EXHIBIT 2006
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`EXHIBIT 2006
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`
`Original Article
`
`Bendamustine Is Effective Therapy in
`Patients With Rituximab-Refractory, Indolent
`B-cell Non-Hodgkin Lymphoma
`
`Results From a Multicenter Study
`
`Brad S. Kahl, MD1; Nancy L. Bartlett, MD2; John P. Leonard, MD3; Ling Chen, PhD4; Kristen Ganjoo, MD5;
`Michael E. Williams, MD6; Myron S. Czuczman, MD7; K. Sue Robinson, MD8; Robin Joyce, MD9;
`Richard H. van der Jagt, MD10; and Bruce D. Cheson, MD11
`
`BACKGROUND: Bendamustine hydrochloride is a novel alkylating agent. In this multicenter study, the authors evaluated
`the efficacy and toxicity of single-agent bendamustine in patients with rituximab-refractory, indolent B-cell lymphoma.
`METHODS: Eligible patients (N ¼ 100, ages 31-84 years) received bendamustine at a dose of 120 mg/m2 by intrave-
`nous infusion on Days 1 and 2 every 21 days for 6 to 8 cycles. Histologies included follicular (62%), small lymphocytic
`(21%), and marginal zone (16%) lymphomas. Patients had received a median of 2 previous regimens (range, 0-6 previ-
`ous regimens), and 36%were refractory to their most recent chemotherapy regimen. Primary endpoints included
`overall response rate (ORR) and duration of response (DOR). Secondary endpoints were safety and progression-free
`survival (PFS). RESULTS: An ORR of 75% (a 14% complete response rate, a 3% unconfirmed complete response rate,
`and a 58% partial response rate) was observed. The median DOR was 9.2 months, and median PFS was 9.3 months.
`Six deaths were considered to be possibly treatment related. Grade 3 or 4 (determined using National Cancer Insti-
`tute Common Toxicity Criteria [version 3.0.19]. reversible hematologic toxicities included neutropenia (61%), thrombo-
`cytopenia (25%), and anemia (10%). The most frequent nonhematologic adverse events (any grade) included nausea
`(77%), infection (69%), fatigue (64%), diarrhea (42%), vomiting (40%), pyrexia (36%), constipation (31%), and ano-
`rexia (24%). CONCLUSIONS: Single-agent bendamustine produced a high rate of objective responses with acceptable
`toxicity in patients with recurrent, rituximab-refractory indolent B-cell lymphoma. Cancer 2010;116:106–14. VC 2010
`American Cancer Society.
`
`KEYWORDS: bendamustine, non-Hodgkin lymphoma, B-cell lymphoma, rituximab-refractory, clinical trial.
`
`The anti-CD20 monoclonal antibody rituximab, either as a single agent or, particularly, in combination with chemo-
`therapy, has changed the therapeutic landscape for patients with indolent B-cell lymphoma. In follicular lymphoma,
`which is the most common indolent non-Hodgkin lymphoma (NHL), rituximab combined with chemotherapy has led
`to notable improvements in response rates, progression-free survival (PFS), and overall survival (OS).1-4 Treatment guide-
`lines from the National Comprehensive Cancer Network now recommend a rituximab-based regimen as initial therapy
`for patients with B-cell lymphoma.5 Unfortunately, patients tend to become refractory to rituximab over time. Although
`yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab have demonstrated activity in patients who are refractory
`
`Corresponding author: Brad S. Kahl, MD, University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, 600 Highland Avenue, H4/534
`CSC, Madison, WI 53792; Fax: (608) 262-1982; bsk@medicine.wisc.edu
`
`1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; 2Department of Medicine, Washington University
`School of Medicine, St Louis, Missouri; 3Department of Medicine, Weill Medical College of Cornell University, New York, New York; 4Cephalon, Inc, Frazer, Pennsyl-
`vania; 5Department of Oncology, Stanford University School of Medicine, Palo Alto, California; 6Department of Medicine, University of Virginia School of Medicine,
`Charlottesville, Virginia; 7Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York; 8Department of Medicine, Queen Elizabeth II Health Science
`Center, Halifax, Nova Scotia, Canada; 9Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 10Department of Hematology,
`Ottawa Hospital, Ottawa, Ontario, Canada; 11Department of Medicine, Georgetown University Hospital, Washington, DC
`
`Preliminary research findings from this study were presented at the 2007 American Society of Hematology Annual Meeting and Exposition, Atlanta, Georgia, De-
`cember 8-11, 2007.
`
`We thank Jill Luer, PharmD, for editorial assistance in the preparation of this article.
`
`DOI: 10.1002/cncr.24714, Received: February 26, 2009; Revised: April 6, 2009; Accepted: April 27, 2009, Published online November 4, 2009 in Wiley
`InterScience (www.interscience.wiley.com)
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`to single-agent rituximab, their use has been limited by
`strict eligibility criteria and other factors.6,7 Moreover,
`patients with indolent B-cell
`lymphoma currently are
`more likely to be treated with rituximab-chemotherapy
`combinations than with single-agent rituximab.8 Conse-
`quently, rituximab resistance often develops within the
`context of generalized chemotherapy resistance, and inno-
`vative treatments are needed for this ‘‘rituximab-refrac-
`tory’’ patient population.
`Bendamustine (Treanda; Cephalon, Inc., Frazer,
`Pa) is a novel alkylator whose mechanisms of action
`involve induction of apoptosis through activation of
`DNA-damage stress responses,
`inhibition of mitotic
`checkpoints, and induction of mitotic catastrophe.9
`The compound also contains a benzimidazole ring,
`which may confer purine analogue-like properties in
`addition to the alkylating properties. In vitro studies
`indicate that the DNA repair mechanisms that operate
`after exposure to the drug are different from those
`evoked
`by
`other
`agents,
`potentially
`explaining
`observed antitumor effects in cell lines that are resist-
`ant to other alkylating agents.10 Several German stud-
`ies have evaluated its efficacy as a single agent or in
`combination with chemotherapy and/or rituximab in
`lymphoma.11-
`patients with recurrent,
`indolent B-cell
`16 Bendamustine is indicated for the treatment of in-
`dolent
`lymphoma, multiple myeloma, and chronic
`lymphocytic leukemia (CLL)
`in Germany and was
`approved for the treatment of CLL in the United
`States
`in March 2008. A recent North American
`phase 2 multicenter study in patients with recurrent,
`rituximab-refractory,
`indolent B-cell
`lymphoma dem-
`onstrated that bendamustine produced durable objec-
`tive responses with acceptable toxicity.17 The purpose
`of the current phase 3 multicenter study was to fur-
`ther evaluate the effects of bendamustine in a larger
`group of patients with rituximab-refractory,
`indolent
`B-cell
`lymphoma and to provide the pivotal evalua-
`tion in this patient population.
`
`MATERIALS AND METHODS
`Study Design and Objectives
`This multicenter, open-label, single-arm clinical trial was
`designed to investigate the efficacy and safety of benda-
`mustine in patients with rituximab-refractory, indolent B-
`cell NHL. Primary endpoints
`included the overall
`response rate (ORR) and the duration of response
`
`Bendamustine&Rituximab-Refractory NHL/Kahl et al
`
`(DOR). Secondary endpoints included progression-free
`survival (PFS) and the safety profile. The study was per-
`formed at 24 centers in the United States and at 4 centers
`in Canada. The protocol was approved by the institu-
`tional review board (IRB) at each site, and an IRB-
`approved consent form was signed by each patient before
`study enrollment.
`
`Eligibility
`
`Patients aged 18 years with a World Health Organiza-
`tion performance status 2 were eligible for study partici-
`pation if
`they had documented rituximab-refractory,
`indolent B-cell lymphoma. Rituximab-refractory disease
`was defined as no objective response or documented pro-
`gression within 6 months of 1) receiving the first dose of a
`full course of single-agent rituximab (4 doses of 375
`mg/m2 weekly), 2) completion of rituximab maintenance
`therapy or progression before the next scheduled rituxi-
`mab dose, or 3) completion of a full course of rituximab
`in combination with chemotherapy. Patients were
`required to have bidimensionally measurable disease with
`at least 1 lesion that measured 2.0 cm in a single dimen-
`sion. Patients may have received from 1 to 3 previous
`chemotherapy regimens. Prior autologous stem cell trans-
`plantation was permitted. The baseline
`evaluation
`included a complete medical history, physical examina-
`tion, radiographic imaging studies (computed tomogra-
`phy [CT] or magnetic resonance imaging [MRI] studies),
`bone marrow evaluation, electrocardiogram, and routine
`laboratory studies,
`including lactate dehydrogenase
`(LDH) levels. The following baseline laboratory parame-
`ters were required: absolute neutrophil count (ANC)
`1000 cells/mm3, platelet count 100,000 cells/mm3
`(or 75,000 cells/mm3 in patients who had thrombocy-
`topenia attributable to bone marrow involvement with
`NHL), creatinine clearance >30 mL per minute, and
`adequate hepatic function (<2.5 times the upper limit of
`normal [ULN] range for aspartate aminotransferase and
`alanine aminotransferase and <1.5 times the ULN for
`total bilirubin).
`Patients were excluded from study participation
`for the following reasons: chemotherapy, immunother-
`apy,
`radioimmunotherapy, or
`investigational
`therapy
`within 28 days before the start of Cycle 1 or failure to
`recover from adverse events (AEs) associated with prior
`treatment; myeloid growth factor treatment within 14
`days
`(chronic
`erythropoietic-stimulating
`agent was
`allowed); concurrent treatment with therapeutic doses
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`Original Article
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`of systemic steroids within 14 days; transformed dis-
`ease; history of prior high-dose chemotherapy with
`allogeneic stem cell support; concurrent, active malig-
`nancy (except nonmelanoma skin cancer, in situ cervi-
`cal cancer, or localized prostate cancer treated with
`hormone therapy); central nervous system or leptome-
`ningeal lymphoma; serious infection or another medi-
`cal or psychiatric condition that might interfere with
`achieving the study objectives; pregnancy or lactation;
`or expected survival <3 months.
`
`Treatment
`Bendamustine at a dose of 120 mg/m2 was infused
`intravenously over 60 to 120 minutes on Days 1 and
`2 every 21 days. Treatment was planned for 6 to 8
`cycles as long as a response or stable disease (SD) was
`observed. The development of grade 4 hematologic or
`grade 3/4 nonhematologic toxicities after any cycle led
`to a bendamustine dose reduction to 90 mg/m2 for the
`subsequent cycle; if grade 4 hematologic or grade 3/4
`nonhematologic toxicities were observed at the reduced
`dose level, then bendamustine was reduced further to a
`dose of 60 mg/m2. All dose reductions were perma-
`nent. If further toxicity occurred, then study treatment
`was discontinued.
`Subsequent cycles could be administered if nonhe-
`matologic toxicities resolved to grade 1 and if the ANC
`recovered to 1000 cells/mm3 and the platelet count
`recovered to 75,000 cells/mm3 by the time of the next
`scheduled dose. Dosing was delayed up to 4 weeks until
`these criteria were met. Patients who did not meet these
`criteria after a 4-week delay were removed from protocol
`therapy.
`Primary prophylactic use of growth factors was not
`allowed during Cycle 1. Subsequent filgrastim or pegfil-
`grastim therapy was allowed for patients who had grade 4
`neutropenia that lasted 1 week, failure of the white
`blood cell count to recover to grade 1 by the next sched-
`uled dose, or febrile neutropenia in a previous treatment
`cycle. Low-dose corticosteroids (10 mg daily of predni-
`sone or equivalent) were allowed for non-neoplastic disor-
`ders; however, other on-study use of corticosteroids was
`not permitted (with the exception of 2 doses per cycle as
`an antiemetic). Any patient who demonstrated disease
`progression during therapy was removed from the study.
`
`Criteria for Response and Toxicity
`Response was evaluated by contrast-enhanced CT scans
`or MRI studies at Week 6, Week 12, and every 12 weeks
`
`thereafter until the end of treatment. An end-of-treatment
`scan was obtained within 28 days. Investigators used the
`International Working Group Response criteria for ma-
`lignant lymphoma to determine response to treatment.18
`Patients underwent bone marrow aspiration and biopsy to
`confirm a complete response (CR) if the patient’s bone
`marrow initially had been positive for lymphoma. LDH
`levels also were measured at each disease assessment.
`Tumor response was assessed by investigators and also by
`an independent review committee (IRC) (RadPharm,
`Princeton NJ). The ORR was defined as the proportion
`of patients who achieved as their best response a CR, an
`unconfirmed CR (CRu), and a partial response (PR).
`DOR was defined as the time from the first documenta-
`tion of response until disease progression, death, or
`change of therapy. PFS was calculated as the time from
`the first dose of bendamustine administered until disease
`progression or death from any cause. Patients who
`remained progression free at the end of treatment were
`evaluated every 3 months until death, disease progression,
`or the start of a new anticancer therapy up to a maximum
`of 2 years after treatment. AEs were recorded and their se-
`verity was assessed according to the National Cancer Insti-
`tute’ Common Toxicity Criteria for Adverse Events
`(version 3.0).19 Serious AEs (SAEs) were defined as those
`that were life-threatening, required hospitalization, or
`resulted in significant disability, congenital anomaly of
`offspring, or death.
`
`Statistical Methods
`The primary efficacy and safety analyses were performed
`on all patients who received treatment with bendamustine
`(the primary analysis set). Patients were classified accord-
`ing to their best overall response at the completion of ther-
`apy. Response assessments were made by the investigator
`and an IRC, and the latter assessment informed the pri-
`mary endpoint analysis. The number and percentage of
`patients in each response category (CR, CRu, PR, SD, or
`progressive disease [PD]) were summarized along with a
`2-sided binomial exact 95% confidence interval (95% CI)
`for ORR.
`The statistical criterion for success relative to the
`response outcome was evidence of a true response proba-
`bility >40% with the trial powered for a response proba-
`bility 60%. Therefore,
`the trial
`tested the null
`hypothesis that the true response probability was 40%
`with a planned trial size of 100 patients who had no major
`screening or eligibility violations.
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`Table 1. Patient Demographics and Disease Characteristics
`
`Table 2. Previous Therapies
`
`Bendamustine&Rituximab-Refractory NHL/Kahl et al
`
`No. of
`Patients (%)
`
`Variable
`
`No. of
`Patients (%)
`
`Characteristic
`
`No. of patients treated
`No. of men/women
`Median age [range], y
`
`Disease stage
`I
`II
`III
`IV
`
`Histology
`Follicular
`Grade 1
`Grade 2
`Grade 3
`Unknown
`Small lymphocytic lymphoma
`Lymphoplasmacytic lymphoma
`Marginal zone
`
`100
`65/35
`60 [31-84]
`
`8 (8)
`16 (16)
`33 (33)
`43 (43)
`
`62 (62)
`33 (33)
`16 (16)
`8 (8)
`5 (5)
`21 (21)
`1 (1)
`16 (16)
`
`No. of previous chemotherapy regimens
`0
`1
`2
`3
`>3
`Median [range]
`
`Type of previous therapy
`Single-agent rituximab
`CHOP-like chemotherapy rituximab
`CVP 6 rituximab
`Purine analogue-based
`combinations6rituximab
`Radioimmunotherapy
`External beam radiotherapy
`
`1 (1)
`41 (41)
`36 (36)
`14 (14)
`8 (8)
`2 [0-6]
`
`1 (1)
`37 (37)
`38 (38)
`44 (44)
`
`24 (24)
`20 (20)
`
`CHOP indicates combined cyclophosphamide, doxorubicin, vincristine, and
`prednisone; , with or without; CVP, combined cyclophosphamide, vincris-
`tine, and prednisone.
`
`phoma (n ¼ 16). The patients who had follicular
`histologies were categorized according to the Follicular
`Lymphoma International Prognostic Index (FLIPI) as fol-
`lows: low risk, 29%; intermediate risk, 42%; and high
`risk, 29%. Table 2 summarizes prior treatment history for
`all patients. The median number of prior chemotherapy
`regimens was 2 (range, 0-6 regimens). One patient had
`not received prior chemotherapy (having received only
`single-agent rituximab), and 8 patients had received >3
`prior chemotherapy regimens. These 9 patients were in
`violation of the protocol, which mandated at least 1 but
`not more than 3 prior chemotherapy regimens. They were
`included in the primary analysis, consistent with prespeci-
`fied analysis conditions. Prior treatments included single-
`agent rituximab, chemotherapy with or without rituxi-
`mab, single-agent chemotherapy, radioimmunotherapy,
`and external beam radiation. Thirty-six patients (36%)
`had disease that was refractory to their most recent
`chemotherapy.
`
`Tolerability and Safety
`The median number of cycles completed was 6 (range,
`1-8 cycles). Sixty patients (60%) received at least 6 cycles
`of bendamustine. Forty patients discontinued treatment
`early for the following reasons: AEs (n ¼ 27), disease pro-
`gression (n ¼ 10), patient decision (n ¼ 1), bone marrow
`transplantation referral (n ¼ 1), and an excessive treat-
`ment delay (n ¼ 1) (Table 3). Twenty-four patients
`(24%) had dose reductions because of AEs: Twenty
`
`Follicular Lymphoma Prognostic Index, n ¼ 62
`
`Low risk: 0-1 risk factor
`Intermediate risk: 2 risk factors
`High risk: 3-5 risk factors
`
`18 (29)
`26 (42)
`18 (29)
`
`The median DOR and PFS were assessed using the
`Kaplan-Meier method.20 If the patient did not experience
`disease progression, death, or change of therapy at the
`time of the computation of the DOR or PFS, then the
`patient had a censored observation at the date of the most
`recent progression-free visit. The criterion for success with
`respect to the duration of response was demonstrating
`that the DOR was not significantly less than 6 months
`(defined as the lower end of the 95% CI for the median
`DOR of >4 months).
`
`RESULTS
`Patients
`Between October 2005 and July 2007, 102 patients were
`enrolled at 28 institutions. Two patients did not receive
`treatment and were excluded from the study analysis. One
`hundred patients received at least 1 dose of bendamustine,
`and these patients comprise the current primary analysis
`set. Demographics and baseline characteristics of the 100
`patients in the primary analysis set are summarized in Ta-
`ble 1. The median age was 60 years (range, 31-84 years),
`and 76% of patients had advanced-stage disease at enroll-
`ment. Histologies included follicular lymphoma (n ¼
`63), small lymphocytic lymphoma (n ¼ 21), lymphoplas-
`macytoid lymphoma (n ¼ 1), and marginal zone lym-
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`Table 3. Patient Disposition and Study Drug Tolerability
`
`Table 4. Incidence of Adverse Events by Severity
`(N ¼ 100)
`
`Variable
`
`No. of patients enrolled
`No. of patients treated
`No. of patients completing 6 cycles
`Median no. of cycles completed [range]
`
`Reasons for early termination*
`Total no. of AEs
`Thrombocytopenia
`Fatigue
`Neutropenia
`Infusion-related reaction
`Nausea
`Renal failure
`Cough
`Pulmonary alveolar hemorrhage
`Decline in performance status
`Increase in platelet count
`Leukopenia
`Disease progression
`Patient preference for reason other than AE
`Other†
`
`No. of
`Patients (%)
`
`102
`100
`60 (60)
`6 [1-8]
`
`27
`9
`6
`4
`1
`1
`1
`1
`1
`1
`1
`1
`10
`1
`2
`
`AE indicates adverse event.
`* Forty patients completed <6 treatment cycles.
`y Other reasons for early termination included referral
`for bone marrow
`transplantation in 1 patient and a treatment delay >4 weeks in 1 patient.
`
`percent involved reductions from 120 mg/m2 to 90 mg/
`m2, and 4% were reduced further to 60 mg/m2. Overall,
`68 patients either had dose reductions or dose delays or
`did not receive both doses in any given cycle. Neutropenia
`and thrombocytopenia were the most common reasons
`for dose reductions or delays. The mean relative dose in-
`tensity was 88%.
`Toxicities are summarized in Table 4. Grade 3/4
`neutropenia was noted in 61% of patients over the course
`of the study and led to filgrastim or pegfilgrastim adminis-
`tration in 38% of patients. Grade 3/4 thrombocytopenia
`was noted in 25% of patients and was the second most
`common reason for dose delays or reductions. Failure to
`recover platelet counts to a threshold of 75,000/mm3 was
`the most common reason for premature treatment discon-
`tinuation (9%).
`Infections (any grade) were reported in 69 patients.
`The most frequently reported infections included urinary
`tract infections (n ¼ 11), upper respiratory tract infections
`(n ¼ 9), pneumonia (n ¼ 9), and sinusitis (n ¼ 8).
`Twenty-two grade 3 infections were documented in 15
`patients. Eight grade 4 infections were reported in 6
`patients and included pneumonia (n ¼ 2), sepsis (n ¼ 1),
`Clostridium difficile infection (n ¼ 1), septic shock (n ¼
`1), mycobacterial infection (n ¼ 1), tuberculosis (n ¼ 1),
`
`AE
`
`All Grades
`
`Grade 3
`
`Grade 4
`
`No. of Patients (%)
`
`Hematologic AEs*
`Anemia
`Thrombocytopenia
`Neutropenia
`Febrile neutropenia
`
`Nonhematologic AEsy
`
`Nausea
`Infection
`Fatigue
`Diarrhea
`Vomiting
`Fever
`Constipation
`Anorexia
`Headache
`Stomatitis
`Infusion reaction
`
`94 (94)
`88 (88)
`83 (83)
`6 (6)
`
`77 (77)
`69 (69)
`64 (64)
`42 (42)
`40 (40)
`36 (36)
`31 (31)
`24 (24)
`21 (21)
`21 (21)
`14 (14)
`
`7 (7)
`19 (19)
`38 (38)
`5 (5)
`
`4 (4)
`15 (15)
`12 (12)
`5 (5)
`2 (2)
`1 (1)
`
`3 (3)
`
`0
`
`0
`0
`
`3 (3)
`6 (6)
`23 (23)
`1 (1)
`
`6 (6)
`2 (2)
`
`0
`
`0
`0
`0
`0
`0
`0
`0
`
`1 (1)
`
`1 (1)
`
`AE indicates adverse event.
`* Severity was determined using National Cancer Institute Common Toxicity
`Criteria (version 3.0.19).
`y Listed are common nonhematologic AEs that occurred in >20% of
`patients and all grade 3/4 nonhematologic AEs that occurred in >1 patient.
`
`and noncharacterized infection (n ¼ 1). Five episodes of
`cytomegalovirus (CMV) infection were reported. Nonhe-
`matologic AEs predominantly involved the gastrointesti-
`nal tract, and most were grade 1 or 2 in severity.
`Secondary malignancies were reported in 2 patients.
`The first was a man aged 63 years who developed myelo-
`dysplastic syndrome (MDS) on Day 470 of the study.
`Prior therapies for this patient included combined rituxi-
`mab, fludarabine, mitoxantrone, and dexamethasone (R-
`FND) and I-131 tositumomab. Cytogenetic testing was
`not performed at baseline. MDS was considered by the in-
`vestigator to be possibly related to bendamustine treat-
`ment. The second patient was a man aged 70 years who
`underwent excision of a squamous cell carcinoma on Day
`185 that was considered unrelated to bendamustine.
`There were 2 episodes of tumor lysis syndrome (1
`grade 3 and 1 grade 4), which resolved with appropriate
`supportive care, and both patients were able to continue
`therapy. Infusion-related or hypersensitivity reactions
`were relatively infrequent. Twelve patients experienced
`grade 1 or 2 events within 24 hours of bendamustine infu-
`sion, including chills, fever, rash, back or shoulder pain,
`pruritus, hypotension, and swelling. One grade 3 and 1
`grade 4 hypersensitivity reaction occurred after Day 1 of
`Cycle 3 and after Day 1 of Cycle 2, respectively, and
`resolved with discontinuation of bendamustine.
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`Table 5. Response Rates (in Percentages) According to Non-Hodgkin Lymphoma Histology
`
`Histology
`
`No. of Patients
`
`ORR
`
`CR
`
`CRu
`
`Follicular
`Small lymphocytic
`Lymphoplasmacytic
`Lymph node marginal zone
`Extralymph node marginal zone
`Total
`
`62
`21
`1
`9
`7
`100
`
`74
`71
`100
`78
`86
`75*
`
`15
`5
`0
`11
`43
`14
`
`5
`0
`0
`0
`0
`3
`
`PR
`
`55
`67
`100
`67
`43
`58
`
`SD
`
`PD
`
`Unknown
`
`15
`19
`0
`22
`14
`16
`
`10
`5
`0
`0
`0
`7
`
`2
`5
`0
`0
`0
`2
`
`ORR indicates overall response rate (complete responses plus unconfirmed complete responses plus partial responses); CR, complete response; CRu,
`unconfirmed complete response; PR, partial response; SD, stable disease; PD, progressive disease.
`* The 95% confidence interval was from 65% to 83%.
`
`One or more SAEs were reported in 39 patients. In
`addition, 7 patients experienced SAEs that resulted in
`death: CMV pneumonia (considered to be related to
`bendamustine); pneumonia, diffuse intra-alveolar hemor-
`rhage, and thrombocytopenia (related to bendamustine);
`pneumonia and respiratory failure (most likely related to
`bendamustine); pneumonia and sepsis (most likely related
`to bendamustine); respiratory failure (possibly related to
`bendamustine); worsened chronic obstructive pulmonary
`disease with neutropenia (possibly related to bendamus-
`tine); and cardiopulmonary arrest (considered unrelated
`to bendamustine). Four additional deaths were attributed
`to disease progression.
`
`Efficacy
`Responses to therapy are summarized in Table 5. In the
`100 patients who received at least 1 dose of bendamustine,
`an ORR of 75% (95% CI, 65-83%), as assessed by the
`IRC, was achieved. In patients with follicular histologies
`(n ¼ 62), the ORR was 72%, 77%, and 72% for patients
`who had FLIPI low-risk, intermediate-risk, and high-risk
`disease, respectively. Response rates did not vary appreci-
`ably by histology.
`The ORR in patients who were sensitive to their last
`chemotherapy regimen (ie, patients who had at least a PR;
`n ¼ 51) was 88%, whereas patients who were refractory to
`their last chemotherapy regimen (ie, patients who had no
`response; n ¼ 36) demonstrated an ORR of 64%. Among
`alkylator-sensitive patients (n ¼ 51), the ORR was 86%
`and, among alkylator-refractory patients (n ¼ 30), the
`ORR was 60%. The responses rates among patients who
`had bulky disease (10 cm) and nonbulky disease (<10
`cm) were 50% and 80%, respectively.
`The median DOR in patients who achieved an
`objective response (n ¼ 75) was 9.2 months (95% CI,
`7.1-10.8 months) (Table 6). The DOR was 10 months in
`chemosensitive patients compared with 6.3 months in
`
`Table 6. Median Response Duration in Responders and
`Subgroups*
`
`Patient
`Group
`
`No. of
`Responders
`
`Duration of Response
`(95% CI), mo
`
`Overall
`Chemosensitive
`Chemorefractory
`Alkylator sensitive
`Alkylator refractory
`
`75
`45
`23
`44
`18
`
`9.2 (7.1-10.8)
`10.0 (8.4-11.7)
`6.3 (4.9-NA)
`9.7 (8.3-11.7)
`7.7 (4.9 to NA)
`
`95% CI indicates 95% confidence interval; NA, not available.
`* Subgroups do not total 75 patients, because some patients could not be
`characterized as sensitive versus refractory.
`
`chemorefractory patients. On the basis of a median fol-
`low-up of 11.8 months, the median PFS for the overall
`study population was 9.3 months (95% CI, 8.1-11.9
`months) (Fig. 1 Top). The median PFS for patients who
`were sensitive (n ¼ 51) and refractory (n ¼ 36) to their
`last chemotherapy regimen was 11.8 months (95% CI, 9-
`13 months) and 7.5 months (95% CI, 4.4-12 months),
`respectively (Fig. 1 Bottom). Among patients who were
`sensitive (n ¼ 51) and refractory (n ¼ 30) to previous
`alkylator therapy, the median PFS was 11.8 months (95%
`CI, 8.4-13 months) and 7.5 months (95% CI, 4.4-12
`months), respectively.
`
`DISCUSSION
`Bendamustine is a unique cytotoxic compound. Its chem-
`ical structure contains a 2-chloroethyl (nitrogen mustard)
`group that confers alkylating (DNA-damaging) properties
`and a benzimidazole ring. The precise contribution of the
`benzimidazole ring to the activity of the drug has not been
`defined, but it may affect the types of cross-links formed
`and the susceptibility to DNA repair.9,10
`Two previous German studies have demonstrated
`substantial single-agent activity in recurrent,
`indolent
`lymphoma. Heider and Niederle conducted a study of
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`American study confirmed the efficacy of single-agent
`bendamustine in recurrent NHL.17 Seventy-six patients
`with rituximab-refractory indolent and transformed B-
`cell lymphoma were treated using a dose and schedule of
`120 mg/m2 on Days 1 and 2 every 21 days. An ORR of
`77% was observed, and the median DOR was 6.7
`months. The median DOR was only 2.3 months in the
`transformed population, but limiting the analysis to the
`patients who had indolent histology resulted in a median
`DOR of 9 months. Toxicities were mainly hematologic
`and reversible.
`The current trial confirms and expands upon the
`results observed in the previous North American study.17
`Our trial used the same dose and schedule of bendamus-
`tine in a very similar patient population and produced an
`ORR of 75% and a median DOR of 9.2 months. When
`evaluating these results, it is important to consider the
`patient population under study. This trial included 100
`patients who had received a median of 2 prior chemother-
`apy regimens (range, 0-6 regimens), and almost all of them
`(97 of 100 patients) were refractory to rituximab. Most
`patients (91 of 100) had received prior alkylating-agent
`therapy, 44 patients had received prior purine analogue
`therapy, and 24 patients had received prior radioimmuno-
`therapy. Thirty-six patients were deemed chemotherapy-re-
`fractory (30 patients were alkylator-refractory) based on
`the lack of an objective response to their most recent chem-
`otherapy treatment. Despite the heavily pretreated nature
`of this population, single-agent bendamustine demon-
`strated encouraging efficacy, including an ORR of 64%
`and a PFS of 7.5 months in the chemotherapy-refractory
`population. These clinical data support the in vitro find-
`ings of bendamustine’s activity in cell lines that are resistant
`to other alkylating agents.9,10 The efficacy appears to be
`comparable in the different indolent histologic subtypes.
`For example, the ORR was 74% among the 62 patients
`who had follicular lymphoma and 71% among the 21
`patients who had small lymphocytic lymphoma.
`All of the patients in this study were refractory to rit-
`uximab, and most developed rituximab resistance after
`they received rituximab-chemotherapy combinations
`rather than single-agent rituximab. Preclinical data sug-
`gest that the biologic basis of rituximab resistance may
`vary as a function of the prior therapies received.21,22
`Thus, it is important to establish benchmarks of activity
`in this unique and growing patient population for which
`there are no published trials evaluating other agents or
`regimens. The closest comparison that can be made is to
`radioimmunotherapy studies in a rituximab-refractory
`
`Original Article
`
`5 (cid:9)
`
`1U (cid:9)
`
`15
`
`26
`
`Pragre5sion-Free Survival (Months)
`
`Mo. of Subiesl (cid:9)
`ICC (cid:9)
`
`Ere% (cid:9)
`57%157) (cid:9)
`
`Censored
`43% 6.011 (cid:9)
`
`141,Ji, Sdonivel (15% C1.1
`9Y71695
`
`Netballlity Of RIMiairl I rig Progression-Free
`
`Probability of Remaining Progression-ke.t.
`
`Progoesslon-Foe Survival (Months)
`
`ienzierge- (cid:9)
`fief resluv (cid:9)
`
`NE. of 'Whim& (cid:9)
`51 (cid:9)
`36 (cid:9)
`
`Pont (cid:9)
`45% (15) (cid:9)
`51% (cid:9)
`
`Cmuor•O Male. Loom% t115% C1.1
`5I% 041 (cid:9)
`11.$$ O698 1.051
`39% liii (cid:9)
`7.53[4.41 12.031
`
`Figure 1. Kaplan-Meier curves for progression-free survival in
`patients who received bendamustine are shown both (Top)
`overall (N ¼ 100) and (Bottom) for patients who were sensi-
`tive versus those who were refractory to prior chemotherapy.
`95% CL indicates 95% confidence limits.
`
`single-agent bendamustine at a dose of 120 mg/m2 on
`Days 1 and 2 repeated every 21 days.11 Despite a high fre-
`quency of alkylator-resistant disease, the ORR in that
`study was 73%, and the median DOR was 16 months.
`Bremer evaluated single-agent bendamustine in a similar
`patient population but at a dose and schedule of 60 mg/
`m2 daily for 5 days every 4 to 6 weeks and observed an
`ORR of 82%.12 A recently published, multicenter North
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`population, which was defined as no response or a time to
`progression of <6 months after single-agent rituximab.
`Witzig et al6 reported an ORR of 74% and a median
`DOR of 6.8 months using yttrium-90 ibritumomab tiux-
`etan, and Horning et al7 reported an ORR of 65% and a
`median DOR of 10.4 months using iodine-131 tositumo-
`mab in such patients.6,7
`The major toxicities associated with bendamustine
`were reversible myelosuppression, gastrointestinal toxicity,
`and infection. Some of the infections observed suggested a
`degree of immunosuppression beyond what would be antici-
`pated from transient neutropenia, including 12 episodes of
`herpes zoster and 5 episodes of CMV infection. The CMV
`reactivation was unexpected, because this infection has not
`been reported in other bendamustine trials. No clear risk
`profile for CMV reactivation emerged from the data (of the
`5 patients with CMV, 2 had received prior purine nucleoside
`analogues, 2 had CLL/small lymphocytic lymphoma, and 3
`had follicular lymphoma). Given the absence of CMV in
`other bendamustine trials, we do not advocate monitoring
`CMV viral load in asymptomatic individuals who are receiv-
`ing bendamustine, but we do recommend a low threshold
`for testing in individuals who develop signs or symptoms
`compatible with CMV reactivation. It is important for clini-
`cians to be aware of the potential