination of bortezomib with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is particularly active in the activated Bcell-like subtype of DLBCL.(Dunleavy, et al 2009) There were two episodes of grade 4 autonomic neuropathy in this study, and 10 cases of grade 3 neuropathy, resulting in the recommendation that bortezomib be limited to a dose of 1.3 mg/m2 on days 1 and 4 of a 21-day cycle. In untreated DLBCL, the ORR of a combination of bortezomib with standard R-CHOP was 100%, with a CR rate of 86%, in a study also evaluating a1.3 mg/m2 dose on days 1 and 4.(Ruan, et al 2011) Grade 3 neuropathy was much less common with this regimen, effecting only 4% of patients. A randomized study comparing R-CHOP to VR-CHOP in untreated non-germinal centre Bcell-like DLBCL has completed accrual and results are currently pending (NCT00931918).
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We aimed to maintain therapeutic doses of bortezomib in our study while incorporating vincristine, with a dose capped at 1.5 mg per cycle. As a result, we observed a significant but manageable rate of grade 3 neurological toxicity of 6.9% and no episodes of grade 4 toxicity while employing a dose of 1.6 mg/m2. However, we did note that a large portion of our patients experienced grade 1–2 neuropathy, which can be challenging to manage. In the StiL study, 29% of patients receiving R-CHOP had neuropathy (defined as “paresthesias”) of any grade, which is less than that encountered in the current regimen. Despite the challenges associated with neuropathy, omission of vincristine from induction regimens may decrease PFS and OS. In the study of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) vs R-CHOP in mantle cell lymphoma (MCL), the inclusion of bortezomib was clearly beneficial and did not appear to result in undue toxicity.(Robak, et al 2015) However, the benefit of including both vincristine and bortezomib has not been confirmed in MCL or indolent NHL.
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Although an every 8 week maintenance approach is more commonly used in the current era, based on the results of the PRIMA (Primary rituximab and maintenance) study (Salles, et al 2011), we selected a 3-monthly schedule based on earlier findings suggesting that a therapeutic rituximab level of roughly 25 μg/ml could be achieved by administering rituximab every 3 months.(Berinstein, et al 1998, Gordan, et al 2005) Our study also incorporated a response-adapted approach to maintenance therapy, with patients that achieved less than a CR receiving a combination of rituximab and bortezomib. Among the
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10 patients who achieved a PR, 1 patient refused maintenance, 2 patients progressed after receiving 1 cycle of V-R maintenance, 1 was lost to follow-up after completing a portion of maintenance, 3 never received bortezomib due to residual toxicity from induction and 3 actually completed scheduled maintenance. Two patients who completed V-R maintenance and one patient who completed rituximab alone due to neuropathy improved the response from a PR to a CR during maintenance.
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We recognize that R-CHOP may be used less frequently for indolent NHL in the current era based on the results of the StIL study.(Rummel, et al 2013) However, the present study provides further evidence that bortezomib can be safely combined in the front-line setting in B-cell NHL and results in manageable toxicity and excellent efficacy. In addition, the combination of R-CHOP with a proteasome inhibitor remains a viable consideration for investigation in aggressive NHL(Robak, et al 2015) Finally, we eagerly await the results of the currently enrolling randomized study, E2408 (NCT01216683), which will compare the outcomes for patients with FL receiving BR vs BR with bortezomib. These findings, coupled with our report, may further define the role of proteasome inhibition in the upfront setting for NHL. In addition, novel proteasome inhibitors, such as carfilzomib and the oral agent, ixazomib, may improve ease of administration and/or have decreased neuropathy compared to bortezomib. These compounds also should be evaluated in combination with standard agents in the front-line and relapsed setting for patients with indolent NHL.
Acknowledgments
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Support: Dr. Cohen is a Lymphoma Research Foundation scholar. Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support for the conduct of this trial was provided by Millennium.
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Author Manuscript Author Manuscript Figure 1.
Progression-free and Overall Survival for patients with untreated indolent NHL who received bortezomib and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).
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Table I
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Characteristics of Enrolled and Treated Patients (N=29). Characteristic
N
Male, N (%)
16 (55)
Age (years); Median (Range)
58 (31–71)
Morphology, N (%) Follicular Lymphoma, Grade 1
6 (21)
Follicular Lymphoma, Grade 2
12 (41)
Follicular Lymphoma, Grade 3
2 (7)
Marginal Zone Lymphoma
5 (17)
Small Lymphocytic Lymphoma
4 (14)
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Stage, N (%) I
2 (7)
II
1 (3)
III
11 (38)
IV
13 (45)
Missing
1 (3)
B-Symptoms Present at Diagnosis, No (%)
3 (10)
ECOG Performance Status, N (%)
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0
13 (45)
1
14 (48)
2
1 (3)
Missing
1 (3)
FLIPI (N=20 patients with FL), N (%) 1
2 (10)
2
4 (20)
3
11 (55)
4
3 (15)
Note: ECOG – Eastern Cooperative Oncology Group; FLIPI – Follicular lymphoma international prognostic index
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Table II
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Therapy Received and Outcomes for Treated Patients. Treatment/Outcome Initiated VR-CHOP
29 (100%)
Number of Induction Cycles (N=29 treated patients), N (%) 4
1 (3)
6
10 (34)
8
18 (62)
Response to Induction (N=29 treated patients), N (%)
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CR
19 (66)
PR
10 (34)
Overall Response Rate (CR+PR)
29 (100)
CR Rate for Induction for Patients with follicular lymphoma (N=20)
75%
Initial Maintenance Therapy Received, No (%) Rituximab
19 (66)
Rituximab-Bortezomib
6 (21)
None
4 (14)
Induction Response → Maintenance Response, N
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CR → CR
16
CR → Progression
1
CR, Lost to follow-up/No maintenance/Not evaluated
2
PR → CR
3
PR → PR
2
PR → Progression
3
PR, Lost to follow-up/No maintenance/Not evaluated
2
Current Status (N=29 treated patients; Median follow-up 48.7 months) Alive, Relapse Free
23
Alive with Relapsed Disease
4
Died of Disease
2
Died of Other Cause
0
2-year Progression-free survival
82.8%
2-year Overall survival
92.7%
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VR-CHOP, bortezomib rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; CR, complete response; PR, partial response
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Table III
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Grade ≥3 Adverse Events, Regardless of Attribution
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Adverse Event (N=29)
Grade 3 (No of Patients)
Grade 4 (No of Patients)
Peripheral Neuropathy
2
0
Neutropenia
10
4
Thrombocytopenia
3
0
Anaemia
1
0
Febrile Neutropenia
1
0
Vomiting
3
0
Abdominal Pain
2
0
Nausea
2
0
Fatigue
2
0
Hyperglycaemia
2
0
Hypokalaemia
2
0
Anxiety/Depression
1
0
Cellulitis
1
0
Dehydration
1
0
Diarrhoea
2
0
Dyspnoea
1
0
Extravasation
1
0
Fever
1
0
Hypoxia
1
0
Parotitis
1
0
Weakness
1
0
Prolonged QT Interval
1
0
Tachycardia
1
0
Author Manuscript Br J Haematol. Author manuscript; available in PMC 2016 November 01.
Br J Haematol. Author manuscript; available in PMC 2016 November 01. Published in final edited form as: Br J Haematol. 2015 November ; 171(4): 539–546. doi:10.1111/bjh.13637.
A Phase II Study of Bortezomib Added to Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Patients with Previously Untreated Indolent non-Hodgkin’s Lymphoma
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Jonathon B. Cohen1,2, Jeffrey M. Switchenko3, Jean L. Koff1, Rajni Sinha1,2, Jonathan L. Kaufman1,2, H. Jean Khoury1,2, Nassoma Bumpers2, Amanda Colbert2, Amanda HutchisonRzepka2, Loretta J. Nastoupil1, Leonard T. Heffner1,2, Amelia Langston1,2, Mary Jo Lechowicz1,2, Sagar Lonial1,2, and Christopher R. Flowers1,2 1Hematology 2Winship
and Medical Oncology, Emory University, Atlanta, Georgia
Cancer Institute, Emory University, Atlanta, Georgia
3Biostatistics
and Bioinformatics, Emory University, Atlanta, Georgia
Summary
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Bortezomib-containing combinations are active in non-Hodgkin lymphoma (NHL) although peripheral neuropathy can limit its dose intensity. Based on our phase I findings, we conducted a phase II trial of bortezomib in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with a modified dose of vincristine. Patients with untreated indolent NHL received bortezomib (1.6 mg/m2) on days 1 and 8 of a 21-day cycle for up to 8 cycles and R-CHOP with a 1.5 mg cap of vincristine. Patients achieving a complete response (CR) received maintenance rituximab, and remaining patients received maintenance rituximab and bortezomib. The primary endpoint was CR rate; secondary survival analyses were evaluated using the Kaplan-Meier method. Among 29 eligible patients, NHL morphologies included follicular
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Corresponding Author: Christopher R. Flowers, MD, MS, Director, Lymphoma Program, Associate Professor, Department of Hematology & Medical Oncology, Emory University School of Medicine, 1365 Clifton Road, NE, Atlanta, GA 30322, Phone: 404-778-3942, Fax: 404-778-3366, [email protected]. Author contributions: JC analysed data, wrote the manuscript, and cared for patients on the study. JS analysed data, reviewed and edited the manuscript. JKoff cared for patients on the study, reviewed and edited the manuscript. RS cared for patients on the study, reviewed, and edited the manuscript. JKaufman cared for patients on the study, reviewed and edited the manuscript. HJK cared for patients on the study, reviewed and edited the manuscript. NB cared for patients on the study, reviewed and edited the manuscript. AC maintained patient data, coordinated the care for patients on the study, reviewed and edited the manuscript. A H-R maintained patient data, coordinated the care for patients on the study, reviewed and edited the manuscript. LN cared for patients on the study, reviewed and edited the manuscript. LH cared for patients on the study, reviewed and edited the manuscript. AL cared for patients on the study, reviewed and edited the manuscript. MJL cared for patients on the study, reviewed and edited the manuscript. SL cared for patients on the study, reviewed and edited the manuscript. CRF designed the research study, supervised all aspects of the trial, cared for patients on the study, reviewed and edited the manuscript. ALL authors have approved the final, submitted version of the manuscript.
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(n=20), marginal zone (n=5) and small lymphocytic lymphoma (n=4). Nineteen patients had CR (66%) and 10 had partial response (34%), yielding a 100% overall response rate. With a median follow-up of 48.7 months, the 4-year progression-free and overall survivals were 83% and 93%. Twenty-two patients experienced peripheral neuropathy of any grade, and 2 had grade 3 neuropathy. The combination of bortezomib with R-CHOP is effective for indolent NHL, and we plan to evaluate therapies incorporating novel proteasome inhibitors in future studies in NHL.
Keywords Non-Hodgkin lymphoma; Bortezomib; Neuropathy; Follicular lymphoma; Indolent Lymphoma
Introduction Author Manuscript Author Manuscript
Although combination chemo-immunotherapy regimens for follicular lymphoma (FL) and other forms of indolent B-cell non-Hodgkin lymphoma (NHL) have varied in the United States(Friedberg, et al 2012), rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) compared favourably to rituximab, cyclophosphamide, vincristine and prednisone (R-CVP) in a recent analysis of the National LymphoCare study, with a 5-year overall survival (OS) of 86% for R-CHOP and 76% for R-CVP.(Nastoupil, et al 2015) In addition, bendamustine and rituximab (BR) demonstrated improved progressionfree survival (PFS) over R-CHOP for untreated patients with FL (median not reached for BR vs 40.9 months for R-CHOP, p=0.0072) in one German study, and another US study indicated that BR was non-inferior to standard therapy with investigators’ choice of RCHOP/R-CVP for patients with indolent NHL.(Flinn, et al 2014, Rummel, et al 2013) Maintenance rituximab following initial therapy also can improve PFS although this does not appear to improve OS.(Salles, et al 2011) However, despite continued improvement in the front-line management of indolent B-cell NHL with chemo-immunotherapy induction regimens, such as BR(Rummel, et al 2013) and R-CHOP(Press, et al 2013) and maintenance rituximab(Salles, et al 2011), nearly all patients relapse and high risk patients respond poorly to initial therapy and have shortened survival.(Nooka, et al 2013) In each of these studies, approximately 20% of patients experienced progression or death within 2 years of first-line therapy.(Casulo, et al 2013, Federico, et al 2013, Press, et al 2013, Rummel, et al 2013, Salles, et al 2011) These consistent findings highlight the existence of a subgroup of patients with “indolent” NHL who experience a disease course with an aggressive biological behaviour that may benefit from alternative approaches to initial therapy, maintenance, or salvage therapy.
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While the single agent response rate in a phase II study of bortezomib in relapsed or refractory indolent NHL is modest, at 13% with a median PFS of 5.1 months,(Di Bella, et al 2010) bortezomib has been successfully administered in combination with rituximab alone, BR and additional chemotherapy combinations in the relapsed/refractory setting.(Baiocchi, et al 2011, Coiffier, et al 2011, Fowler, et al 2011) In addition, bortezomib shows more promising activity as a single agent in both untreated and relapsed/refractory marginal zone lymphoma, with CR rates of up to 43% in untreated marginal zone lymphoma.(Conconi, et
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al 2011, Troch, et al 2009) In the front-line setting, bortezomib-containing combinations are also effective. When combined with R-CVP in a phase II in Canada, the overall response rate (ORR) was 83%, and there were no incidents of grade 4 neurotoxicity.(Sehn, et al 2011) In this study, bortezomib was administered at a dose of 1.3 mg/m2 on days 1 and 8, and vincristine was administered at standard dose. A non-vincristine containing combination of bortezomib, cyclophosphamide and dexamethasone has also been evaluated with bortezomib administered on a weekly schedule at 1.6 mg/m2, with an ORR of 90% and a median time to progression not reached with a limited sample of 12 patients.(Nabhan, et al 2012) Full dose bortezomib and vincristine have been evaluated in the front-line setting, in a 2-arm study in which patients received either weekly bortezomib at 1.6 mg/m2 or twice-weekly dosing at 1.3 mg/m2 combined with R-CHOP administered at standard dose (vincristine dose: 1.4 mg/m2 with cap of 2 mg).(Ribrag, et al 2009) Despite outstanding efficacy with a CR rate ranging from 79–90%, there was a 41% incidence of grade 3 peripheral neuropathy, suggesting that this regimen may be too toxic at the full doses of vincristine and bortezomib.
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Our group has previously reported the results of a phase I study of bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (VR-CHOP) on a 21-day schedule.(Sinha, et al 2012) In this dose-finding study, the maximum tolerated dose (MTD) for bortezomib was 1.6 mg/m2 on days 1 and 8, with the vincristine dose on day 1 capped at 1.5 mg. Overall, the incidence of grade ≥3 neuropathy was 11%, and the ORR for this phase I study was 100%, including a CR rate of 68%. Based on the demonstrated tolerability and preliminary evidence of efficacy in the phase I study, we now performed a phase II study of VR-CHOP in patients with previously untreated indolent NHL.
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Methods Patients
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This study was open to all patients with untreated indolent NHL meeting modified GELF (Groupe d’Etude des Lymphomes Folliculaires) criteria for treatment.(Brice, et al 1997) In addition, patients with FL with a FL international prognostic index (FLIPI) score ≥ 3 were eligible for enrolment even if they did not meet modified GELF criteria.(Nooka, et al 2013, Solal-Celigny, et al 2004) While prior chemotherapy was not allowed, patients with prior radiation therapy to 1 or 2 sites of disease were eligible to enrol. In addition, subjects were required to have adequate bone marrow, renal, and hepatic function and to have an Eastern cooperative Oncology Group (ECOG) performance status of 0–2. All patients completed the informed consent form and were enrolled in accordance with the Declaration of Helsinki. This study was approved by the Institutional Review Board of Emory University. Treatment Plan Based on our previously reported phase I study, patients were treated at the recommended phase 2 dose for this regimen.(Sinha, et al 2012) This consisted of a 21-day cycle wherein patients received rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2) and vincristine (1.4 mg/m2 with a cap of 1.5 mg) on day 1. In addition, all patients received bortezomib 1.6 mg/m2 intravenously on days 1 and 8, and all patients received
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prednisone 100 mg orally days 1–5. Patients received at least 6 cycles of induction therapy and could receive up to 8 cycles at the discretion of the treating investigator, with the goal being to treat for 2 cycles after best response. At the conclusion of induction, all patients without progressive disease were eligible for maintenance therapy. Patients achieving a CR received rituximab monotherapy (375 mg/m2) every 12 weeks for 2 years, and patients with partial response (PR) or stable disease received rituximab (375 mg/m2) and bortezomib (1.6 mg/m2) administered weekly for 4 weeks every 6 months for up to 2 years.
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Toxicity was assessed for all patients at prescribed time points using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 (http://ctep.cancer.gov/ protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). Given the well-described incidence of neuropathy with both bortezomib and vincristine, an aggressive dosemodification algorithm for patients with neuropathic pain and/or peripheral sensory neuropathy was incorporated into the protocol. In addition, patients completed the Functional Assessment of Cancer Therapy/Gynecological Oncology Group (FACT/GOG) neurotoxicity questionnaire to assist with evaluation of neuropathy and neurological toxicity (Cella, et al 1993). Dose reductions were instituted for all patients with grade 1 neuropathy with pain and higher grade events. Therapy with bortezomib was held for all patients with grade 2 neuropathy with pain or grade 3 neuropathy and therapy was re-introduced at a reduced dose only if the toxicity resolved. Patients with grade 4 neuropathy received no further bortezomib or vincristine. In order to allow patients receiving benefit to continue on study therapy, patients could proceed through up to 3 dose reductions due to toxicity before having to discontinue bortezomib, including reductions to 1.3 mg/m2, 1.0 mg/m2, and 0.7 mg/m2, with patients continuing to receive bortezomib on days 1 and 8 of each cycle. Dose reductions of R-CHOP were not incorporated into the protocol. Statistical Plan
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The primary objective of this phase II study was to determine whether VR-CHOP provides benefit to subjects with previously untreated follicular NHL and other low grade B-cell NHL subtypes, assessed primarily using the CR rate, as determined by international working group criteria.(Cheson, et al 1999) Response was assessed by computerized tomography (CT) after every 2 cycles of induction therapy, one time at least 4 weeks after completing induction (i.e., prior to maintenance), and then every 3 months while on maintenance therapy. At the conclusion of maintenance therapy, patients underwent one post-treatment scan, with further scans completed at the discretion of the treating physician. Positron emission tomography was permitted but only CT measurements were used to determine response. CR rate was determined in an intention-to-treat fashion by dividing the total number of CRs by the total number of patients registered. In addition to the intention-to-treat population, a safety population was identified as all patients receiving at least 1 dose of study therapy. For the primary endpoint, our hypothesis was that VR-CHOP would improve the CR rate from a historical rate of 41% for R-CVP to at least 87%. With a power of 80% to detect this
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improvement and alpha of 0.05, the planned sample size was 30 patients. The estimated CR rate was compared to the historical rate using a one-sided binomial test. Secondary survival endpoints included OS, PFS and duration of CR. For OS and PFS, the time was calculated from the date of first dose of treatment until the date of the event or last follow-up, and duration of CR was calculated from the date of confirmed CR to the date of documented disease progression or death. Median time to event was estimated using the Kaplan-Meier method. Neurological, haematological, and other non-haematological toxicities were reported according to CTCAE version 3.0 and presented in tabular form. All statistical analyses were performed using SAS 9.3 (SAS Institute, Cary, NC), and survival curves were generated using R 3.1.1 (http://cran.r-project.org). Significance was assessed at the 0.05 level.
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Results Patient Characteristics
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Thirty patients were initially enrolled on the study. However, one patient was found to have diffuse large B-cell lymphoma when the pathology was re-reviewed at Emory following enrolment and was thus excluded from further analyses. The remaining 29 patients included 16 males (55%) and had a median age of 58 years (range: 31–71). Most patients had follicular lymphoma (n=20, 69%), including 6 with grade 1, 12 with grade 2 and two with grade 3. Among the patients with FL, 70% had a FLIPI ≥ 3 (high risk). In addition, 5 patients had marginal zone lymphoma (17%) and 4 patients had small lymphocytic lymphoma (14%). Most patients had advanced stage disease, including 38% with Stage III and 45% with stage IV disease. Remaining baseline characteristics for enrolled patients are described in Table I. Therapy Received
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Of the 29 eligible patients, one patient discontinued induction therapy after 4 cycles due to thrombocytopenia while 10 patients received 6 cycles and 18 patients received 8 cycles of induction therapy with VR-CHOP. No patient progressed while receiving induction therapy and 25 patients received maintenance therapy, including 19 who received rituximab alone and 6 who received bortezomib and rituximab. The reasons that 4 patients did not receive maintenance therapy were progression (n=1), thrombocytopenia (n=1), refusal (n=1) and loss to follow-up (n=1). As of 1 January 2015, all patients have completed induction and 5 patients remain on maintenance therapy. The remaining patients have discontinued treatment due to completion of maintenance (n=15), grade 3 thrombocytopenia after cycle 4 of induction which precluded further therapy (n=1), progression while on maintenance treatment (n=4), refusal/loss to follow-up before receiving maintenance (n=2) or loss to follow-up after 1 (n=1) and 3 (n=1) cycles of maintenance therapy. See Table II for therapy received and outcomes for treated patients. Response to Therapy All 29 patients were evaluable for response; 19 achieved a CR after induction therapy, resulting in a CR rate of 66%, which was significantly improved over the historical
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comparison of 41% (p=0.007). The PR rate was 34%, resulting in an ORR for this population of 100%. Among the 6 patients who received bortezomib and rituximab as maintenance therapy, 3 converted from a PR to CR. The remaining 3 patients progressed after one maintenance cycle (n=2) or were lost to follow-up after 3 maintenance cycles (n=1). Twenty patients with FL were evaluable for response, and the CR rate for these patients was 75%, with a PR rate of 25% (ORR 100%). Survival Outcomes With a median follow-up of 48.7 months, the 2- and 4-year PFS estimates were both 82.8%. No relapses have occurred between 2 and 4 years. The 2- and 4-year OS estimates were both 92.7% (See Fig 1). Median PFS and OS have not been reached. As of the last available follow-up, 2 patients have died of disease, 4 patients are alive with relapsed disease and 23 patients are alive in continuous remission without documented relapse.
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Adverse Events and Toxicity
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This regimen was generally well tolerated with manageable severity and incidence of peripheral neuropathy, with 2 cases of grade 3 and no cases of grade 4 neuropathy. Grade 1– 2 neuropathy occurred in 20 patients, including 16 patients with grade 1 and four patients with grade 2 neuropathy. Grade 4 neutropenia occurred in 4 patients, and additional grade 3 haematological toxicities included neutropenia (n=10), thrombocytopenia (n=3), anemia (n=1), and febrile neutropenia (n=1). Additional grade 3–4 non-haematological toxicities are identified in Table III and were infrequent. One patient discontinued induction after 4 cycles due to thrombocytopenia and was unable to be retreated. Bortezomib was held during some or all of the maintenance treatments for 4 patients with PR, including 3 cases due to neuropathy (Grade 2 = 2 and Grade 3 = 1) and one case due to grade 3 diarrhoea. There were no identified cardiac toxicities that were felt to be directly related to study therapy aside from tachycardia associated with infection.
Discussion
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As the development of novel therapies for NHL continues, it will be increasingly important to understand their optimal integration into standard therapies, and herein we describe a regimen with manageable toxicity and evidence of efficacy in the front-line setting for indolent NHL. The observed CR rate of 66% compares favourably to historical reports of RCVP (41%), R-CHOP (30%) and BR (40%) in indolent NHL.(Marcus, et al 2005, Rummel, et al 2013) Notably, the percentage of FL patients with FLIPI scores ≥ 3 is greater in this cohort (70%) was greater than that seen in the StiL (Study Group Indolent Lymphoma) study (46% for BR group and 48% for R-CHOP group). Despite the known propensity for indolent NHL to relapse, the achievement of a CR to initial therapy has been associated with improved OS. In a review of 536 patients with untreated FL who received initial therapy across a series of GELA studies in the pre-rituximab era, patients achieving a CR had an improved OS (p< 0.001) as well as an improved survival after first relapse (p=0.025). (Bachy, et al 2010)
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In the current era, in which nearly all patients receive rituximab and in which there are numerous salvage options, CR rate may not be as essential. However, 2-year PFS is also associated with improved long-term outcomes. Casulo et al (2013) reported outcomes of 588 patients in the National Lymphocare Study and found that FL patients with an early progression of disease (i.e., < 2 years after therapy with R-CHOP) had significantly worsened OS at 5 years (50% vs 95%). The 2- and 4- year PFS of 82.8% in the current study compares favourably to prior reports and would suggest a large portion of our sample may experience prolonged OS. Indeed, with the current follow-up, our estimated 4-year OS is 92.7%.
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Integration of bortezomib with additional regimens in other subtypes of NHL has also resulted in excellent response rates and survival, although these regimens have been complicated by the development of peripheral neuropathy. In relapsed DLBCL, the combination of bortezomib with dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is particularly active in the activated Bcell-like subtype of DLBCL.(Dunleavy, et al 2009) There were two episodes of grade 4 autonomic neuropathy in this study, and 10 cases of grade 3 neuropathy, resulting in the recommendation that bortezomib be limited to a dose of 1.3 mg/m2 on days 1 and 4 of a 21-day cycle. In untreated DLBCL, the ORR of a combination of bortezomib with standard R-CHOP was 100%, with a CR rate of 86%, in a study also evaluating a1.3 mg/m2 dose on days 1 and 4.(Ruan, et al 2011) Grade 3 neuropathy was much less common with this regimen, effecting only 4% of patients. A randomized study comparing R-CHOP to VR-CHOP in untreated non-germinal centre Bcell-like DLBCL has completed accrual and results are currently pending (NCT00931918).
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We aimed to maintain therapeutic doses of bortezomib in our study while incorporating vincristine, with a dose capped at 1.5 mg per cycle. As a result, we observed a significant but manageable rate of grade 3 neurological toxicity of 6.9% and no episodes of grade 4 toxicity while employing a dose of 1.6 mg/m2. However, we did note that a large portion of our patients experienced grade 1–2 neuropathy, which can be challenging to manage. In the StiL study, 29% of patients receiving R-CHOP had neuropathy (defined as “paresthesias”) of any grade, which is less than that encountered in the current regimen. Despite the challenges associated with neuropathy, omission of vincristine from induction regimens may decrease PFS and OS. In the study of VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) vs R-CHOP in mantle cell lymphoma (MCL), the inclusion of bortezomib was clearly beneficial and did not appear to result in undue toxicity.(Robak, et al 2015) However, the benefit of including both vincristine and bortezomib has not been confirmed in MCL or indolent NHL.
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Although an every 8 week maintenance approach is more commonly used in the current era, based on the results of the PRIMA (Primary rituximab and maintenance) study (Salles, et al 2011), we selected a 3-monthly schedule based on earlier findings suggesting that a therapeutic rituximab level of roughly 25 μg/ml could be achieved by administering rituximab every 3 months.(Berinstein, et al 1998, Gordan, et al 2005) Our study also incorporated a response-adapted approach to maintenance therapy, with patients that achieved less than a CR receiving a combination of rituximab and bortezomib. Among the
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10 patients who achieved a PR, 1 patient refused maintenance, 2 patients progressed after receiving 1 cycle of V-R maintenance, 1 was lost to follow-up after completing a portion of maintenance, 3 never received bortezomib due to residual toxicity from induction and 3 actually completed scheduled maintenance. Two patients who completed V-R maintenance and one patient who completed rituximab alone due to neuropathy improved the response from a PR to a CR during maintenance.
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We recognize that R-CHOP may be used less frequently for indolent NHL in the current era based on the results of the StIL study.(Rummel, et al 2013) However, the present study provides further evidence that bortezomib can be safely combined in the front-line setting in B-cell NHL and results in manageable toxicity and excellent efficacy. In addition, the combination of R-CHOP with a proteasome inhibitor remains a viable consideration for investigation in aggressive NHL(Robak, et al 2015) Finally, we eagerly await the results of the currently enrolling randomized study, E2408 (NCT01216683), which will compare the outcomes for patients with FL receiving BR vs BR with bortezomib. These findings, coupled with our report, may further define the role of proteasome inhibition in the upfront setting for NHL. In addition, novel proteasome inhibitors, such as carfilzomib and the oral agent, ixazomib, may improve ease of administration and/or have decreased neuropathy compared to bortezomib. These compounds also should be evaluated in combination with standard agents in the front-line and relapsed setting for patients with indolent NHL.
Acknowledgments
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Support: Dr. Cohen is a Lymphoma Research Foundation scholar. Research reported in this publication was supported in part by the Biostatistics and Bioinformatics Shared Resource of Winship Cancer Institute of Emory University and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support for the conduct of this trial was provided by Millennium.
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Progression-free and Overall Survival for patients with untreated indolent NHL who received bortezomib and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone).
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Table I
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Characteristics of Enrolled and Treated Patients (N=29). Characteristic
N
Male, N (%)
16 (55)
Age (years); Median (Range)
58 (31–71)
Morphology, N (%) Follicular Lymphoma, Grade 1
6 (21)
Follicular Lymphoma, Grade 2
12 (41)
Follicular Lymphoma, Grade 3
2 (7)
Marginal Zone Lymphoma
5 (17)
Small Lymphocytic Lymphoma
4 (14)
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Stage, N (%) I
2 (7)
II
1 (3)
III
11 (38)
IV
13 (45)
Missing
1 (3)
B-Symptoms Present at Diagnosis, No (%)
3 (10)
ECOG Performance Status, N (%)
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0
13 (45)
1
14 (48)
2
1 (3)
Missing
1 (3)
FLIPI (N=20 patients with FL), N (%) 1
2 (10)
2
4 (20)
3
11 (55)
4
3 (15)
Note: ECOG – Eastern Cooperative Oncology Group; FLIPI – Follicular lymphoma international prognostic index
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Table II
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Therapy Received and Outcomes for Treated Patients. Treatment/Outcome Initiated VR-CHOP
29 (100%)
Number of Induction Cycles (N=29 treated patients), N (%) 4
1 (3)
6
10 (34)
8
18 (62)
Response to Induction (N=29 treated patients), N (%)
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CR
19 (66)
PR
10 (34)
Overall Response Rate (CR+PR)
29 (100)
CR Rate for Induction for Patients with follicular lymphoma (N=20)
75%
Initial Maintenance Therapy Received, No (%) Rituximab
19 (66)
Rituximab-Bortezomib
6 (21)
None
4 (14)
Induction Response → Maintenance Response, N
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CR → CR
16
CR → Progression
1
CR, Lost to follow-up/No maintenance/Not evaluated
2
PR → CR
3
PR → PR
2
PR → Progression
3
PR, Lost to follow-up/No maintenance/Not evaluated
2
Current Status (N=29 treated patients; Median follow-up 48.7 months) Alive, Relapse Free
23
Alive with Relapsed Disease
4
Died of Disease
2
Died of Other Cause
0
2-year Progression-free survival
82.8%
2-year Overall survival
92.7%
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VR-CHOP, bortezomib rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; CR, complete response; PR, partial response
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Table III
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Grade ≥3 Adverse Events, Regardless of Attribution
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Adverse Event (N=29)
Grade 3 (No of Patients)
Grade 4 (No of Patients)
Peripheral Neuropathy
2
0
Neutropenia
10
4
Thrombocytopenia
3
0
Anaemia
1
0
Febrile Neutropenia
1
0
Vomiting
3
0
Abdominal Pain
2
0
Nausea
2
0
Fatigue
2
0
Hyperglycaemia
2
0
Hypokalaemia
2
0
Anxiety/Depression
1
0
Cellulitis
1
0
Dehydration
1
0
Diarrhoea
2
0
Dyspnoea
1
0
Extravasation
1
0
Fever
1
0
Hypoxia
1
0
Parotitis
1
0
Weakness
1
0
Prolonged QT Interval
1
0
Tachycardia
1
0
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