advances in the treatment of non-hodgkin’s lymphoma · tle cell lymphoma, ... • successfully...

© 2009 Green Hill Healthcare Communications, LLC

Jointly sponsored by University of Nebraska Medical Center, Center for Continuing Education and Center of Excellence Media, LLC

Advances in the Treatment ofNon-Hodgkin’s LymphomaUpdates from the 2009 Pan PacificLymphoma Conference

The non-Hodgkin’s lymphomas (NHLs)are a diverse group of lymphoidmalignancies that vary greatly in

their molecular biology, clinical presenta-tion, and prognosis. Recent advances intherapy, including the incorporation ofnew, more effective agents into combina-tion regimens, have led to improvedpatient outcomes in several subtypes ofNHL. However, prognosis remains poorfor many patients, especially those withrelapsed and refractory disease. As a result,investigators continue to evaluate novelapproaches to treatment, with the ultimategoal of offering patients the best chance atsurvival with the least amount of toxicity.In order to provide their patients with opti-mal care, clinicians must have access to themost recent clinical updates regardingthese newer therapies, as well as informa-

tion on best practices related to diagnosis,treatment, and supportive care.The Pan Pacific Lymphoma Conference

was convened in June 2009 to present state-of-the-art knowledge regarding varioussubtypes of NHL and to stimulate discus-sion among experts and attendees on un -resolved issues related to treatment.Numerous presentations sought to deter-mine the most effective integration ofnewer therapies into existing treatmentparadigms in the first-line, relapsed, andmaintenance settings. This supplementprovides an overview of several topics pre-sented at the conference, including conser-vative versus aggressive therapy for man-tle cell lymphoma, the use of rituximabmaintenance therapy in follicular lym-phoma, and strategies for improving out-comes in diffuse large B-cell lymphoma.

INTRODUCTION

Supported by an

educational grant from

GenentechIMED

InsIde thIs Issue:

Highlights from the 2009Pan Pacific Lymphoma Conference

Advances in theTreatment of Non-Hodgkin’s Lymphoma

Betty M. Chan, PharmD, BCOPUSC/Norris CancerHospitalLos Angeles, CA

Improving Outcomes inMantle Cell Lymphoma

Katherine L. Byar,MSN, APRN, BCUniversity of Nebraska Medical CenterOmaha, NE

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Visit us at: www.coexm.com October 2009 • Vol. 2 • No. 9

A Supplement to

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CME INFORMATION

Sponsor This activity has been planned and implemented in accordance with theEssential Areas and policies of the Accreditation Council for ContinuingMedical Education through the joint sponsorship of the University ofNebraska Medical Center, Center for Continuing Education and Center ofExcellence Media, LLC.

Target AudienceThe target audience for this activity is physicians, nurses, and pharmacists.

Learning ObjectivesAt the conclusion of this activity, the participants should be better able to:• Identify traditional anthracycline-based treatments for non-Hodgkin’s lym-

phoma (NHL) and discuss the need for newer, more effective therapies.• Describe novel treatment approaches for newly diagnosed and refracto-

ry/relapsed NHL and recent clinical findings on the safety and efficacy ofthese therapies.

• Explore common toxicities associated with various agents used to treatNHL and discuss appropriate management strategies.

Financial SupportThis activity is supported by an educational grant from Genentech IMED.

Instructions for CreditThere is no fee for this activity. To receive credit, participants must:• Review the entire activity• Log on to www.unmc.edu/cce/ocme_nhl• Successfully complete the post-test (70% accuracy)• Complete the evaluation instrument • Print your certificate online

Physician AccreditationThe University of Nebraska Medical Center, Center for ContinuingEducation is accredited by the Accreditation Council for Continuing MedicalEducation to provide continuing medical education for physicians.

The University of Nebraska Medical Center, Center for ContinuingEducation designates this educational activity for a maximum of 1.0 AMA PRACategory 1 Credits™. Physicians should only claim credit commensurate withthe extent of their participation in the activity.

Registered Nurse DesignationThe University of Nebraska Medical Center, Col lege of Nursing ContinuingNursing Education is accredited as a provider of continuing nursing educationby the American Nurses Credentialing Center’s Commission on Accreditation.This activity is provided for 1.5 contact hours under ANCC criteria. Providedfor 1.8 contact hours under Iowa Provider #78. Provider approved by theCalifornia Board of Registered Nursing, Provider #13699 for 1.8 contact hours.

Registered Pharmacy Designation The University of Nebraska Medical Center, Center for ContinuingEducation is accredited by the Accreditation Council for Pharmacy

Education as a provider of continuing pharmacy education. The ACPEprovider number is 0447-9999-09-082-H04-P. To receive the 1 contacthour of continuing education credit, pharmacists should complete theactivity requirements and evaluation at the conclusion of the activity.Approval is valid from the initial release date of October 30, 2009. Theexpiration date is October 30, 2010. A statement of credit will be availablefor printing online upon completion of the post-test with a score of 70%or better and the evaluation instrument.

Faculty/Planner DisclosuresAll planners and faculty participating in continuing education activities provid-ed by the University of Nebraska Medical Center, Center for ContinuingEducation are expected to disclose to the audience any significant support orsubstantial relationship(s) with providers of commercial products and/or devicesdiscussed in this activity and/or with any commercial supporters of the activity.In addition, all faculty are expected to openly disclose any off-label, experimen-tal, or investigational use of drugs or devices discussed in their presentation.Having an interest in or affiliation with a commercial entity does not precludemaking a presentation at a CME activity, but the relationship must be disclosedin advance and any potential conflict of interest must be resolved in accordancewith the ACCME Updated Standards for Commercial Support. The plannersand faculty have been advised that this activity must be free from commercialbias and based upon all the available scientifically rigorous data from researchthat conforms to accepted standards of experimental design, data collection, andanalysis. Disclosure of these commitments and/or relationships is included inthe materials so that participants in the activity may formulate their own judg-ment in interpreting its content and evaluating its recommendations.

The authors, reviewers, and planning committee members listed below havestated they have no significant or substantial relationship with providers orcommercial products and/or devices discussed in this activity and/or with anycommercial supporter of this activity.• Lisa Anzai, RN, MA• Barbara Bekiesz• Susan Berry• Catherine Bevil, RN, EdD• Katherine L. Byar, MSN, APRN, BC• Lois Colburn• Brenda Ram, CMP

The following author has stated that she has the following financial relation-ships:• Betty M. Chan, PharmD, BCOP, has received research/grant support from

Merck & Co.

DisclaimersThe opinions or views expressed in this continuing education activity are thoseof the faculty and do not necessarily reflect the opinions or recommendationsof the University of Nebraska Medical Center, Center for ContinuingEducation and Center of Excellence Media, LLC.

Healthcare professionals and other individuals should review and consider otherpublications and materials on the subject before relying solely upon the infor-mation contained within this educational activity.

Contact InformationIf you have any questions about this activity, please contact Brenda Ram, CMP,in the Center for Continuing Education at the University of Nebraska MedicalCenter, 402-559-9250, or via email at [email protected]

Date of original release: October 30, 2009Expiration date: October 30, 2010.

The estimated time to complete this activity: 60-90 minutes.

Multidisciplinary Cancer Care n 3

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EDITORIAL BOARD

Anna M. Butturini, MDUniversity of Southern CaliforniaPediatricsScott E. Eggener, MDUniversity of ChicagoGenitourinary CancerMehra Golshan, MDDana-Farber Cancer InstituteBreast CancerShaji K. Kumar, MDMayo ClinicHematologic MalignanciesTheodore F. Logan, MDIndiana UniversityMelanoma Beryl McCormick, MDMemorial Sloan-Kettering Cancer CenterRadiation Oncology Laura L. Morris, MDGoshen Center for Cancer CareSurgical OncologyRitu Salani, MDOhio State University Medical CenterGynecologic Malignancies

EDITORIAL CORRESPONDENCE should be addressed toEDITORIAL DIRECTOR, Green Hill Healthcare Com -munications, LLC, 241 Forsgate Drive, Suite 205C, MonroeTownship, NJ 08831. E-mail: [email protected]: CORRESPONDENCE REGARDING SUB-SCRIPTIONS OR CHANGE OF ADDRESS should be direct-ed to CIRCULATION DIRECTOR, Green Hill HealthcareCommunications, LLC, 241 Forsgate Drive, Suite 205C,Monroe Township, NJ 08831. YEARLY SUBSCRIPTIONRATES: One year: $99.00 USD; Two years: $149.00 USD;Three years: $199.00 USD. Correspondence re garding per-mission to reprint all or part of any article published in thisjournal should be addressed to REPRINT PERMISSIONSDEPARTMENT, Green Hill Healthcare Communications,LLC, 241 Forsgate Drive, Suite 205C, Monroe Township, NJ08831. The ideas and opinions expressed in MultidisciplinaryCancer Care‘, The Oncology Nurse®, and The OncologyPharmacist® do not necessarily reflect those of the EditorialBoard, the Editorial Director, or the Publisher. Publication ofan advertisement or other product mention in Multi -disciplinary Cancer Care‘, The Oncology Nurse®, or The On -cology Pharmacist® should not be construed as an endorse-ment of the product or the manufacturer’s claims. Readersare encouraged to contact the manufacturer with questionsabout the features or limitations of the products mentioned.Neither the Editorial Board nor the Publisher assumes anyresponsibility for any injury and/or damage to persons orproperty arising out of or related to any use of the materialcontained in this periodical. Please convey any errors to theEditorial Director. ISSN# applied for January 2008.

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1 INTRODUCTION

2 CME INFORMATION

4 HIGHLIGHTS FROM THE 2009 PAN PACIFIC LYMPHOMA CONFERENCE

10 ADVANCES IN THE TREATMENT OF NON-HODGKIN'S LYMPHOMABetty M. Chan, PharmD, BCOP

11 IMPROVING OUTCOMES IN MANTLE CELL LYMPHOMAKatherine L. Byar, MSN, APRN, BC

Mantle Cell Lymphoma:Conservative Versus AggressiveInduction Therapy Mantle cell lymphoma (MCL) is a

rare, aggressive, B-cell lymphoma thataccounts for approximately 8% of allcases of non-Hodgkin’s lymphoma(NHL).1 Median survival is about 4years, and there is currently no cura-tive regimen for the disease using con-ventional chemotherapy.2 Survivaltimes appear to be increasing, howev-er, due to the incorporation of targetedagents, such as the monoclonal anti-body rituximab, into the treatment par-adigm. Nevertheless, controversy existsas to whether conservative or aggres-sive treatment is the best first-lineapproach for patients with MCL. At the 2009 Pan Pacific Lymphoma

Conference, this issue was debated byJohn Leonard, MD, from Weill CornellMedical College, New York, NY, andJulie Vose, MD, from the University ofNebraska Medical Center, Omaha, NE.

Conservative Induction TherapyDr Leonard began his presentation

by saying that it is difficult to deter-mine if intensive treatments for MCLare better than conservative treat-ments, as data from randomized trialscomparing these 2 approaches are lim-ited. Intensive treatments, which areclearly more toxic, may be useful inyounger patients with very aggressivedisease (eg, the blastoid mantle cellvariant), but not in elderly patients. Hewent on to say that the positive resultsfrom intensive-therapy trials need tobe interpreted with the understandingthat patients enrolled in these trials aregenerally younger and healthier thanthose receiving conservative treatment,and that their baseline features areoften associated with more favorableoutcomes. Thus, patient selection biasmay partially account for the outcomesreported in small studies of aggressivetreatments in MCL. For asymptomaticpatients, some evidence suggests that a“watch-and-wait” approach may beappropriate.

Dr Leonard presented results of aretrospective analysis of 111 patientsfrom his own Weill Cornell MedicalCenter who were treated between 1997and 2007 with either conservative oraggressive induction therapy forMCL.3 The majority of patients in thestudy received conservative therapyconsisting of rituximab plus cyclo -phosphamide, doxorubicin, vin-cristine, and prednisone (R-CHOP) ora similar regimen; only 7% of patientswere treated with an aggressive thera-py such as rituximab plus fractionated

cyclophosphamide, vincristine, dox-orubicin, and dexamethasone (R-HyperCVAD), alternating with ritux-imab plus high-dose methotrexate andcytarabine and/or autologous stemcell transplantation (ASCT). The 3- and 5-year overall survival

(OS) rates for all treated patients in thisanalysis were 86% and 66%, respec-tively. These results were comparableto those of other single-institutionstudies that have evaluated R-HyperCVAD or ASCT induction regi-mens, indicating that aggressive strate-gies may not yield consistently betteroutcomes than conservative strategies.Dr Leonard went on to discuss

another retrospective analysis fromWeill Cornell Medical Center, whichevaluated the effect on outcomes ofdeferring initial therapy (using a“watch-and-wait “ approach) in newlydiagnosed patients with MCL.4 Of the97 patients in the study, 31 wereobserved for more than 3 monthsbefore receiving initial systemic thera-

py, and 66 patients received early treat-ment. Patients in the observationgroup tended to have better perform-ance status and lower InternationalPrognostic Index (IPI) risk at baseline.The median time to first treatment inthe observation group was 12 months(range, 4-128 months), and nearly halfof the patients who did not requiretherapy over the 3-month observationperiod did not initiate therapy for atleast 1 year. On multivariate analysis, the time to

treatment was not predictive of OS.However, OS was better in the obser-vation group than in the group receiv-ing early treatment (OS not reached vs64 months; P = .004). These findingssuggest that deferred initial treatmentmay be an acceptable strategy for select-ed asymptomatic patients with MCL.Dr Leonard suggested that a prog-

nostic index specifically for MCLwould be helpful in individualizingthe risk-benefit analysis for patients.The IPI and the Follicular LymphomaInternational Prognostic Index arewidely used, but these tools weredeveloped for types of NHL other thanMCL. A new prognostic index specifi-cally for MCL, the Mantle CellLymphoma International PrognosticIndex (MIPI), was recently developed.5

This index groups patients into low-,intermediate-, and high-risk groups forOS based on 4 factors (age, perform-ance status, lactate dehydrogenase[LDH] values, and leukocyte count).He concluded by stating that the MIPImay become an important decision-making tool, especially for patientswith advanced-stage MCL.

Aggressive Induction TherapyIn favor of aggressive induction

therapy for selected patients, Dr Vosepointed to a trial by the German Low-Grade Lymphoma Study Group(GLSG), which compared traditionaltherapy consisting of cyclophos-phamide, doxorubicin, vincristine, andprednisone (CHOP) with R-CHOP asfirst-line treatment for MCL.6 Although

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HIGHLIGHTS FROM THE 2009 PAN PACIFIC LYMPHOMA CONFERENCE

These findings suggest thatdeferred initial treatmentmay be an acceptable strategy for selectedasymptomatic patients with MCL.

R-CHOP was significantly superior toCHOP in terms of overall response rate(ORR) (94% vs 75%) and time to treat-ment failure (21 vs 14 months), it didnot yield an advantage for progres-sion-free survival (PFS). Long-termresults of this trial, after 65 months offollow-up, still did not show signifi-cantly better OS with R-CHOP.7 At thetime of reporting, median OS had notbeen reached in the CHOP group, andwas 59 months in the R-CHOP group.OS rates at 5 years were 46% for CHOPand 59% for R-CHOP (P=NS).However, the results did confirm thesuperior time to treatment failure andduration of response (DOR) observedwith R-CHOP. Dr Vose cited results from studies

conducted by the MD Anderson CancerCenter, which used more aggressiveinduction regimens for patients withMCL.8-10 Despite the fact that these regi-mens can be highly toxic, a median fol-low-up of 40 months demonstratedsome very good survival rates. In one of these studies, 99 patients

aged 80 years or younger were treatedwith 6 to 8 cycles of R-HyperCVAD,without subsequent transplantationunless they had not achieved a com-plete response (CR) after 6 cycles.Among patients aged 65 years oryounger, the failure-free survival ratewas 52% at 7 years.8 This regimen isbeing combined with bortezomib in acurrent study,9 and in upcoming trials,maintenance treatment after R-HyperCVAD will also be examined. Dr Vose went on to present data from

a nonrandomized phase 2 study by theNordic Lymphoma Group, in which159 consecutive untreated patientsyounger than 66 years were treatedwith rituximab plus a HyperCVAD-like induction regimen alternatingwith rituximab plus high-dose cytara-bine.11 Responders then received high-dose chemotherapy with carmustine,etoposide, cytarabine, and melphalan(BEAM) or carmustine, etoposide,cytarabine, and cyclophosphamideplus rituximab with in vivo–purged

stem-cell support. ORR was 96% andthe CR was 54%; 6-year OS, PFS, andevent-free survival (EFS) rates were70%, 66%, and 56%, respectively, withno relapses occurring after 5 years.12

Dr Vose also presented results from astudy conducted at her institution, theUniversity of Nebraska MedicalCenter, in which patients with MCLreceived either a standard anthracy-cline-based CHOP-like induction regi-men (with or without rituximab) or aHyperCVAD regimen (with or withoutrituximab) prior to ASCT. The medianage of patients in this trial was 56years, and 58% had elevated LDH levels. Results showed that patientswho received HyperCVAD (with orwithout rituximab) plus ASCT did better than those who received anthra-cyclines with ASCT (Table 1) or with-out ASCT.13

In conclusion, Dr Vose recommend-ed aggressive therapy for symptomaticor intermediate-/high-risk patients,stating that overall, high-dose therapyand ASCT clearly improves PFS overconventional chemotherapy. However,she acknowledged that aggressivetherapy should probably not be givento patients with indolent MCL, as therehave been no randomized trials withHyperCVAD in this population. Inaddition, she recommended less-inten-sive therapy for elderly patients.

Novel Therapies forRelapsed/Refractory MCLThe optimal treatment approach for

relapsed and refractory MCL has yet tobe determined. Various strategies havebeen evaluated, including rituximab-based combinations and regimensincorporating novel targeted agents.The GLSG evaluated the addition ofrituximab to fludarabine, cyclophos-phamide, and mitoxantrone (R-FCM)for the treatment of patients withrelapsed or refractory lymphomas,including MCL.14 This combinationresulted in significantly improvedORR compared with that observed inpatients receiving the 3-drug regimenwithout rituximab (FCM) (79% vs 58%,respectively). For the entire populationtreated with R-FCM, both OS and PFSwere significantly longer than withFCM alone. In the MCL subgroup,treatment with R-FCM significantlyimproved OS, although not PFS, ver-sus treatment with FCM alone.14

Development of chemotherapy re -sistance and the resulting short DORassociated with conventional therapiesmake MCL an appropriate disease in which to study novel agents.Bortezomib, a first-in-class proteasomeinhibitor, has recently been approvedfor use in patients with relapsed/refractory MCL. In the PINNACLEtrial, which evaluated the single-agent



Table 1. Results of Aggressive Therapy (HyperCVAD ± Rituximab + ASCT)Versus Standard Therapy (CHOP-Like Regimen ± Rituximab + ASCT)13

HyperCVAD ± CHOP-Like Regimen ±

Outcome Rituximab + ASCT Rituximab + ASCT

Measure (n=32) (n=48) P Value

1-Year PFS, % 97 76

3-Year PFS, % 78 55 P=.05

1-Year OS, % 97 94

3-Year OS, % 97 68 P=.01

ASCT indicates autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vin-cristine, and prednisone; HyperCVAD, fractionated cyclophosphamide, vincristine, doxorubicin, anddexamethasone, alternating courses with high-dose methotrexate and cytarabine; OS, overall sur-vival; PFS, progression-free survival.

activity of bortezomib in patients withrelapsed/refractory disease, the re -sponse rate was 33%, median DORwas 9.2 months, and median time toprogression was 6.2 months.15 Anupdated analysis after a median of 26.4months confirmed these initial find-ings.16 ORR was 32% (including 8% CRor unconfirmed CR [CRu]), and medi-an DOR was 9.2 months (Table 2).Survival at 1 year was 69% overall and91% among responders.16

Bendamustine, a unique cytotoxicagent with structural similarities toalkylating agents and antimetabolites,has shown activity in relapsed lym-phomas that are resistant to priorchemotherapy, including alkylatingagent–based regimens.17-20 In a phase 2trial of patients with relapsed or refrac-tory MCL, bendamustine combinedwith rituximab produced an ORR of75% and a CR rate of 50%.20

Another class of agents under investi-gation for relapsed/refractory MCL ismammalian target of rapamycininhibitors, including temsirolimus. Arecent phase 3 trial investigated 2 differ-ent regimens of temsirolimus versusinvestigator’s choice of therapy in aheavily pretreated MCL population.21

The ORR seen with temsirolimus 175mg/wk × 3 doses followed by 75mg/wk (arm 1) was 22%, comparedwith an ORR of 6% with temsirolimus175 mg/wk × 3 doses followed by 25mg/wk (arm 2) and 2% with investiga-tor’s choice (arm 3). Median PFS was 4.8months (arm 1), 3.4 months (arm 2), and1.9 months (arm 3). However, OScurves showed no statistical differencebetween groups.21

The immunomodulatory agent lena -lidomide is also being studied in re -lapsed/refractory MCL. A subanalysisof a recent phase 2 trial (NHL-002) oflenalidomide in MCL demonstrated anORR of 53% with a median DOR of 13.7months.22 In a confirmatory phase 2 trial(NHL-003), the ORR in a subset ofpatients with relapsed/refractory MCLwas 43%, including 17% CR/ CRu and26% partial response (PR).23

Rituximab Maintenance forFollicular LymphomaFollicular lymphoma (FL) is an indo-

lent form of NHL that has a variablehistologic classification and clinicalcourse. Transformation to the far moreaggressive diffuse large B-cell lym-phoma (DLBCL) occurs at a 3% annualrate. There are many established thera-pies for FL; however, the disease is stillconsidered incurable. Even whenpatients respond well to initial treat-ment, relapses are common.

The addition of rituximab tochemotherapy regimens has beenshown to improve clinical outcomes inFL. A randomized trial conducted bythe GLSG compared R-CHOP withCHOP alone as initial therapy inpatients with advanced FL.24 R-CHOPreduced treatment failure by 60%, sig-nificantly prolonged time to treatmentfailure, and increased response rates(R-CHOP, 96% vs CHOP, 90%).Similarly, initial therapy with ritux-imab plus cyclophosphamide, vin-

cristine, and prednisone (R-CVP) hasbeen shown to significantly improvetime to progression, response rate, andOS compared with cyclophosphamide,vincristine, and prednisone (CVP)alone in patients with advanced FL.25

The use of rituximab as maintenancetherapy continues to be explored as ameans of prolonging response and sur-vival in patients with FL. At the PanPacific Lymphoma Conference, recentdata on this approach were presentedby Bruce Cheson, MD, from the George -town University Lombardi Com -prehensive Cancer Center, Washington,DC, and Sonali Smith, from theUniversity of Chicago Medical Center.A prospective, randomized, phase 3

trial conducted by the GLSG showedbeneficial results with rituximab main-tenance after rituximab-containingchemotherapy.14 In this trial, patientswho had recurrent or persistent dis-ease after 1 or more induction chemo -therapy regimens were initially ran-domized to receive either FCM orR-FCM every 4 weeks for 4 cycles.However, upon evidence that out-comes were superior with R-FCM, allpatients were switched to this regimen. Patients achieving CR or PR were

randomized again for maintenancetherapy, receiving either rituximabmaintenance for 2 further courses, at 3and 9 months, or observation. Themedian DOR was significantly betterwith rituximab maintenance than withobservation, in both the population

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Table 2. Outcomes With Bortezomib in Relapsed/Refractory MCL16

Refractory MCL Patients With Prior

All Patients Patients High-Intensity Therapy

Result (N=155) (n=58) (n=58)

ORR, % 32 29 25

CR/CRu, % 8 6 10

Median DOR in

responding patients, mo 9.2 5.9 NR

CR/CRu indicates complete response/complete response, unconfirmed; DOR, duration of response;MCL, mantle cell lymphoma; NR, not reached; OS, overall survival; PFS, progression-free survival.

The use of rituximab asmaintenance therapy continues to be explored asa means of prolongingresponse and survival inpatients with FL.

overall (not reached vs 17 months), aswell as in the subset of patients with FLwho received R-FCM (not reached vs26 months). Estimated 3-year OS forrituximab maintenance and observa-tion was 77% and 57%, respectively (P= NS). In this trial, the only adverseevent that was more common with rit-uximab was grade 3/4 neutropenia.14

A prospective, randomized, phase 3trial of rituximab maintenance therapywas also conducted by the EuropeanOrganization for Research andTreatment of Cancer (EORTC 20981).26

Patients with relapsed/refractory FLwere randomized to receive 6 cycles ofCHOP or R-CHOP. Those achievingCR or PR were further randomized tomaintenance therapy with rituximabevery 3 months until relapse (or for upto 2 years of total therapy) or observa-tion. ORRs were 72% and 85% for theCHOP and R-CHOP arms, respectively(P<.001). PFS from the time of first ran-domization was 20 months in theCHOP arm versus 33 months in the R-CHOP arm (P <.001). No statisticallysignificant difference in OS wasobserved. An update of this study, at a median

follow-up of 6 years of the mainte-nance phase, reported on data from334 patients receiving maintenancetherapy.27 Rituximab maintenance wasassociated with a PFS advantage afterboth CHOP and R-CHOP inductiontherapy (Table 3). The investigatorsattributed the lack of advantage in OSto the high proportion (41%) ofpatients receiving rituximab as salvage

therapy after study completion.Although the incidence of grade 3/4infections was higher with rituximabmaintenance than observation (9.4% vs2.4%, respectively), only 4% of patientsdiscontinued rituximab maintenancebecause of lack of tolerability.27

Two ongoing studies may help tofurther clarify the role of rituximabmaintenance in FL. The PRIMA(Primary Rituximab and Maintenance)trial is investigating 2 years of ritux-imab maintenance in FL patients whohave responded to rituximab chemo -therapy. In this study, patients arereceiving investigator’s choice ofinduction therapy (rituximab plusmitoxantrone, chlorambucil, and pred-

nisolone [R-MCP], R-CHOP, R-CVP, orR-FCM). Responding patients are thenrandomized to either rituximab main-tenance or observation. Data from thistrial are scheduled to be presented atthe 2009 annual meeting of theAmerican Society of Hematology. The RESORT (Rituximab Extended

Schedule or Retreatment) trial is beingconducted by the Eastern CooperativeOncology Group for patients withnewly diagnosed FL. All patients inthis phase 3 trial will receive 4 weeks ofrituximab induction therapy, afterwhich they will be randomized to rit-uximab maintenance or retreatmentupon progression. The effects of ritux-imab maintenance and retreatment onoutcome measures will be compared.The presenters emphasized that tox-

icity and treatment resistance areimportant factors to consider beforeinitiating rituximab maintenance ther-

apy. Patients may experience delayedcytopenias, especially neutropenia andthrombocytopenia, which can lead tofurther complications. Maintenancerituximab therapy can also triggerreactivation of viruses. Due to the pos-sibility of rituximab resistance, investi-gation into alternative therapies, suchas radioimmunotherapy, immuno -modulators, and other monoclonalanti bodies, should continue.

New Treatment Strategies for DLBCLThe addition of rituximab to chemo -

therapy regimens has significantlyimproved outcomes for patients withDLBCL, the most common subtype ofaggressive NHL. Currently, R-CHOP isthe standard of care for the first-line treat-ment of patients with this disease.28

Although this regimen can produce goodinitial response rates, relapses are com-mon. Optimal second-line therapy inDLBCL consists of high-dose chemo -therapy plus ASCT; however, somepatients are not candidates for this inten-sive therapy. At the Pan Pacific Lym -phoma Conference, Richard Fisher, MD,from the University of Rochester MedicalCenter, Rochester, NY, presented findingsfrom clinical trials evaluating newerstrategies for patients with DLBCL.The advanced age of many patients

with DLBCL, as well as the presence ofcomorbidities, may preclude the use ofintensive treatment strategies such asASCT. Nevertheless, dose-intensivetherapies have been investigated inolder patients. The NHL-B2 trial, con-ducted by the German High-GradeNon-Hodgkin’s Lymphoma StudyGroup (GHSG), compared CHOP regi-mens administered either every 2weeks (CHOP-14) or every 3 weeks(CHOP-21), with or without etoposide,in patients with DLBCL aged 61 to 75years.29 OS and EFS at 5 years were bet-ter with CHOP-14 than with CHOP-21(Figure). Given that toxicity was simi-lar in the 2 arms, CHOP-14 has beenrecommended as a new standard ofcare for DLBCL patients aged 60 yearsor older.



Table 3. Survival Outcomes inthe EORTC 20981 Trial27

PFS OS

Rituximab maintenance 3.7 yrs 74%

Observation 1.3 yrs 64%

P value <.0001 .07

OS indicates overall survival; PFS, progression-free survival.

Optimal second-line thera-py in DLBCL consists ofhigh-dose chemotherapyplus ASCT; however, somepatients are not candidatesfor this intensive therapy.

In the RICOVER-60 trial, also con-ducted by the GHSG, dose-intensetherapy was evaluated in 1222 patientsaged 61 to 80 years,�this time with theaddition of rituximab.30 Patientsenrolled in this trial received CHOP-14x 6 or 8 cycles or R-CHOP-14 x 6 or 8cycles. R-CHOP-14 was superior interms of EFS, PFS, and OS. R-CHOP-14was not directly compared with R-CHOP-21 in this trial, but 2 upcomingtrials will compare these regimens.One of these studies, conducted by theNational Cancer Research Institute,has yielded early results.31 This largestudy enrolled 1080 previouslyuntreated patients with DLBCL andrandomized them to receive 8 cycles ofR-CHOP-21 or 6 cycles of R-CHOP-14,followed by 2 cycles of rituximabalone. The preliminary analysis, basedon 831 evaluable patients, showed nosignificant differences in outcomesbetween the 2 arms of the study. Ratesof CR were 40% and 49% for R-CHOP-14 and R-CHOP-21, respectively.31 DrFisher noted that the final results ofthese 2 ongoing trials may help todetermine whether dose-escalated R-CHOP-14 can be used in place ofstandard R-CHOP-21 in older patients

with DLBCL.Improved therapies are also needed

for younger patients with relapsed/refractory DLBCL. Salvage therapy forpatients eligible for transplantationwas investigated in the CORAL (Col -laborative Trial in Relapsed AggressiveLymphoma) study, in which rituximabplus ifosfamide, carboplatin, andetoposide was compared with ritux-imab plus dexamethasone, cytarabine,and cisplatin followed by BEAM con-ditioning for ASCT in respondingpatients.32 The results from the firstrandomization showed that responserates were comparable in both arms ofthe study (64% and 63%, respectively),as were PFS (45% and 42%, respective-ly) and OS (56% for both arms). Inpatients without adverse prognosticfactors, a response rate of >80% wasobserved. However, early relapsersand patients refractory to first-line rit-uximab-based chemotherapy had poorresponse rates and prognoses.32

Data on the use of lenalidomide forpatients with relapsed/refractoryDLBLC were also presented.33 In theNHL-003 study, which enrolledpatients ranging in age from 21 to 87years who had received at least 1 line

of previous therapy (79% received rit-uximab), the rate of response tolenalidomide treatment was 30% in theintent-to-treat population. Rates of CR/CRu, PR, and stable disease were 7%,23%, and 21%, respectively. At the timeof reporting, the median DOR had notbeen reached. Thrombocytopenia wasthe main treatment-limiting adverseeffect. The investigators concludedthat, based on these results, lenalido-mide appears to warrant further inves-tigation as salvage therapy in DLBCL.

ConclusionAdvances in therapy for NHL have

improved patient outcomes in recentyears. Further extension of survival,however, is still urgently needed.International congresses such as thePan Pacific Lymphoma Conference arean important venue for bringing tolight the latest results from basic andclinical research and for assessing theimplications for current and futurepatient management. Final resultsfrom ongoing clinical trials may help toresolve some of the issues of concernregarding optimal patient care. n

References1. National Comprehensive Cancer Network.

NCCN™ Clinical Practice Guidelines inOncology: Non-Hodgkin’s Lymphoma.V.2.2009. http://www.nccn.org. Accessed May8, 2009.

2. Dreyling M, Weigert O, Hiddemann W, forthe European MCL Network. Current treat-ment standards and future strategies in mantlecell lymphoma. Ann Oncol. 2008;19(suppl 4):iv41-iv44.

3. Martin P, Chadburn A, Christos P, et al.Intensive treatment strategies may not providesuperior outcomes in mantle cell lymphoma:overall survival exceeding 7 years with standardtherapies. Ann Oncol. 2008;19(7):1327-1330.

4. Martin P, Chadburn A, Christos P, et al. Out -come of deferred initial therapy in mantle-celllymphoma. J Clin Oncol. 2009;27(8):1209-1213.

5. Hoster E, Dreyling M, Klapper W, et al. Anew prognostic index (MIPI) for patients withadvanced-stage mantle cell lymphoma. Blood.2008;111(2):558-565.

6. Lenz G, Dreyling M, Hoster E, et al.Immunochemotherapy with rituximab andcyclophosphamide, doxorubicin, vincristine,and prednisone significantly improves responseand time to treatment failure, but not long-termoutcome in patients with previously untreatedmantle cell lymphoma: results of a prospective

8 n October 2009

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Figure. 5-Year EFS and OS in older patients with DLBCL: CHOP-14 versusCHOP-21.29

% Patients

60

50

40

30

20

10

0

CHOP-14 CHOP-21

43.8

CHOP-14 indicates cyclophosphamide, doxorubicin, vincristine, prednisone, given once every 2 weeks;CHOP-21, cyclophosphamide, doxorubicin, vincristine, and prednisone, given once every 3 weeks; DLBCL,diffuse large B-cell lymphoma; EFS, event-free survival; OS, overall survival.

EFS OS53.3

32.5

40.6

randomized trial of the German Low-GradeLymphoma Study Group (GLSG). J Clin Oncol.2005;23(9):1984-1992.

7. Hoster E, Unterhalt M, Wörmann B, et al, onbehalf of the German Low-Grade LymphomaStudy Group (GLSG) and the EuropeanMCL Network. The addition of rituximab tofirst-line chemotherapy (R-CHOP) results insuperior response rates, time to treatment fail-ure and response duration in patients withadvanced stage mantle cell lymphoma: longterm results of a randomized GLSG trial.Blood. 2008;112(11):3049.

8. Romaguera J, Fayad L, Rodriguez A, et al.Rituximab (R) + hyperCVAD alternating withR-methotrexate/cytarabine after 9 years contin-ued high rate of failure-free survival in untreat-ed mantle cell lymphoma (MCL). Blood. 2008;112(11):833.

9. Romaguera J, Fayad L, McLaughlin P, et al.Phase I trial of bortezomib in combinationwith rituximab-hyperCVAD/methotrexate andcytarabine for untreated mantle cell lym-phoma. Blood. 2008;112(11):3051.

10. Romaguera JE, Fayad L, Rodriguez MA, et al.High rate of durable remissions after treat-ment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus Hyper -CVAD alternating with rituximab plushigh-dose methotrexate and cytarabine. J ClinOncol. 2005;23(28):7013-7023.

11. Geisler CH, Elonen E, Kolstad A, et al.Mantle cell lymphoma can be cured by inten-sive immunochemotherapy with in-vivopurged stem-cell support: final report of theNordic Lymphoma Group MCL2 Study.Blood. 2007;110(11):LB-1.

12. Geisler GH, Kolstad A, Laurell A, et al. Long-term progression-free survival of mantle celllymphoma after intensive front-line immuno -chemotherapy with in vivo-purged stem cellrescue: a nonrandomized phase 2 multicenterstudy by the Nordic Lymphoma Group. Blood.2008;112(7):2687-2693.

13. Vose J, Loberiza F, Bierman P, et al. Mantle celllymphoma (MCL): induction therapy withHyperCVAD/high-dose methotrexate andcytarabine (M-C) (± rituximab) improves resultsof autologous stem cell transplant in first remis-sion. J Clin Oncol. 2006;24(18S):7511.

14. Forstpointner R, Dreyling M, Repp R, et al,for the German Low-Grade Lymphoma StudyGroup. The addition of rituximab to a combi-nation of fludarabine, cyclophosphamide,mitoxantrone (FCM) significantly increasesthe response rate and prolongs survival ascompared with FCM alone in patients withrelapsed and refractory follicular and mantle

cell lymphomas: results of a prospective ran-domized study of the German Low-GradeLymphoma Study Group. Blood. 2004;104(10):3064-3071.

15. Fisher RI, Bernstein SH, Kahl BS, et al.Multicenter phase II study of bortezomib inpatients with relapsed or refractory mantle celllymphoma. J Clin Oncol. 2006;24(30):4867-4874.

16. Goy A, Bernstein SH, Kahl BS, et al.Bortezomib in patients with relapsed orrefractory mantle cell lymphoma: updatedtime-to-event analyses of the multicenterphase 2 PINNACLE study. Ann Oncol. 2009;20(3):520-525.

17. Cheson BD, Rummel MJ. Bendamustine: r ebirth of an old drug. J Clin Oncol. 2009;27(9):1492-1501.

18. Robinson KS,Williams ME, van der Jagt RH, etal. Phase II multicenter study of bendamustineplus rituximab in patients with relapsed indolentB-cell and mantle cell non-Hodgkin’s lym-phoma. J Clin Oncol. 2008;26(27):4473-4479.

19. Weide R, Hess G, Köppler H, et al. High anti-lymphoma activity of bendamustine/mitox-antrone/rituximab in rituximab pretreatedrelapsed or refractory indolent lymphomasand mantle cell lymphomas: a multicenterphase II study of the German Low GradeLymphoma Study Group (GLSG). LeukLymphoma. 2007;48(7):1299-1306.

20. Rummel MJ, Al-Batran SE, Kim S-Z, et al.Bendamustine plus rituximab is effective and hasa favorable toxicity profile in the treatment ofmantle cell and low-grade non-Hodgkin’s lym-phoma. J Clin Oncol. 2005;23(15):3383-3389.

21. Hess G, Herbrecht R, Romaguera J, et al.Phase III study to evaluate temsirolimus com-pared with investigator’s choice therapy forthe treatment of relapsed or refractory mantlecell lymphoma. J Clin Oncol. 2009;27(23):3822-3829.

22. Wiernik PH, Lossos IS, Tuscano JM, et al.Lenalidomide monotherapy in relapsed orrefractory aggressive non-Hodgkin’s lym-phoma. J Clin Oncol. 2008;26(30):4952-4957.

23. Zinzani P, Reeder C, Witzig T, et al.Lenalidomide oral monotherapy in patientswith relapsed or refractory mantle cell lym-phoma: efficacy and safety results from an inter-national study (NHL-003). Presented at the PanPacific Lymphoma Conference, June 22-26,2009, Kohala Coast, Hawaii.

24. Hiddemann W, Kneba M, Dreyling M, et al.Frontline therapy with rituximab added to thecombination of cyclophosphamide, doxoru-bicin, vincristine, and prednisone (CHOP)significantly improves the outcome for

patients with advanced-stage follicular lym-phoma compared with therapy with CHOPalone: results of a prospective randomizedstudy of the German Low-Grade LymphomaStudy Group. Blood. 2005;106:3725-3732.

25. Marcus R, Imrie K, Solal-Celigny P, et al.Phase III study of R-CVP compared withcyclophosphamide, vincristine, and pred-nisone alone in patients with previouslyuntreated advanced follicular lymphoma. JClin Oncol. 2008;26:4579-4586.

26. Van Oers MH, Klasa R, Marcus RE, et al.Rituximab maintenance improves clinical out-come of relapsed/resistant follicular non-Hodgkin lymphoma in patients both with andwithout rituximab during induction: results ofa prospective randomized phase III intergrouptrial. Blood. 2006;108(10):3295-3301.

27. Van Ores M, Van Glabbeke M, Baila L, et al.Rituximab maintenance treatment of relapsed/resistant follicular non-Hodgkin’s lymphoma:long-term outcome of the EORTC 20981phase III randomized intergroup trial. Blood.2008;112:836.

28. Friedberg JW, Fisher RI. Diffuse large B-celllymphoma. Hematol Oncol Clin N Am. 2008;22:941-952.

29. Pfreundschuh M, Trumper L, Kloess M, et al.Two-weekly or 3-weekly CHOP chemothera-py with or without etoposide for the treatmentof elderly patients with aggressive lymphomas:results of the NHL-B2 trial of the DSHNHL.Blood. 2004;104(3):634-641.

30. Pfreundschuh M, Schubert J, Ziepert M, et al.Six versus eight cycles of bi-weekly CHOP-14with or without rituximab in elderly patientswith aggressive CD20+ B-cell lymphomas: arandomized controlled trial (RICOVER-60).Lancet Oncol. 2008;9(2):105-116.

31. Cunningham D, Smith P, Mouncey P, et al. Aphase III trial comparing R-CHOP-14 and R-CHOP-21 for the treatment of patients withnewly diagnosed diffuse large B-cell non-Hodgkin’s lymphoma. J Clin Oncol.2009;27:8506.

32. Gisselbrecht C, Glass B, Mounier N, et al. R-ICE versus R-DHAP in relapsed patients withCD20 diffuse large B-cell lymphoma(DLBCL) followed by autologous stem celltransplantation: CORAL study ]. J Clin Oncol.2009;27:8509.

33. Witzig T, Czuczman M, Haioun C, et al.Patients with relapsed or refractory diffuselarge B-cell lymphoma treated with orallenalidomide monotherapy: results from theinternational study NHL-003. Presented atthe Pan Pacific Lymphoma Conference, June22-26, 2009, Kohala Coast, Hawaii.



The majority of cases of non-Hodgkin’s lymphoma (NHL)diagnosed in the United States

are B-cell lymphomas (diffuse large B-cell, follicular, mantle cell), whereasonly 15% to 20% are T-cell lymphomas.1

Treatment selection for patients with B-cell lymphomas is dependent onwhether the disease is consideredindolent or aggressive. If chemothera-py is chosen as the best approach totreatment, the type of regimen usedwill depend on several factors, such aswhether patients are candidates forstem cell transplantation (SCT), theirability to tolerate intensive treatment,and whether they have symptomaticor asymptomatic disease. Althoughmost patients respond to conventionalfirst-line treatments, duration of re -mission may be short and relapses are common. In younger patients with aggressive

B-cell lymphomas, intensive chemo -therapy regimens with or without SCThave been shown in some studies to pro-duce superior outcomes. How ever, thesetreatments are associated with more tox-icities than conventional chemo therapy.Treatment options for patients withrelapsed/refractory aggres sive lym-phomas who are not eligible for SCT orwho cannot tolerate intensive chemo -therapy regimens are limited.Recent studies evaluating newer

agents, such as bortezomib, tem-sirolimus, bendamustine, and lenalido-mide, have reported antitumor activitywith manageable toxicities. On goingsafety and efficacy studies will help todetermine the optimal role of theseagents for various subtypes of NHL.

Treatment-related Toxicities Although standard chemotherapy is

tolerated in most patients, toxicities dooccur and must be addressed by allmembers of the oncology team. In gen-

eral, grade 3/4 hematologic toxicitiesare less common with conventionalchemo therapy than with more inten-sive regimens. The use of granulocytecolony-stimulating factors (ie, filgras-tim or sargramostim) may be necessary

for treatments that carry a high risk offebrile neutropenia or for patientswith grade 3/4 hematologic toxicitiesfrom previous cycles of chemotherapy.Nonhematologic toxicities, includingnausea and vomiting, peripheral neu-ropathy (PN), and fatigue, may vary inincidence and severity, depending onspecific agents used and patient-relat-ed factors. These toxicities can usuallybe managed with appropriate anti -emetics, dose modifications, bloodtransfusions, and/or erythropoietinagents. The addition of rituximab to chemo -

therapy regimens may increase the riskof infusion-related toxicities, such asfever, chills, rigors, urticaria, and flush-ing. In severe cases, hypotension,bronchospasm, and/or angioedemahave also been observed.2 These toxici-ties can be managed with premedica-tions (ie, acetaminophen or diphenhy-dramine with or without corti -costeroids) and by titrating the rate ofrituximab infusion, as tolerated bypatients. Interventions may includereducing the rate of infusion for a mildreaction or, for more severe reactions,stopping the infusion altogether. In

many cases, after symptoms have sub-sided, the infusion may be restarted ata rate 50% slower than the previousinfusion rate. In severe cases, ritux-imab may need to be discontinuedaltogether.2

Recent concerns have been raisedregarding viral reactivation in patientstreated with chemo therapy plus ritux-imab. As a result, the NCCN guidelinesrecommend Hepatitis B testing prior toinitiation of treatment (with Hepatitis Ctesting only in high-risk patients), andcareful monitoring for symptoms of pro-gressive multifocal leukoencephalopa-thy in these patients.1

Preliminary studies report a lowerincidence of grade 3/4 hematologictoxicities with novel agents than withconventional chemotherapy regimens.Nonhematologic toxicities with theseagents also appear to be manageable. In clinical studies, bor tezomib use

has been commonly associated withfatigue, gastrointestinal toxicities, anddose-limiting grade 3/4 PN (13%),myelo suppression with leukopenia,and thrombocytopenia (11%).3,4

Treatment with temsirolimus hasbeen associated with dose-limitinggrade 3/4 myelosuppression with neu-tropenia (15%-22%) and thrombocy-topenia (52%-59%).5 Anemia, asthenia,and diarrhea have also been reportedwith this agent.5 Due to the possibilityof hypersensitivity reactions, patientson temsirolimus should receivediphenhydramine 30 to 60 minutesprior to treatment.6 They should also bemonitored for electrolyte abnormalities,hyperlipidemia, and hyperglycemia.6

Treatment with bendamustine hasbeen commonly associated with dose-limiting grade 3/4 leukopenia (16%).7

However, thrombocytopenia is rare,with only 3% of patients experiencinggrade 3/4 events.7 Gastrointestinal tox-icities such as mild nausea, vomiting,

10 n October 2009

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PHARMACIST PERSPECTIVE

ADVANCES IN THE TREATMENT OF NON-HODGKIN’S LYMPHOMA

Betty M. Chan, PharmD, BCOP, USC/Norris Cancer Hospital, Los Angeles, CA

Preliminary studies reporta lower incidence of grade3/4 hematologic toxicitieswith novel agents than with conventionalchemotherapy regimens.

and diarrhea have also been reported.8

Treatment with lenalidomide is asso-ciated with dose-limiting grade 3/4neutropenia (24.5% and 8.2%, respec-tively) and thrombocytopenia (12.2%and 8.2%, respectively).9 Therefore,complete blood counts should be mon-itored frequently, and dose reductionsor support with blood transfusionsmay be necessary to mitigate theseadverse effects.

ConclusionThe treatment paradigm for NHL

continues to evolve, due in large partto the emergence of novel targetedagents. While these new therapieshave the potential to improve patientoutcomes in various subtypes of thedisease, prompt and effective manage-ment of treatment-related toxicitieswill be key to ensuring maximumtherapeutic benefit. n

References1. National Comprehensive Cancer Network.

NCCN™ Clinical Practice Guidelines inOncology: Non-Hodgkin’s Lymphoma.V.2.2009. http//www.nccn.org. AccessedOctober 15, 2009.

2. Rituxan [package insert]. South San Francisco,CA: Biogen Idec, Inc and Genentech, Inc; 2007.

3. Fisher RI, Bernstein SH, Kahl BS, et al.Multicenter phase III study of bortezomib inpatients with relapsed or refractory mantle celllymphoma. J Clin Oncol. 2006;24(30):4867-4874.

4. Goy A, Bernstein SH, Kahl BS, et al.Bortezomib in patients with relapsed or refrac-tory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PIN-NACLE study. Ann Oncol. 2009;20(3):520-525.

5. Hess G, Herbrecht R, Romaguera J, et al. PhaseIII study to evaluate temsirolimus comparedwith investigator’s choice therapy for the treat-ment of relapsed or refractory mantle cell lym-phoma. J Clin Oncol. 2009;27(23):3822-3829.

6. Torisel™ [package insert]. Philadelphia, PA:Wyeth Pharmaceuticals, Inc.; 2007.

7. Rummel MJ, Al-Batran SE, Kim S-Z, et al.Bendamustine plus rituximab is effective andhas a favorable toxicity profile in the treat-ment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23(15):3383-3389.

8. Treanda [package insert]. Frazer, PA:Cephalon, Inc; 2009.

9. Wiernik PH, Lossos IS, Tuscano JM, et al.Lenalidomide monotherapy in relapsed oraggressive non-Hodgkin’s lymphoma. J ClinOncol. 2008;26(30):4952-4957.


PHARMACIST PERSPECTIVE NURSE PERSPECTIVE

IMPROVING OUTCOMES IN MANTLE CELLLYMPHOMAKatherine L. Byar, MSN, APRN, BCUniversity of Nebraska Medical Center, Omaha, NE

Mantle cell lymphoma (MCL),one of several subtypes ofnon-Hodgkin’s lymphoma

(NHL), occurs more frequently inolder adults, with the average age atdiagnosis in the mid-60s. It is a sys-temic disease with frequent involve-ment of the bone marrow and the gas-trointestinal tract.For first-line treatment, rituximab

plus cyclophosphamide, doxorubicin,vincristine, and prednisone (R-CHOP)is the most common regimen and isoften given on an outpatient basis.Rituximab plus fractionated cyclo -phosphamide, vincristine, doxorubicin,and dexamethasone (R-HyperCVAD),alternating with high-dose cytarabineand methotrexate, is given on an inpa-tient basis. R-HyperCVAD has shownbetter complete remission and progres-sion-free survival (PFS) rates than R-CHOP regimens, but is associated withconsiderably more toxicities. As aresult, this regimen is generally givento patients younger than 65 years, butmay be used in older patients withgood performance status and fewcomorbid conditions. Results of autologous stem cell

transplant (ASCT) for MCL are vari-able, with many studies showing nobenefit and others showing subsets of patients with favorable event-freesurvival (EFS) rates. The NordicLymphoma Group1 treated MCLpatients (n=159) with 6 cycles alternat-ing R-CHOP and rituximab plus high-dose cytarabine. Responders receivedBEAM (carmustine, etoposide, cytara-bine, melphalan)/BEAC (carmustine,etoposide, cytarabine, cyclo phos -phamide) with in vivo rituximab–purged ASCT. EFS was significantlyimproved in these patients comparedwith another group who were treated

up to 12 years prior and who did nothave the benefit of in vivo–purgedstem cells. Among the 144 responderswho completed treatment, 72% had a 5-year duration of response (DOR).1

These results were substantiated byTam and colleagues,2 who found thatMCL patients who responded to R-HyperCVAD or R-CHOP induction

followed by conditioning with ritux-imab-cyclophosphamide and totalbody irradiation (TBI) or rituximabplus BEAM and ASCT had a signifi-cantly better response after 2 yearsthan those who had not received ritux-imab. Although autologous trans-plants may not cure patients withMCL, it is thought that they may pro-vide long-term disease-free survival.

Treatment of Relapsed DiseaseDespite good initial response rates,

patients with MCL almost alwaysdevelop disease progression. There fore,new, more effective approaches arebeing investigated for relapsed disease.Bortezomib is a proteasome in hibitor

approved for use in multiple myelomaand relapsed MCL.3 Its mechanism ofaction is not clearly understood but isbased on the theory that proteasomeinhibition causes de creased breakdownor increased stability of various pro-apoptotic or regulatory proteins.

Although autologous transplants may not curepatients with MCL, it isthought that they may provide long-term disease-free survival.

Fisher and colleagues4 conducted amulticenter phase 2 study of borte-zomib in 155 patients with relapsed/refractory MCL. Results demonstrateda median DOR of 9.2 months, andmedian overall survival (OS) is ongo-ing at 13.4 months (66%). The mostcommon adverse events were fatigue,peripheral neuropathy, and gastroin-testinal toxicities. Bortezomib is alsobeing studied with combinationchemotherapy regimens such as R-EPOCH (rituximab plus etoposide,doxorubicin, vincristine, cyclophos-phamide, and prednisone), R-CHOP,and R-HyperCVAD in both untreatedand refractory MCL.Bendamustine consists of both an

alkylating and purine analog, thusoffering a unique mechanism of action.This agent is approved for the treat-ment of chronic lymphocytic leukemiaand for use in patients with relapsedlow-grade lymphoma in whom a priorrituximab-containing regimen failed.5

Bendamustine is currently being stud-ied in MCL with rituximab alone or incombination chemotherapy followingmultiple relapses. The most commomtoxicities are hematologic, along withnausea/vomiting, fatigue, and diarrhea.5

Lenalidomide, a thalidomide analog,is approved for use in combination withdexamethasone in patients with re -lapsed multiple myeloma and as a sin-gle agent in patients with 5q-associatedmyelodysplastic syndrome.6 Wiernikand colleagues completed a phase 2,single-arm, multicenter trial evaluatingthe safety and efficacy of lenalidomidemonotherapy in 49 patients with re -lapsed/refractory aggressive NHL(including MCL).7 The most commonhistology was diffuse large B-cell lym-phoma (DLBCL) (53%), and patientshad received a median of 4 prior treat-ment regimens. An objective responserate of 35% was observed, including a12% rate of complete response/uncon-firmed complete response. Responseswere observed in each aggressive histo-logic subtype tested (DLBCL, follicularlymphoma [grade 3], MCL, and trans-

formed lymphomas). Estimated medi-an DOR was 6.2 months, and medianPFS was 4.0 months. The most commongrade 3/4 toxicities were hematologic.Early results of lenalidomide in MCLpatients show favorable efficacy withmanageable toxicity, and this agent isnow being evaluated in combinationwith rituximab.Both myeloablative and nonmyelo -

ablative allogeneic transplantations arepotential options for patients withrelapsed MCL. In a myeloablative allo-geneic stem cell transplant, the patientreceives high doses of chemotherapy,usually with TBI, followed by donorstem cells. Evidence supports a graft-versus-lymphoma effect with this typeof transplant (along with reports oflower relapse rates after allogeneicperipheral stem cell transplant) butwith no clear OS benefit due to highmorbidity/mortality. Donor availabili-ty, prior autologous transplant, comor-bidities, and age of the recipients arefactors that need to be considered withthis type of transplant.8

There are fewer reports of nonmye-loablative transplants in the literature.The goal of nonmyeloablative trans-plants is to capitalize on the graft-ver-sus-malignancy effect while minimiz-ing the toxicity of the preparativeregimen by administering low-dosetherapy pretransplant. In general, entrycriteria are less strict for nonmyeloabla-tive transplants in terms of age andnumber of prior therapies, includingprior ASCT, making this an option forsome patients with MCL.

Emerging Therapies for MCLThere are a number of new drugs

and treatment combinations beingevaluated for MCL, including: • Radioimmunotherapy with iodine-131 tositumomab and yttrium-90ibritumomab tiuxetan;

• Maintenance rituximab followingcombination chemotherapy forrelapsed/refractory disease;

• Temsirolimus, a mammalian targetof rapamycin inhibitor being stud-

ied for pa tients with relapsed MCLalone and in combination with rituximab;

• Monoclonal antibodies (eg, be va ci -z umab in combination with R-CHOP for untreated MCL; alem-tuzumab as part of a conditioningregimen in allogeneic transplants;and epratuzumab, an anti-CD22monoclonal antibody).

ConclusionIn MCL, R-HyperCVAD is the stan-

dard first-line therapy for patients whocan tolerate this treatment. ASCT pro-vides initial remissions and mayincrease OS but is not thought to becurative. There are a number of regi-mens for second-line therapy, but long-term disease-free survival is shorterwith these treatments. New agents areexpanding available treatment options,and novel combinations continue to bestudied. Nurses play a vital role insymptom management and patienteducation and must be aware of alltherapeutic options, as well as thepotential toxicities associated withthese therapies. n

References1. Geisler CH, Elonen E, Kolstad A, et al.

Mantle cell lymphoma can be cured by inten-sive immunochemotherapy with in-vivopurged stem-cell support; final report of theNordic Lymphoma Group MCL2 study.Blood. 2007;110(11):LB-1.

2. Tam CS, Bassett R, Ledesma C, et al.Rituximab containing autologous stem celltransplantation may be curative in mantle celllymphoma for patients in first remission, butnot for patients with recurrent disease. Blood.2008;112(11):1142.

3. Velcade [package insert]. Cambridge, MA:Millennium Pharmaceuticals, Inc; 2008.

4. Fisher RI, Bernstein SH, Kahl BS, et al. Multi -center phase II study of bortezomib in patientswith relapsed or refractory mantle cell lym-phoma. J Clin Oncol. 2006;24(30):4867-4874.

5. Treanda [package insert]. Frazer, PA: Cephalon,Inc; 2009.

6. Revlimid [package insert]. Summit, NJ: CelgeneCorporation; 2009.

7. Wiernik PH, Lossos IS, Tuscano JM, et al.Lenalidomide monotherapy in relapsed orrefractory aggressive non-Hodgkin’s lym-phoma. J Clin Oncol. 2008;26(30):4952-4957.

8. Kasamon YL. Blood or marrow transplanta-tion for mantle cell lymphoma. Curr OpinOncol. 2007;19(2):128-135.

12 n October 2009

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NURSE PERSPECTIVE

COE0509-A

advances in the treatment of non-hodgkin’s lymphoma · tle cell lymphoma, ... • successfully...

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