Research ArticleClinical Factors Associated with Responseor Survival after Chemotherapy in Patients with WaldenstroumlmMacroglobulinemia in Korea

Ho Sup Lee1 Kihyun Kim2 Dok Hyun Yoon3 Jin Seok Kim4

Soo-Mee Bang5 Jeong-Ok Lee5 Hyeon Seok Eom6 Hyewon Lee6 Inho Kim7

Won Sik Lee8 Sung Hwa Bae9 Se Hyung Kim10 Mark Hong Lee11

Young Rok Do12 Jae Hoon Lee13 Junshik Hong13 Ho-Jin Shin14

Ji Hyun Lee15 Yeung-Chul Mun16 and Chang-Ki Min17

1 Department of Internal Medicine Kosin University College of Medicine 262 Gamcheon-ro Seo-gu Busan 602-702 Republic of Korea2Department of Internal Medicine Samsung Medical Center School of Medicine Sungkyunkwan University 81 Irwon-roGangnam-gu Seoul 135-710 Republic of Korea

3 Department of Oncology Asan Medical Center University of Ulsan College of Medicine 13 Gangdong-daeroSongpa-gu Seoul 138-736 Republic of Korea

4Department of Internal Medicine Yonsei University College of Medicine 50-1 Yonsei-ro Seodaemun-guSeoul 120-752 Republic of Korea

5 Department of Internal Medicine Seoul National University Bundang Hospital 82 Gumi-ro 173 Beon-gil Bundang-guSeongnam-si Gyeonggi-do 463-707 Republic of Korea

6Department of Internal Medicine National Cancer Center of Korea 323 Ilsan-ro Ilsandong-gu Goyang-siGyeonggi-do 410-769 Republic of Korea

7Department of Internal Medicine Seoul National University Hospital 101 Daehak-ro Jongno-gu Seoul 110-744 Republic of Korea8Department of Internal Medicine Busan Paik Hospital 75 Bokji-ro Busanjin-gu Busan 614-735 Republic of Korea9Department of Internal Medicine Daegu Catholic University Medical Center 33 Duryugongwon-ro 17-gil Nam-guDaegu 705-718 Republic of Korea

10Department of Internal Medicine Soonchunhyang University College of Medicine Bucheon Hospital 170 Jomaru-roWonmi-gu Bucheon-si Gyeonggi-do 420-767 Republic of Korea

11Department of Internal Medicine Konkuk University Hospital 120-1 Neungdong-ro Gwangjin-gu Seoul 143-729 Republic of Korea12Department of Internal Medicine Keimyung University College of Medicine 56 Dalseong-ro Jung-guDaegu 700-712 Republic of Korea

13Department of Internal Medicine Gachon University Gil Hospital 21 Namdong-daero 774 Beon-gil Namdong-guIncheon 405-760 Republic of Korea

14Department of Internal Medicine Pusan National University Hospital 179 Gudeok-ro Seo-gu Busan 602-739 Republic of Korea15Department of Internal Medicine Dong-A University College of Medicine 26 Daesingongwon-ro Seo-guBusan 602-715 Republic of Korea

16Department of Internal Medicine Ewha Womans University School of Medicine 1071 Anyangcheon-ro Yangcheon-guSeoul 158-710 Republic of Korea

17Division of Hematology Department of Internal Medicine Seoul St Maryrsquos Hospital College of MedicineThe Catholic University of Korea 222 Banpo-daero Seocho-gu Seoul 137-701 Republic of Korea

Correspondence should be addressed to Chang-Ki Min hemonhsgmailcom

Received 27 March 2014 Revised 12 May 2014 Accepted 12 May 2014 Published 4 June 2014

Academic Editor Dong Soon Lee

Copyright copy 2014 Ho Sup Lee et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 253243 7 pageshttpdxdoiorg1011552014253243

2 BioMed Research International

Waldenstromrsquos macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonalgammopathy and bonemarrow infiltration by lymphoplasmacytic cells Clinical features and cytogenetics ofWM in Asia includingRepublic of Korea remain unclear Moreover no study has reported treatment outcomes in patients with WM treated with novelagent combined with conventional chemotherapy This study investigated clinical features and assessed treatment outcomes withnovel agent and conventional chemotherapy in Republic of Korea Data from all (119899 = 71) patients with newly diagnosed WMat 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively The medianage of patients was 66 years (range 37ndash92 years) and male to female ratio was 5 1 Patients treated with novel agent combinedchemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (929 versus 526119875 = 0006)The 5-year overall survival rate was 626 (95 confidence interval 3473ndash11107) Use of novel agents produced higherORR but survival benefit was not apparent due to the small number of patients and short follow-up duration Further studies areneeded to confirm the efficacy of novel agents in patients with WM

1 Introduction

The consensus group at the Second International Work-shop on Waldenstromrsquos macroglobulinemia (WM) in 2002redefined WM as a distinct clinicopathologic entity charac-terized by bone marrow infiltration by lymphoplasmacyticlymphoma (LPL) and immunoglobulinM (IgM)monoclonalgammopathy [1] Diagnostic criteria for WM are IgM mon-oclonal gammopathy of any concentration bone marrowinfiltration by small lymphocytes showing plasmacytoid orplasma cell differentiation intertrabecular pattern of bonemarrow infiltration and surface IgM+ CD5plusmn CD10minus CD19+CD20+ CD22+ CD23minus CD25+ CD27+ FMC7+ CD103minusand CD138minus immunophenotype [2]

WM is a very rare lymphoid malignancy with an overallincidence estimated at 035 forWMand063 for LPLWMper100000 person-years during 2001ndash2003 representing 12 or21 of all non-Hodgkinrsquos lymphomas in the United StatesSurveillance Epidemiology and End Results (SEER) cancerregistries respectively [3] Between 1996 and 2003 the crudeincidence of LPLWM was 0078 per 100000 person-yearsin Japan (0112 for men and 0048 for women) and 0032 per100000 person-years in Taiwan (0042 for men and 0021 forwomen) [4] A previous nationwide survey of the incidenceof lymphoma based on the REAL classification reported theincidence of LPL in Korea as 08 with the exact incidencerate of WMLPL not recognized [5] The incidence rate ofWM is lower in the Republic of Korea than those in the USAwhich was documented to be about 03 per million person-years according to data of the National Cancer InformationCenter in the Republic of Korea

The most common clinical manifestations are hep-atomegaly (20) splenomegaly (15) and lymphadenopa-thy (15) [6] The most common presenting symptom isfatigue related to normochromic or normocytic anemia Themedian hemoglobin value at diagnosis is 10 gdL [7] Patientswith a disease-related hemoglobin level lt10 gdL plateletcount lt100 times 109L bulky adenopathy or organomegalysymptomatic hyperviscositymoderate to severe or advancingperipheral neuropathy on the basis of disease symptomaticamyloidosis cryoglobulinemia or cold-agglutinin diseaseshould be considered for therapy but asymptomatic patientsshould be observed [8] Recently the superior efficacy ofchemotherapy combined with novel agent including ritux-imab bendamustine bortezomib lenalidomide and thalido-mide than that of conventional chemotherapy has been estab-lished However little is known about the clinical features

epidemiology and cytogenetics of WM in Asia including theRepublic of Korea Novel agent combined chemotherapy forpatients with WM has been restricted in the Republic ofKorea because of very low incidence and insurance coveragelimitation

Treatment outcomes in the Republic of Korea patientswith WM treated by novel agent combined chemotherapyare unclear This study is aimed at investigating the clinicalfeatures and assess the treatment outcomes of novel agentcombined chemotherapy and conventional chemotherapy

2 Materials and Methods

21 Patients Data from 71 patients newly diagnosed withWM who received chemotherapy at 17 university hospi-tals in the Republic of Korea between January 2005 andDecember 2012 were collected retrospectively All casesfulfilled the diagnostic criteria [1] and were confirmed asWM by hematopathologists and hematologists The pre-treatment evaluation included a physical examination withperformance status evaluation complete blood cell countwith differential count blood chemistry including lactasedehydrogenase (LDH) protein electrophoresis (PEP) IgMfree light chain kappa and lambda bonemarrowbiopsy chro-mosomal study fluorescence in situ hybridization (FISH)and computed tomography (CT) of the chest abdomen andpelvis

22 Treatment All patients were treated with conventionalchemotherapy or chemotherapy along with novel agent(rituximab bortezomib thalidomide and bendamustine)Bendamustine is old chemotherapeutic agent but recently theroles of this drug were rediscovered by its efficacy and toxici-ties in indolent lymphoma including WM [9 10] Rituximabcombined chemotherapy included rituximab cyclophos-phamide vincristine and prednisolone (R-CVP) and ritux-imab cyclophosphamide doxorubicin vincristine and pred-nisolone (R-CHOP) Bortezomib combined chemotherapyincluded bortezomib plus dexamethasone (VD) Thalido-mide combined chemotherapy included thalidomide plusdexamethasone (TD) and thalidomide plus cyclophos-phamide and dexamethasone (TCD) Bendamustine wasused along with prednisolone Conventional chemother-apy included chlorambucil CVP CHOP melphalan plusprednisolone (MP) cyclophosphamide plus prednisolone(CP) fludarabine plus cyclophosphamide (FC) and flu-darabine plus cyclophosphamide and mitoxantrone (FCM)

BioMed Research International 3

All patients were treated with one or more chemother-apeutic regimens Patients who displayed progression orintolerance against previous chemotherapy were changedfrom chemotherapy to a salvage regimen Introduction ofnovel agents was applied to four patients as first-line threeas second-line five at third-line and two at fourth-linechemotherapy

23 Analysis Overall response rates (ORR) of patientstreated with conventional and novel therapy were esti-mated as the best response at first-line and applied peri-ods ORR were estimated by clinical para-meters in allpatients including age sex hemoglobin levels plateletcounts absolute lymphocyte counts (ALC) C-reactive pro-tein (CRP) LDH serum 1205732-microglobulin serum albuminhepatosplenomegaly Eastern Cooperative Oncology Group(ECOG) performance status presence of B symptoms andhyperviscosity syndrome Those clinical parameters andinternational staging system (ISS) International Prognos-tic Scoring System for Waldenstromrsquos Macroglobulinemia(ISSWM) and treatment modalities were estimated to findprognostic markers for survival The treatment response wasassessed according to the Sixth International Workshop onWM [11]

24 Statistical Analyses We investigated independent prog-nostic factors associated with survival in above clinical andlaboratory parametersThe definition of overall survival (OS)was calculated from the date of diagnosis to the date ofdeath from disease-related cause or final follow-up dateProgression-free survival (PFS) was from the date of start-ing treatment (conventional chemotherapy or novel agentcombined chemotherapy) to the date of disease progressionrelapse or death from disease-related cause Associationsbetween the clinical parameters and ORR were analyzedusing the chi-square test A multiple logistic regression anal-ysis was used for multivariate analysis of independent prog-nostic factors for ORR Survival probabilities were calculatedaccording to the Kaplan-Meier method and compared usingthe log-rank test The Cox proportional hazards regressionmodel was used for multivariate analysis of independentprognostic factors for survival Information about the base-line medical status and treatment modalities was collectedfrom the medical records Approval for these studies wasobtained from the Institutional Review Board

3 Results

31 Clinical and Laboratory Characteristics The median ageof the 71 patients was 66 years (range 37ndash92 years) and themale to female ratio was 5 1 (Table 1) 254 and 380 ofpatients had clinical or radiological evidence of splenomegalyand of lymphadenopathy respectively 113 of patients had Bsymptoms before the initiation of treatment Hyperviscosityand involvement of other organs were shown in 113 and408 of patients respectively The median serum mono-clonal protein level was 3640 gdL (range 00183ndash10795)The cytogenetic abnormalities identified included deletion ofthe long arm of chromosome 6 in two cases and absence of

Table 1 Clinical and laboratory characteristics

Characteristic 119873 () or median (range)Patients 71Age years median (range) 66 (37ndash92)Gender

Male 59 (831)Female 12 (169)

Hemoglobin gdL median (range) 96 (380ndash1710)Platelet count times109L median (range) 213 (23ndash575)ALC times109L median (range) 170 (010ndash1230)CRP mgdL median (range) 244 (005ndash2380)Serum 1205732-microglobulin mgLmedian (range) 420 (134ndash3000)

Serum albumin gdL median (range) 32 (150ndash460)LDH IUL median (range) 2610 (740ndash9680)BM lymphocyte median (range) 14 (5ndash100)Cytogenetic abnormalities present () 8 (113)Serum monoclonal protein mgdLmedian (range) 36400 (1830ndash107950)

B symptom present () 8 (113)ECOG () ge2 23 (324)Hyperviscosity present () 8 (113)Lymphadenopathy yes () 27 (380)Extranodal involvement yes () 29 (408)Splenomegaly yes () 18 (254)Hepatomegaly yes () 7 (99)ISS ()

I 13 (183)II 26 (366)III 26 (366)Unknown 6 (85)

Treatment regimenNovel agent combinedchemotherapy 14 (197)

Conventional chemotherapy 57 (803)TreatmentNovel group

R-combined CTx R-CVP R-CHOP 6 (85)VD 5 (70)TD 2 (28)Bendamustine plus prednisolone 1 (14)

Conventional groupChlorambucil 25 (352)CVP or CHOP 14 (197)MP or CP 15 (211)FC or FCM 3 (42)

ALC absolute lymphocyte count CRP C-reactive protein LDH lactatedehydrogenase BM bone marrow ECOG Eastern Cooperative OncologyGroup performance status ISS international staging system R-combinedCTx rituximab combined chemotherapy R-CVP rituximab cyclophos-phamide vincristine and prednisolone R-CHOP rituximab cyclophos-phamide doxorubicin vincristine and prednisolone VD bortezomib plusdexamethasone TD thalidomide plus dexamethasone MP melphalan plusprednisolone CP cyclophosphamide plus prednisolone FC fludarabineplus cyclophosphamide FCM fludarabine plus cyclophosphamide andmitoxantrone

trisomy 4 Other cytogenetic abnormalities were identified in113 of cases Other clinical or laboratory characteristics aresummarized in Table 1

4 BioMed Research International

32 Treatment and Outcomes The 71 patients were treatedwith novel agent combined chemotherapy or conventionalchemotherapy 25 patients were treated with chlorambucilwith or without prednisone 14 were treated with CVPor CHOP regimen 15 were treated with the MP or CPregimen and three were treated with FC or FCM as first-line therapy Other patients were treated with novel agentcombined chemotherapy Six patients were treated with R-CVP R-CHOP five with VD two with thalidomide plus dex-amethasone and one with bendamustine plus prednisolone(Table 1) Overall an objective response (complete or partialresponse) and more than minimal response (MR) rates weredocumented in 535 and 690 of patients respectivelyThemedian follow-up was 2297 months The 5-year PFS and OSrates were 505 and 626 (95 confidence interval (95CI) 4832ndash8141 and 3473ndash11107) respectively

33 Analysis of Prognostic Factors for Response and SurvivalMultiple parameters were analyzed for their possible prog-nostic impact on ORR and OS Univariate analysis showedthat the following factors were associated with higher ORR(Table 2) higher ALC (lt10times 109L versusge10times 109L 200versus 646 119875 = 0069) good ECOG performance status(lt2 versus ge2 674 versus 435 119875 = 0057) and novel agentcombined chemotherapy versus conventional chemotherapy(929 versus 526 119875 = 0006) The following factorswere associated with superior 5-year OS (Table 2) youngerage (lt65 years versus ge65 years 822 versus 368 119875 =0024) good ECOG performance status (lt2 versus ge2 726versus 269 119875 = 0004) higher serum albumin levels(lt35 gdL versus ge35 gdL 448 versus 841 119875 = 0010)lower risk international staging system (ISS I II and III857 848 and 368 resp 119875 = 0004) and novel agentcombined chemotherapy versus conventional chemotherapy(100 versus 530 119875 = 0067) In the multivariate analysisnovel agent combined chemotherapy was an independentprognostic value for ORR (119875 = 0046) and lower ISS was anindependent prognostic value for OS (119875 = 0008) (Table 3)

4 Discussion

The clinical manifestations and laboratory abnormalitiesassociated with WM are related to direct tumor infiltrationand to the amount and specific properties ofmonoclonal IgMThe most common symptoms are weakness and fatigue usu-ally secondary to anemia Symptoms of weight loss excessivesweating and low-grade fever affect a quarter of patientsHepatomegaly splenomegaly and lymphadenopathy eachoccur in 15ndash30 of patients Similarly previous Koreanstudies reported the most common symptoms as anemia andthrombocytopenia with other frequently expressed symp-toms being (20ndash40) hepatosplenomegaly (25ndash35) andlymphadenopathy (25ndash40) [12ndash14] In this study anemiawas the most frequent symptom and thrombocytopeniawas secondary frequent symptom with lymphadenopathyhepatomegaly and splenomegaly being expressed in 10ndash40 of the cases However hyperviscosity syndrome wasdocumented only in eight cases which was a relatively lowincidence compared towestern results [6]Themost common

cytogenetic abnormality was deletion of the long arm ofchromosome 6 (6q deletion) and trisomy 4 [15 16] Howeverthere was only one report about cytogenetics of Korean WMpatients which documented a low rate of 6q deletion (10)and no trisomy 4 [13] Similar to a previous Korean studythis study documented a low rate of 6q deletion and othercytogenetic abnormalities

In this study novel agent combined chemotherapy wasthe only independent predictive factor for response ratesalthough higher ALC count and good performance statuswere also associated with higher ORR in univariate analysisMany studies have been shown to improve response andsurvival rates in patients with WM Gertz et al presentedmeaningful results about efficacy of rituximab in patientswith WM [17] The efficacy of rituximab in WM has beenamply described Rituximab combined chemotherapy includ-ing R-CHOP R-CVP R-CP R-F (fludarabine) R-cladribineand R-CD (cyclophosphamide and dexamethasone) pro-duces superior response rates to conventional chemotherapy[18ndash23] Rituximab combined with thalidomide reportedlyproduced a 72 response rate and rituximab combinedwith lenalidomide produced a 50 response rate [24 25]Bortezomib has high levels of activity in the managementof relapsed WM with response rates ranging from 81to 96 [26 27] In a prospective randomized study ofbendamustine plus rituximab compared with R-CHOP inpatients with WM of whom 22 received bendamustine andrituximab and 19 received R-CHOP the response rate was95 in both groups but median progression-free survivalwas significantly prolonged with bendamustine The medianprogression-free survival for R-CHOPwas 36months in con-trast to not being reached with bendamustine and rituximab(119875 lt 00001) [28]

In our study only lower risk ISS showed superior survivalto those of higher risk ISS although younger age goodperformance status higher serum albumin levels and novelagent combined chemotherapy were associated with longerOS in univariate analysis Patients treated with novel agentcombined chemotherapy especially did not show superiorsurvival rates to conventional chemotherapy in spite ofhigher ORR in patients receiving novel agents These resultsmight be associated with small sample size short follow-up duration and the clinical features of WM (which seemsto be indolent lymphoma) Prior studies have documentedseveral prognostic factors for survival [29ndash33] Age anemialeukopenia thrombocytopenia serum albumin levels and1205732-microglobulin values were linked to survival Howeverthese prognostic factors were not meaningful in this studyVery low incidence rates ofWMand restriction of using novelagents because of the limitation of medical reimbursementin Korea might be reasons for the insufficient comparisonbetween novel agent combined chemotherapy and conven-tional chemotherapy in this study

5 Conclusions

Clinical features of Korean WM are similar to westernWM except for the low incidence of hyperviscosity syn-drome Response rates after chemotherapy were improved by

BioMed Research International 5

Table 2 Clinical and laboratory values associated with survival on univariate analysis

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

Age yearslt65 667 0327 648 0708 822 0024ge65 553 370 368

GenderMale 644 0197 468 0530 659 0130Female 417 779 450

BM lymphocyte lt50 630 0461 618 0478 406 0610ge50 529 262 525

Cytogenetic abnormalitiesPresence 750 0466 643 0599 500 0444Absence 587 509 424

Hemoglobin gdLlt115 613 0732 543 0140 602 0700ge115 556 00 875

Platelet count times109Llt100 692 0479 00 0049 619 0124ge100 586 606 630

ALC times109Llt10 200 0069 333 0611 400 0224ge10 646 543 646

CRP mgdLlt5 580 0817 464 0937 655 0096ge5 615 513 486

Serum 1205732-microglobulin mgLlt3 667 0862 489 0130 500 0143ge3 640 506 584

Serum albumin gdLlt35 585 0683 431 0712 448 0010ge35 633 644 841

LDH IULlt450 597 0688 501 0849 618 0403ge450 667 656 729

B symptomPresence 875 0132 833 0666 600 0385Absence 565 488 628

ECOG ()0-1 674 0057 687 0012 726 0004ge2 435 181 269

Hyperviscosity syndromePresence 250 0055 583 0980 00 0918Absence 638 497 662

SplenomegalyPresence 611 0838 774 0342 00 0300Absence 583 495 527

HepatomegalyPresence 571 0884 400 0246 286 0913Absence 600 425 451

ISSWM ()Low 571

0567667

0912500

0380Intermediate 588 587 580High 750 00 584

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 BioMed Research International

Waldenstromrsquos macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonalgammopathy and bonemarrow infiltration by lymphoplasmacytic cells Clinical features and cytogenetics ofWM in Asia includingRepublic of Korea remain unclear Moreover no study has reported treatment outcomes in patients with WM treated with novelagent combined with conventional chemotherapy This study investigated clinical features and assessed treatment outcomes withnovel agent and conventional chemotherapy in Republic of Korea Data from all (119899 = 71) patients with newly diagnosed WMat 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively The medianage of patients was 66 years (range 37ndash92 years) and male to female ratio was 5 1 Patients treated with novel agent combinedchemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (929 versus 526119875 = 0006)The 5-year overall survival rate was 626 (95 confidence interval 3473ndash11107) Use of novel agents produced higherORR but survival benefit was not apparent due to the small number of patients and short follow-up duration Further studies areneeded to confirm the efficacy of novel agents in patients with WM

1 Introduction

The consensus group at the Second International Work-shop on Waldenstromrsquos macroglobulinemia (WM) in 2002redefined WM as a distinct clinicopathologic entity charac-terized by bone marrow infiltration by lymphoplasmacyticlymphoma (LPL) and immunoglobulinM (IgM)monoclonalgammopathy [1] Diagnostic criteria for WM are IgM mon-oclonal gammopathy of any concentration bone marrowinfiltration by small lymphocytes showing plasmacytoid orplasma cell differentiation intertrabecular pattern of bonemarrow infiltration and surface IgM+ CD5plusmn CD10minus CD19+CD20+ CD22+ CD23minus CD25+ CD27+ FMC7+ CD103minusand CD138minus immunophenotype [2]

WM is a very rare lymphoid malignancy with an overallincidence estimated at 035 forWMand063 for LPLWMper100000 person-years during 2001ndash2003 representing 12 or21 of all non-Hodgkinrsquos lymphomas in the United StatesSurveillance Epidemiology and End Results (SEER) cancerregistries respectively [3] Between 1996 and 2003 the crudeincidence of LPLWM was 0078 per 100000 person-yearsin Japan (0112 for men and 0048 for women) and 0032 per100000 person-years in Taiwan (0042 for men and 0021 forwomen) [4] A previous nationwide survey of the incidenceof lymphoma based on the REAL classification reported theincidence of LPL in Korea as 08 with the exact incidencerate of WMLPL not recognized [5] The incidence rate ofWM is lower in the Republic of Korea than those in the USAwhich was documented to be about 03 per million person-years according to data of the National Cancer InformationCenter in the Republic of Korea

The most common clinical manifestations are hep-atomegaly (20) splenomegaly (15) and lymphadenopa-thy (15) [6] The most common presenting symptom isfatigue related to normochromic or normocytic anemia Themedian hemoglobin value at diagnosis is 10 gdL [7] Patientswith a disease-related hemoglobin level lt10 gdL plateletcount lt100 times 109L bulky adenopathy or organomegalysymptomatic hyperviscositymoderate to severe or advancingperipheral neuropathy on the basis of disease symptomaticamyloidosis cryoglobulinemia or cold-agglutinin diseaseshould be considered for therapy but asymptomatic patientsshould be observed [8] Recently the superior efficacy ofchemotherapy combined with novel agent including ritux-imab bendamustine bortezomib lenalidomide and thalido-mide than that of conventional chemotherapy has been estab-lished However little is known about the clinical features

epidemiology and cytogenetics of WM in Asia including theRepublic of Korea Novel agent combined chemotherapy forpatients with WM has been restricted in the Republic ofKorea because of very low incidence and insurance coveragelimitation

Treatment outcomes in the Republic of Korea patientswith WM treated by novel agent combined chemotherapyare unclear This study is aimed at investigating the clinicalfeatures and assess the treatment outcomes of novel agentcombined chemotherapy and conventional chemotherapy

2 Materials and Methods

21 Patients Data from 71 patients newly diagnosed withWM who received chemotherapy at 17 university hospi-tals in the Republic of Korea between January 2005 andDecember 2012 were collected retrospectively All casesfulfilled the diagnostic criteria [1] and were confirmed asWM by hematopathologists and hematologists The pre-treatment evaluation included a physical examination withperformance status evaluation complete blood cell countwith differential count blood chemistry including lactasedehydrogenase (LDH) protein electrophoresis (PEP) IgMfree light chain kappa and lambda bonemarrowbiopsy chro-mosomal study fluorescence in situ hybridization (FISH)and computed tomography (CT) of the chest abdomen andpelvis

22 Treatment All patients were treated with conventionalchemotherapy or chemotherapy along with novel agent(rituximab bortezomib thalidomide and bendamustine)Bendamustine is old chemotherapeutic agent but recently theroles of this drug were rediscovered by its efficacy and toxici-ties in indolent lymphoma including WM [9 10] Rituximabcombined chemotherapy included rituximab cyclophos-phamide vincristine and prednisolone (R-CVP) and ritux-imab cyclophosphamide doxorubicin vincristine and pred-nisolone (R-CHOP) Bortezomib combined chemotherapyincluded bortezomib plus dexamethasone (VD) Thalido-mide combined chemotherapy included thalidomide plusdexamethasone (TD) and thalidomide plus cyclophos-phamide and dexamethasone (TCD) Bendamustine wasused along with prednisolone Conventional chemother-apy included chlorambucil CVP CHOP melphalan plusprednisolone (MP) cyclophosphamide plus prednisolone(CP) fludarabine plus cyclophosphamide (FC) and flu-darabine plus cyclophosphamide and mitoxantrone (FCM)

BioMed Research International 3

All patients were treated with one or more chemother-apeutic regimens Patients who displayed progression orintolerance against previous chemotherapy were changedfrom chemotherapy to a salvage regimen Introduction ofnovel agents was applied to four patients as first-line threeas second-line five at third-line and two at fourth-linechemotherapy

23 Analysis Overall response rates (ORR) of patientstreated with conventional and novel therapy were esti-mated as the best response at first-line and applied peri-ods ORR were estimated by clinical para-meters in allpatients including age sex hemoglobin levels plateletcounts absolute lymphocyte counts (ALC) C-reactive pro-tein (CRP) LDH serum 1205732-microglobulin serum albuminhepatosplenomegaly Eastern Cooperative Oncology Group(ECOG) performance status presence of B symptoms andhyperviscosity syndrome Those clinical parameters andinternational staging system (ISS) International Prognos-tic Scoring System for Waldenstromrsquos Macroglobulinemia(ISSWM) and treatment modalities were estimated to findprognostic markers for survival The treatment response wasassessed according to the Sixth International Workshop onWM [11]

24 Statistical Analyses We investigated independent prog-nostic factors associated with survival in above clinical andlaboratory parametersThe definition of overall survival (OS)was calculated from the date of diagnosis to the date ofdeath from disease-related cause or final follow-up dateProgression-free survival (PFS) was from the date of start-ing treatment (conventional chemotherapy or novel agentcombined chemotherapy) to the date of disease progressionrelapse or death from disease-related cause Associationsbetween the clinical parameters and ORR were analyzedusing the chi-square test A multiple logistic regression anal-ysis was used for multivariate analysis of independent prog-nostic factors for ORR Survival probabilities were calculatedaccording to the Kaplan-Meier method and compared usingthe log-rank test The Cox proportional hazards regressionmodel was used for multivariate analysis of independentprognostic factors for survival Information about the base-line medical status and treatment modalities was collectedfrom the medical records Approval for these studies wasobtained from the Institutional Review Board

3 Results

31 Clinical and Laboratory Characteristics The median ageof the 71 patients was 66 years (range 37ndash92 years) and themale to female ratio was 5 1 (Table 1) 254 and 380 ofpatients had clinical or radiological evidence of splenomegalyand of lymphadenopathy respectively 113 of patients had Bsymptoms before the initiation of treatment Hyperviscosityand involvement of other organs were shown in 113 and408 of patients respectively The median serum mono-clonal protein level was 3640 gdL (range 00183ndash10795)The cytogenetic abnormalities identified included deletion ofthe long arm of chromosome 6 in two cases and absence of

Table 1 Clinical and laboratory characteristics

Characteristic 119873 () or median (range)Patients 71Age years median (range) 66 (37ndash92)Gender

Male 59 (831)Female 12 (169)

Hemoglobin gdL median (range) 96 (380ndash1710)Platelet count times109L median (range) 213 (23ndash575)ALC times109L median (range) 170 (010ndash1230)CRP mgdL median (range) 244 (005ndash2380)Serum 1205732-microglobulin mgLmedian (range) 420 (134ndash3000)

Serum albumin gdL median (range) 32 (150ndash460)LDH IUL median (range) 2610 (740ndash9680)BM lymphocyte median (range) 14 (5ndash100)Cytogenetic abnormalities present () 8 (113)Serum monoclonal protein mgdLmedian (range) 36400 (1830ndash107950)

B symptom present () 8 (113)ECOG () ge2 23 (324)Hyperviscosity present () 8 (113)Lymphadenopathy yes () 27 (380)Extranodal involvement yes () 29 (408)Splenomegaly yes () 18 (254)Hepatomegaly yes () 7 (99)ISS ()

I 13 (183)II 26 (366)III 26 (366)Unknown 6 (85)

Treatment regimenNovel agent combinedchemotherapy 14 (197)

Conventional chemotherapy 57 (803)TreatmentNovel group

R-combined CTx R-CVP R-CHOP 6 (85)VD 5 (70)TD 2 (28)Bendamustine plus prednisolone 1 (14)

Conventional groupChlorambucil 25 (352)CVP or CHOP 14 (197)MP or CP 15 (211)FC or FCM 3 (42)

ALC absolute lymphocyte count CRP C-reactive protein LDH lactatedehydrogenase BM bone marrow ECOG Eastern Cooperative OncologyGroup performance status ISS international staging system R-combinedCTx rituximab combined chemotherapy R-CVP rituximab cyclophos-phamide vincristine and prednisolone R-CHOP rituximab cyclophos-phamide doxorubicin vincristine and prednisolone VD bortezomib plusdexamethasone TD thalidomide plus dexamethasone MP melphalan plusprednisolone CP cyclophosphamide plus prednisolone FC fludarabineplus cyclophosphamide FCM fludarabine plus cyclophosphamide andmitoxantrone

trisomy 4 Other cytogenetic abnormalities were identified in113 of cases Other clinical or laboratory characteristics aresummarized in Table 1

4 BioMed Research International

32 Treatment and Outcomes The 71 patients were treatedwith novel agent combined chemotherapy or conventionalchemotherapy 25 patients were treated with chlorambucilwith or without prednisone 14 were treated with CVPor CHOP regimen 15 were treated with the MP or CPregimen and three were treated with FC or FCM as first-line therapy Other patients were treated with novel agentcombined chemotherapy Six patients were treated with R-CVP R-CHOP five with VD two with thalidomide plus dex-amethasone and one with bendamustine plus prednisolone(Table 1) Overall an objective response (complete or partialresponse) and more than minimal response (MR) rates weredocumented in 535 and 690 of patients respectivelyThemedian follow-up was 2297 months The 5-year PFS and OSrates were 505 and 626 (95 confidence interval (95CI) 4832ndash8141 and 3473ndash11107) respectively

33 Analysis of Prognostic Factors for Response and SurvivalMultiple parameters were analyzed for their possible prog-nostic impact on ORR and OS Univariate analysis showedthat the following factors were associated with higher ORR(Table 2) higher ALC (lt10times 109L versusge10times 109L 200versus 646 119875 = 0069) good ECOG performance status(lt2 versus ge2 674 versus 435 119875 = 0057) and novel agentcombined chemotherapy versus conventional chemotherapy(929 versus 526 119875 = 0006) The following factorswere associated with superior 5-year OS (Table 2) youngerage (lt65 years versus ge65 years 822 versus 368 119875 =0024) good ECOG performance status (lt2 versus ge2 726versus 269 119875 = 0004) higher serum albumin levels(lt35 gdL versus ge35 gdL 448 versus 841 119875 = 0010)lower risk international staging system (ISS I II and III857 848 and 368 resp 119875 = 0004) and novel agentcombined chemotherapy versus conventional chemotherapy(100 versus 530 119875 = 0067) In the multivariate analysisnovel agent combined chemotherapy was an independentprognostic value for ORR (119875 = 0046) and lower ISS was anindependent prognostic value for OS (119875 = 0008) (Table 3)

4 Discussion

The clinical manifestations and laboratory abnormalitiesassociated with WM are related to direct tumor infiltrationand to the amount and specific properties ofmonoclonal IgMThe most common symptoms are weakness and fatigue usu-ally secondary to anemia Symptoms of weight loss excessivesweating and low-grade fever affect a quarter of patientsHepatomegaly splenomegaly and lymphadenopathy eachoccur in 15ndash30 of patients Similarly previous Koreanstudies reported the most common symptoms as anemia andthrombocytopenia with other frequently expressed symp-toms being (20ndash40) hepatosplenomegaly (25ndash35) andlymphadenopathy (25ndash40) [12ndash14] In this study anemiawas the most frequent symptom and thrombocytopeniawas secondary frequent symptom with lymphadenopathyhepatomegaly and splenomegaly being expressed in 10ndash40 of the cases However hyperviscosity syndrome wasdocumented only in eight cases which was a relatively lowincidence compared towestern results [6]Themost common

cytogenetic abnormality was deletion of the long arm ofchromosome 6 (6q deletion) and trisomy 4 [15 16] Howeverthere was only one report about cytogenetics of Korean WMpatients which documented a low rate of 6q deletion (10)and no trisomy 4 [13] Similar to a previous Korean studythis study documented a low rate of 6q deletion and othercytogenetic abnormalities

In this study novel agent combined chemotherapy wasthe only independent predictive factor for response ratesalthough higher ALC count and good performance statuswere also associated with higher ORR in univariate analysisMany studies have been shown to improve response andsurvival rates in patients with WM Gertz et al presentedmeaningful results about efficacy of rituximab in patientswith WM [17] The efficacy of rituximab in WM has beenamply described Rituximab combined chemotherapy includ-ing R-CHOP R-CVP R-CP R-F (fludarabine) R-cladribineand R-CD (cyclophosphamide and dexamethasone) pro-duces superior response rates to conventional chemotherapy[18ndash23] Rituximab combined with thalidomide reportedlyproduced a 72 response rate and rituximab combinedwith lenalidomide produced a 50 response rate [24 25]Bortezomib has high levels of activity in the managementof relapsed WM with response rates ranging from 81to 96 [26 27] In a prospective randomized study ofbendamustine plus rituximab compared with R-CHOP inpatients with WM of whom 22 received bendamustine andrituximab and 19 received R-CHOP the response rate was95 in both groups but median progression-free survivalwas significantly prolonged with bendamustine The medianprogression-free survival for R-CHOPwas 36months in con-trast to not being reached with bendamustine and rituximab(119875 lt 00001) [28]

In our study only lower risk ISS showed superior survivalto those of higher risk ISS although younger age goodperformance status higher serum albumin levels and novelagent combined chemotherapy were associated with longerOS in univariate analysis Patients treated with novel agentcombined chemotherapy especially did not show superiorsurvival rates to conventional chemotherapy in spite ofhigher ORR in patients receiving novel agents These resultsmight be associated with small sample size short follow-up duration and the clinical features of WM (which seemsto be indolent lymphoma) Prior studies have documentedseveral prognostic factors for survival [29ndash33] Age anemialeukopenia thrombocytopenia serum albumin levels and1205732-microglobulin values were linked to survival Howeverthese prognostic factors were not meaningful in this studyVery low incidence rates ofWMand restriction of using novelagents because of the limitation of medical reimbursementin Korea might be reasons for the insufficient comparisonbetween novel agent combined chemotherapy and conven-tional chemotherapy in this study

5 Conclusions

Clinical features of Korean WM are similar to westernWM except for the low incidence of hyperviscosity syn-drome Response rates after chemotherapy were improved by

BioMed Research International 5

Table 2 Clinical and laboratory values associated with survival on univariate analysis

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

Age yearslt65 667 0327 648 0708 822 0024ge65 553 370 368

GenderMale 644 0197 468 0530 659 0130Female 417 779 450

BM lymphocyte lt50 630 0461 618 0478 406 0610ge50 529 262 525

Cytogenetic abnormalitiesPresence 750 0466 643 0599 500 0444Absence 587 509 424

Hemoglobin gdLlt115 613 0732 543 0140 602 0700ge115 556 00 875

Platelet count times109Llt100 692 0479 00 0049 619 0124ge100 586 606 630

ALC times109Llt10 200 0069 333 0611 400 0224ge10 646 543 646

CRP mgdLlt5 580 0817 464 0937 655 0096ge5 615 513 486

Serum 1205732-microglobulin mgLlt3 667 0862 489 0130 500 0143ge3 640 506 584

Serum albumin gdLlt35 585 0683 431 0712 448 0010ge35 633 644 841

LDH IULlt450 597 0688 501 0849 618 0403ge450 667 656 729

B symptomPresence 875 0132 833 0666 600 0385Absence 565 488 628

ECOG ()0-1 674 0057 687 0012 726 0004ge2 435 181 269

Hyperviscosity syndromePresence 250 0055 583 0980 00 0918Absence 638 497 662

SplenomegalyPresence 611 0838 774 0342 00 0300Absence 583 495 527

HepatomegalyPresence 571 0884 400 0246 286 0913Absence 600 425 451

ISSWM ()Low 571

0567667

0912500

0380Intermediate 588 587 580High 750 00 584

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 3

All patients were treated with one or more chemother-apeutic regimens Patients who displayed progression orintolerance against previous chemotherapy were changedfrom chemotherapy to a salvage regimen Introduction ofnovel agents was applied to four patients as first-line threeas second-line five at third-line and two at fourth-linechemotherapy

23 Analysis Overall response rates (ORR) of patientstreated with conventional and novel therapy were esti-mated as the best response at first-line and applied peri-ods ORR were estimated by clinical para-meters in allpatients including age sex hemoglobin levels plateletcounts absolute lymphocyte counts (ALC) C-reactive pro-tein (CRP) LDH serum 1205732-microglobulin serum albuminhepatosplenomegaly Eastern Cooperative Oncology Group(ECOG) performance status presence of B symptoms andhyperviscosity syndrome Those clinical parameters andinternational staging system (ISS) International Prognos-tic Scoring System for Waldenstromrsquos Macroglobulinemia(ISSWM) and treatment modalities were estimated to findprognostic markers for survival The treatment response wasassessed according to the Sixth International Workshop onWM [11]

24 Statistical Analyses We investigated independent prog-nostic factors associated with survival in above clinical andlaboratory parametersThe definition of overall survival (OS)was calculated from the date of diagnosis to the date ofdeath from disease-related cause or final follow-up dateProgression-free survival (PFS) was from the date of start-ing treatment (conventional chemotherapy or novel agentcombined chemotherapy) to the date of disease progressionrelapse or death from disease-related cause Associationsbetween the clinical parameters and ORR were analyzedusing the chi-square test A multiple logistic regression anal-ysis was used for multivariate analysis of independent prog-nostic factors for ORR Survival probabilities were calculatedaccording to the Kaplan-Meier method and compared usingthe log-rank test The Cox proportional hazards regressionmodel was used for multivariate analysis of independentprognostic factors for survival Information about the base-line medical status and treatment modalities was collectedfrom the medical records Approval for these studies wasobtained from the Institutional Review Board

3 Results

31 Clinical and Laboratory Characteristics The median ageof the 71 patients was 66 years (range 37ndash92 years) and themale to female ratio was 5 1 (Table 1) 254 and 380 ofpatients had clinical or radiological evidence of splenomegalyand of lymphadenopathy respectively 113 of patients had Bsymptoms before the initiation of treatment Hyperviscosityand involvement of other organs were shown in 113 and408 of patients respectively The median serum mono-clonal protein level was 3640 gdL (range 00183ndash10795)The cytogenetic abnormalities identified included deletion ofthe long arm of chromosome 6 in two cases and absence of

Table 1 Clinical and laboratory characteristics

Characteristic 119873 () or median (range)Patients 71Age years median (range) 66 (37ndash92)Gender

Male 59 (831)Female 12 (169)

Hemoglobin gdL median (range) 96 (380ndash1710)Platelet count times109L median (range) 213 (23ndash575)ALC times109L median (range) 170 (010ndash1230)CRP mgdL median (range) 244 (005ndash2380)Serum 1205732-microglobulin mgLmedian (range) 420 (134ndash3000)

Serum albumin gdL median (range) 32 (150ndash460)LDH IUL median (range) 2610 (740ndash9680)BM lymphocyte median (range) 14 (5ndash100)Cytogenetic abnormalities present () 8 (113)Serum monoclonal protein mgdLmedian (range) 36400 (1830ndash107950)

B symptom present () 8 (113)ECOG () ge2 23 (324)Hyperviscosity present () 8 (113)Lymphadenopathy yes () 27 (380)Extranodal involvement yes () 29 (408)Splenomegaly yes () 18 (254)Hepatomegaly yes () 7 (99)ISS ()

I 13 (183)II 26 (366)III 26 (366)Unknown 6 (85)

Treatment regimenNovel agent combinedchemotherapy 14 (197)

Conventional chemotherapy 57 (803)TreatmentNovel group

R-combined CTx R-CVP R-CHOP 6 (85)VD 5 (70)TD 2 (28)Bendamustine plus prednisolone 1 (14)

Conventional groupChlorambucil 25 (352)CVP or CHOP 14 (197)MP or CP 15 (211)FC or FCM 3 (42)

ALC absolute lymphocyte count CRP C-reactive protein LDH lactatedehydrogenase BM bone marrow ECOG Eastern Cooperative OncologyGroup performance status ISS international staging system R-combinedCTx rituximab combined chemotherapy R-CVP rituximab cyclophos-phamide vincristine and prednisolone R-CHOP rituximab cyclophos-phamide doxorubicin vincristine and prednisolone VD bortezomib plusdexamethasone TD thalidomide plus dexamethasone MP melphalan plusprednisolone CP cyclophosphamide plus prednisolone FC fludarabineplus cyclophosphamide FCM fludarabine plus cyclophosphamide andmitoxantrone

trisomy 4 Other cytogenetic abnormalities were identified in113 of cases Other clinical or laboratory characteristics aresummarized in Table 1

4 BioMed Research International

32 Treatment and Outcomes The 71 patients were treatedwith novel agent combined chemotherapy or conventionalchemotherapy 25 patients were treated with chlorambucilwith or without prednisone 14 were treated with CVPor CHOP regimen 15 were treated with the MP or CPregimen and three were treated with FC or FCM as first-line therapy Other patients were treated with novel agentcombined chemotherapy Six patients were treated with R-CVP R-CHOP five with VD two with thalidomide plus dex-amethasone and one with bendamustine plus prednisolone(Table 1) Overall an objective response (complete or partialresponse) and more than minimal response (MR) rates weredocumented in 535 and 690 of patients respectivelyThemedian follow-up was 2297 months The 5-year PFS and OSrates were 505 and 626 (95 confidence interval (95CI) 4832ndash8141 and 3473ndash11107) respectively

33 Analysis of Prognostic Factors for Response and SurvivalMultiple parameters were analyzed for their possible prog-nostic impact on ORR and OS Univariate analysis showedthat the following factors were associated with higher ORR(Table 2) higher ALC (lt10times 109L versusge10times 109L 200versus 646 119875 = 0069) good ECOG performance status(lt2 versus ge2 674 versus 435 119875 = 0057) and novel agentcombined chemotherapy versus conventional chemotherapy(929 versus 526 119875 = 0006) The following factorswere associated with superior 5-year OS (Table 2) youngerage (lt65 years versus ge65 years 822 versus 368 119875 =0024) good ECOG performance status (lt2 versus ge2 726versus 269 119875 = 0004) higher serum albumin levels(lt35 gdL versus ge35 gdL 448 versus 841 119875 = 0010)lower risk international staging system (ISS I II and III857 848 and 368 resp 119875 = 0004) and novel agentcombined chemotherapy versus conventional chemotherapy(100 versus 530 119875 = 0067) In the multivariate analysisnovel agent combined chemotherapy was an independentprognostic value for ORR (119875 = 0046) and lower ISS was anindependent prognostic value for OS (119875 = 0008) (Table 3)

4 Discussion

The clinical manifestations and laboratory abnormalitiesassociated with WM are related to direct tumor infiltrationand to the amount and specific properties ofmonoclonal IgMThe most common symptoms are weakness and fatigue usu-ally secondary to anemia Symptoms of weight loss excessivesweating and low-grade fever affect a quarter of patientsHepatomegaly splenomegaly and lymphadenopathy eachoccur in 15ndash30 of patients Similarly previous Koreanstudies reported the most common symptoms as anemia andthrombocytopenia with other frequently expressed symp-toms being (20ndash40) hepatosplenomegaly (25ndash35) andlymphadenopathy (25ndash40) [12ndash14] In this study anemiawas the most frequent symptom and thrombocytopeniawas secondary frequent symptom with lymphadenopathyhepatomegaly and splenomegaly being expressed in 10ndash40 of the cases However hyperviscosity syndrome wasdocumented only in eight cases which was a relatively lowincidence compared towestern results [6]Themost common

cytogenetic abnormality was deletion of the long arm ofchromosome 6 (6q deletion) and trisomy 4 [15 16] Howeverthere was only one report about cytogenetics of Korean WMpatients which documented a low rate of 6q deletion (10)and no trisomy 4 [13] Similar to a previous Korean studythis study documented a low rate of 6q deletion and othercytogenetic abnormalities

In this study novel agent combined chemotherapy wasthe only independent predictive factor for response ratesalthough higher ALC count and good performance statuswere also associated with higher ORR in univariate analysisMany studies have been shown to improve response andsurvival rates in patients with WM Gertz et al presentedmeaningful results about efficacy of rituximab in patientswith WM [17] The efficacy of rituximab in WM has beenamply described Rituximab combined chemotherapy includ-ing R-CHOP R-CVP R-CP R-F (fludarabine) R-cladribineand R-CD (cyclophosphamide and dexamethasone) pro-duces superior response rates to conventional chemotherapy[18ndash23] Rituximab combined with thalidomide reportedlyproduced a 72 response rate and rituximab combinedwith lenalidomide produced a 50 response rate [24 25]Bortezomib has high levels of activity in the managementof relapsed WM with response rates ranging from 81to 96 [26 27] In a prospective randomized study ofbendamustine plus rituximab compared with R-CHOP inpatients with WM of whom 22 received bendamustine andrituximab and 19 received R-CHOP the response rate was95 in both groups but median progression-free survivalwas significantly prolonged with bendamustine The medianprogression-free survival for R-CHOPwas 36months in con-trast to not being reached with bendamustine and rituximab(119875 lt 00001) [28]

In our study only lower risk ISS showed superior survivalto those of higher risk ISS although younger age goodperformance status higher serum albumin levels and novelagent combined chemotherapy were associated with longerOS in univariate analysis Patients treated with novel agentcombined chemotherapy especially did not show superiorsurvival rates to conventional chemotherapy in spite ofhigher ORR in patients receiving novel agents These resultsmight be associated with small sample size short follow-up duration and the clinical features of WM (which seemsto be indolent lymphoma) Prior studies have documentedseveral prognostic factors for survival [29ndash33] Age anemialeukopenia thrombocytopenia serum albumin levels and1205732-microglobulin values were linked to survival Howeverthese prognostic factors were not meaningful in this studyVery low incidence rates ofWMand restriction of using novelagents because of the limitation of medical reimbursementin Korea might be reasons for the insufficient comparisonbetween novel agent combined chemotherapy and conven-tional chemotherapy in this study

5 Conclusions

Clinical features of Korean WM are similar to westernWM except for the low incidence of hyperviscosity syn-drome Response rates after chemotherapy were improved by

BioMed Research International 5

Table 2 Clinical and laboratory values associated with survival on univariate analysis

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

Age yearslt65 667 0327 648 0708 822 0024ge65 553 370 368

GenderMale 644 0197 468 0530 659 0130Female 417 779 450

BM lymphocyte lt50 630 0461 618 0478 406 0610ge50 529 262 525

Cytogenetic abnormalitiesPresence 750 0466 643 0599 500 0444Absence 587 509 424

Hemoglobin gdLlt115 613 0732 543 0140 602 0700ge115 556 00 875

Platelet count times109Llt100 692 0479 00 0049 619 0124ge100 586 606 630

ALC times109Llt10 200 0069 333 0611 400 0224ge10 646 543 646

CRP mgdLlt5 580 0817 464 0937 655 0096ge5 615 513 486

Serum 1205732-microglobulin mgLlt3 667 0862 489 0130 500 0143ge3 640 506 584

Serum albumin gdLlt35 585 0683 431 0712 448 0010ge35 633 644 841

LDH IULlt450 597 0688 501 0849 618 0403ge450 667 656 729

B symptomPresence 875 0132 833 0666 600 0385Absence 565 488 628

ECOG ()0-1 674 0057 687 0012 726 0004ge2 435 181 269

Hyperviscosity syndromePresence 250 0055 583 0980 00 0918Absence 638 497 662

SplenomegalyPresence 611 0838 774 0342 00 0300Absence 583 495 527

HepatomegalyPresence 571 0884 400 0246 286 0913Absence 600 425 451

ISSWM ()Low 571

0567667

0912500

0380Intermediate 588 587 580High 750 00 584

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 BioMed Research International

32 Treatment and Outcomes The 71 patients were treatedwith novel agent combined chemotherapy or conventionalchemotherapy 25 patients were treated with chlorambucilwith or without prednisone 14 were treated with CVPor CHOP regimen 15 were treated with the MP or CPregimen and three were treated with FC or FCM as first-line therapy Other patients were treated with novel agentcombined chemotherapy Six patients were treated with R-CVP R-CHOP five with VD two with thalidomide plus dex-amethasone and one with bendamustine plus prednisolone(Table 1) Overall an objective response (complete or partialresponse) and more than minimal response (MR) rates weredocumented in 535 and 690 of patients respectivelyThemedian follow-up was 2297 months The 5-year PFS and OSrates were 505 and 626 (95 confidence interval (95CI) 4832ndash8141 and 3473ndash11107) respectively

33 Analysis of Prognostic Factors for Response and SurvivalMultiple parameters were analyzed for their possible prog-nostic impact on ORR and OS Univariate analysis showedthat the following factors were associated with higher ORR(Table 2) higher ALC (lt10times 109L versusge10times 109L 200versus 646 119875 = 0069) good ECOG performance status(lt2 versus ge2 674 versus 435 119875 = 0057) and novel agentcombined chemotherapy versus conventional chemotherapy(929 versus 526 119875 = 0006) The following factorswere associated with superior 5-year OS (Table 2) youngerage (lt65 years versus ge65 years 822 versus 368 119875 =0024) good ECOG performance status (lt2 versus ge2 726versus 269 119875 = 0004) higher serum albumin levels(lt35 gdL versus ge35 gdL 448 versus 841 119875 = 0010)lower risk international staging system (ISS I II and III857 848 and 368 resp 119875 = 0004) and novel agentcombined chemotherapy versus conventional chemotherapy(100 versus 530 119875 = 0067) In the multivariate analysisnovel agent combined chemotherapy was an independentprognostic value for ORR (119875 = 0046) and lower ISS was anindependent prognostic value for OS (119875 = 0008) (Table 3)

4 Discussion

The clinical manifestations and laboratory abnormalitiesassociated with WM are related to direct tumor infiltrationand to the amount and specific properties ofmonoclonal IgMThe most common symptoms are weakness and fatigue usu-ally secondary to anemia Symptoms of weight loss excessivesweating and low-grade fever affect a quarter of patientsHepatomegaly splenomegaly and lymphadenopathy eachoccur in 15ndash30 of patients Similarly previous Koreanstudies reported the most common symptoms as anemia andthrombocytopenia with other frequently expressed symp-toms being (20ndash40) hepatosplenomegaly (25ndash35) andlymphadenopathy (25ndash40) [12ndash14] In this study anemiawas the most frequent symptom and thrombocytopeniawas secondary frequent symptom with lymphadenopathyhepatomegaly and splenomegaly being expressed in 10ndash40 of the cases However hyperviscosity syndrome wasdocumented only in eight cases which was a relatively lowincidence compared towestern results [6]Themost common

cytogenetic abnormality was deletion of the long arm ofchromosome 6 (6q deletion) and trisomy 4 [15 16] Howeverthere was only one report about cytogenetics of Korean WMpatients which documented a low rate of 6q deletion (10)and no trisomy 4 [13] Similar to a previous Korean studythis study documented a low rate of 6q deletion and othercytogenetic abnormalities

In this study novel agent combined chemotherapy wasthe only independent predictive factor for response ratesalthough higher ALC count and good performance statuswere also associated with higher ORR in univariate analysisMany studies have been shown to improve response andsurvival rates in patients with WM Gertz et al presentedmeaningful results about efficacy of rituximab in patientswith WM [17] The efficacy of rituximab in WM has beenamply described Rituximab combined chemotherapy includ-ing R-CHOP R-CVP R-CP R-F (fludarabine) R-cladribineand R-CD (cyclophosphamide and dexamethasone) pro-duces superior response rates to conventional chemotherapy[18ndash23] Rituximab combined with thalidomide reportedlyproduced a 72 response rate and rituximab combinedwith lenalidomide produced a 50 response rate [24 25]Bortezomib has high levels of activity in the managementof relapsed WM with response rates ranging from 81to 96 [26 27] In a prospective randomized study ofbendamustine plus rituximab compared with R-CHOP inpatients with WM of whom 22 received bendamustine andrituximab and 19 received R-CHOP the response rate was95 in both groups but median progression-free survivalwas significantly prolonged with bendamustine The medianprogression-free survival for R-CHOPwas 36months in con-trast to not being reached with bendamustine and rituximab(119875 lt 00001) [28]

In our study only lower risk ISS showed superior survivalto those of higher risk ISS although younger age goodperformance status higher serum albumin levels and novelagent combined chemotherapy were associated with longerOS in univariate analysis Patients treated with novel agentcombined chemotherapy especially did not show superiorsurvival rates to conventional chemotherapy in spite ofhigher ORR in patients receiving novel agents These resultsmight be associated with small sample size short follow-up duration and the clinical features of WM (which seemsto be indolent lymphoma) Prior studies have documentedseveral prognostic factors for survival [29ndash33] Age anemialeukopenia thrombocytopenia serum albumin levels and1205732-microglobulin values were linked to survival Howeverthese prognostic factors were not meaningful in this studyVery low incidence rates ofWMand restriction of using novelagents because of the limitation of medical reimbursementin Korea might be reasons for the insufficient comparisonbetween novel agent combined chemotherapy and conven-tional chemotherapy in this study

5 Conclusions

Clinical features of Korean WM are similar to westernWM except for the low incidence of hyperviscosity syn-drome Response rates after chemotherapy were improved by

BioMed Research International 5

Table 2 Clinical and laboratory values associated with survival on univariate analysis

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

Age yearslt65 667 0327 648 0708 822 0024ge65 553 370 368

GenderMale 644 0197 468 0530 659 0130Female 417 779 450

BM lymphocyte lt50 630 0461 618 0478 406 0610ge50 529 262 525

Cytogenetic abnormalitiesPresence 750 0466 643 0599 500 0444Absence 587 509 424

Hemoglobin gdLlt115 613 0732 543 0140 602 0700ge115 556 00 875

Platelet count times109Llt100 692 0479 00 0049 619 0124ge100 586 606 630

ALC times109Llt10 200 0069 333 0611 400 0224ge10 646 543 646

CRP mgdLlt5 580 0817 464 0937 655 0096ge5 615 513 486

Serum 1205732-microglobulin mgLlt3 667 0862 489 0130 500 0143ge3 640 506 584

Serum albumin gdLlt35 585 0683 431 0712 448 0010ge35 633 644 841

LDH IULlt450 597 0688 501 0849 618 0403ge450 667 656 729

B symptomPresence 875 0132 833 0666 600 0385Absence 565 488 628

ECOG ()0-1 674 0057 687 0012 726 0004ge2 435 181 269

Hyperviscosity syndromePresence 250 0055 583 0980 00 0918Absence 638 497 662

SplenomegalyPresence 611 0838 774 0342 00 0300Absence 583 495 527

HepatomegalyPresence 571 0884 400 0246 286 0913Absence 600 425 451

ISSWM ()Low 571

0567667

0912500

0380Intermediate 588 587 580High 750 00 584

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 5

Table 2 Clinical and laboratory values associated with survival on univariate analysis

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

Age yearslt65 667 0327 648 0708 822 0024ge65 553 370 368

GenderMale 644 0197 468 0530 659 0130Female 417 779 450

BM lymphocyte lt50 630 0461 618 0478 406 0610ge50 529 262 525

Cytogenetic abnormalitiesPresence 750 0466 643 0599 500 0444Absence 587 509 424

Hemoglobin gdLlt115 613 0732 543 0140 602 0700ge115 556 00 875

Platelet count times109Llt100 692 0479 00 0049 619 0124ge100 586 606 630

ALC times109Llt10 200 0069 333 0611 400 0224ge10 646 543 646

CRP mgdLlt5 580 0817 464 0937 655 0096ge5 615 513 486

Serum 1205732-microglobulin mgLlt3 667 0862 489 0130 500 0143ge3 640 506 584

Serum albumin gdLlt35 585 0683 431 0712 448 0010ge35 633 644 841

LDH IULlt450 597 0688 501 0849 618 0403ge450 667 656 729

B symptomPresence 875 0132 833 0666 600 0385Absence 565 488 628

ECOG ()0-1 674 0057 687 0012 726 0004ge2 435 181 269

Hyperviscosity syndromePresence 250 0055 583 0980 00 0918Absence 638 497 662

SplenomegalyPresence 611 0838 774 0342 00 0300Absence 583 495 527

HepatomegalyPresence 571 0884 400 0246 286 0913Absence 600 425 451

ISSWM ()Low 571

0567667

0912500

0380Intermediate 588 587 580High 750 00 584

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 BioMed Research International

Table 2 Continued

Characteristic ORR ge PR () 119875 5-year PFS () 119875 5-year OS () 119875

ISS ()I 615

0522487

0714857

0004II 692 419 848III 538 647 368

Treatment regimenNovel agent combined chemotherapy 929 0006 791 0418 1000 0067Conventional chemotherapy 526 463 530

ORR overall response rates PR partial response rates 5-year PFS 5-year progression-free survival rates 5-year OS 5-year overall survival rates BM bonemarrow ALC absolute lymphocyte count CRP C-reactive protein LDH lactate dehydrogenase ECOG Eastern Cooperative Oncology Group performancestatus ISSWM International Prognostic Scoring System for Waldenstromrsquos Macroglobulinemia ISS international staging system

Table 3 Multivariate analysis for response and survival

Value ORR OSRR 95 CI 119875 value RR 95 CI 119875 value

Age yearslt65ge65 1021 0350ndash2980 0970

ALC times109Llt10ge10 0362 0060ndash2193 0369

ECOG ()0-1ge2 2006 0711ndash5660 0188 0421 0147ndash1208 0108

Serum albumin gdLlt35ge35 1123 0264ndash4772 0875

ISS ()III 0439 0078ndash2486 0352III 0209 0066ndash0665 0008

Treatment regimenNovel agent combined chemotherapyConventional chemotherapy 5048 1032ndash24702 0046 0368 0075ndash1803 0217

ORR overall response rates OS overall survival rates RR relative risk 95 CI 95 confidence interval ALC absolute lymphocyte count ECOG EasternCooperative Oncology Group performance status ISS international staging system

introduction of novel agents such as rituximab bortezomibthalidomide and bendamustine although survival benefitwas not shown Independent prognostic factor for survivalwas high risk ISS inKoreanWMHowever further studywithmore patients is needed to determine the efficacy of novelagent combined chemotherapy and to definitively identify theprognostic factors

Conflict of Interests

The authors declare that they have no conflict of interests

Authorsrsquo Contribution

Ho Sup Lee analyzed the clinical data andwrote the paper HoSup Lee and Chang-Ki Min designed the study Kihyun KimDok Hyun Yoon Jin Seok Kim Soo-Mee Bang Jeong-Ok

Lee Hyeon Seok Eom Hyewon Lee Inho Kim Won Sik LeeSung Hwa Bae Se Hyung Kim Hong-Kee Lee Young-RokDo Jae Hoon Lee Junshik Hong Ho-Jin Shin Ji Hyun LeeYeung-Chul Mun and Korean Multiple Myeloma WorkingParty (KMMWP) contributed to conception of the study andanalyzed the clinical data Chang-Ki Min was involved inrevising the paper critically for intellectual content and gavefinal approval for the submission of the paper

References

[1] R G Owen S P Treon A Al-Katib et al ldquoClinicopatho-logical definition of Waldenstroms macroglobulinemia con-sensus panel recommendations from the Second InternationalWorkshop onWaldenstroms Macroglobulinemiardquo Seminars inOncology vol 30 no 2 pp 110ndash115 2003

[2] A Vijay and M A Gertz ldquoWaldenstrom macroglobulinemiardquoBlood vol 109 no 12 pp 5096ndash5103 2007

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

BioMed Research International 7

[3] L M Morton J J Turner J R Cerhan et al ldquoProposed classifi-cation of lymphoid neoplasms for epidemiologic research fromthe Pathology Working Group of the International LymphomaEpidemiology Consortium (InterLymph)rdquo Blood vol 110 no 2pp 695ndash708 2007

[4] M Iwanaga C-J Chiang M Soda et al ldquoIncidence of lympho-plasmacytic lymphomaWaldenstroms macroglobulinaemia inJapan and Taiwan population-based cancer registries 1996ndash2003rdquo International Journal of Cancer vol 134 no 1 pp 174ndash180 2014

[5] Y H Ko C W Kim C S Park et al ldquoREAL classificationof malignant lymphomas in the Republic of Korea incidenceof recently recognized entities and changes in clinicopatho-logic features Hematolymphoreticular Study Group of theKorean Society of Pathologists Revised European-Americanlymphomardquo Cancer vol 83 no 4 pp 806ndash812 1998

[6] M A Dimopoulos and A Anagnostopoulos ldquoWaldenstromsmacroglobulinemiardquo Best Practice and Research ClinicalHaematology vol 18 no 4 pp 747ndash765 2005

[7] M Bjorkholm E Johansson D Papamichael et al ldquoPatterns ofclinical presentation treatment and outcome in patients withWaldenstroms macroglobulinemia a two-institution studyrdquoSeminars in Oncology vol 30 no 2 pp 226ndash230 2003

[8] S P Treon ldquoHow I treat Waldenstrom macroglobulinemiardquoBlood vol 114 no 12 pp 2375ndash2385 2009

[9] MMerli A Ferrario C Basilico et al ldquoNovel agents in indolentlymphomasrdquoTherapeutic Advances in Hematology vol 4 no 2pp 133ndash148 2013

[10] M J Rummel and S A Gregory ldquoBendamustines emergingrole in the management of lymphoid malignanciesrdquo Seminarsin Hematology vol 48 no 1 pp S24ndashS36 2011

[11] S P Treon GMerlini EMorra C J Patterson andM J StoneldquoReport from the sixth international workshop on Walden-stroms macroglobulinemiardquo Clinical Lymphoma Myeloma andLeukemia vol 11 no 1 pp 68ndash73 2011

[12] S-M Bang S R Park S H Park et al ldquoClinical features ofWaldenstrom macroglobulinemia in Koreardquo Korean Journal ofInternal Medicine vol 19 no 3 pp 137ndash140 2004

[13] S-M Bang J-W Seo K U Park et al ldquoMolecular cytogeneticanalysis of Korean patients withWaldenstrommacroglobuline-miardquo Cancer Genetics and Cytogenetics vol 197 no 2 pp 117ndash121 2010

[14] Y-W Won S J Kim K Kim Y H Ko and W S Kim ldquoClin-ical features and treatment outcomes of lymphoplasmacyticlymphoma a single center experience in Koreardquo Annals ofHematology vol 89 no 10 pp 1011ndash1018 2010

[15] R F J Schop S A VanWier R Xu et al ldquo6q deletion discrim-inatesWaldenstrommacroglobulinemia from IgMmonoclonalgammopathy of undetermined significancerdquo Cancer Geneticsand Cytogenetics vol 169 no 2 pp 150ndash153 2006

[16] C Terre F Nguyen-Khac C Barin et al ldquoTrisomy 4 a newchromosomal abnormality in Waldenstroms macroglobuline-mia a study of 39 casesrdquo Leukemia vol 20 no 9 pp 1634ndash16362006

[17] M A Gertz M Rue E Blood L S Kaminer D H Vesoleand P R Greipp ldquoMulticenter phase 2 trial of rituximab forWaldenstrom macroglobulinemia (WM) an Eastern Cooper-ative Oncology Group Study (E3A98)rdquo Leukemia and Lym-phoma vol 45 no 10 pp 2047ndash2055 2004

[18] S P Treon Z Hunter and A R Branagan ldquoCHOP plus rit-uximab therapy inWaldenstromsmacroglobulinemiardquoClinicalLymphoma vol 5 no 4 pp 273ndash277 2005

[19] L Ioakimidis C Patterson Z Hunter et al ldquoComparative out-comes following CP-R CVP-R and CHOP-R inWaldenstromsmacroglobulinemiardquo Clinical Lymphoma and Myeloma vol 9no 1 pp 62ndash66 2009

[20] M A Dimopoulos A Anagnostopoulos M-C Kyrtsonis et alldquoPrimary treatment of Waldenstrom macroglobulinemia withdexamethasone rituximab and cyclophosphamiderdquo Journal ofClinical Oncology vol 25 no 22 pp 3344ndash3349 2007

[21] S P Treon A R Branagan L Ioakimidis et al ldquoLong-term outcomes to fludarabine and rituximab in WaldenstrommacroglobulinemiardquoBlood vol 113 no 16 pp 3673ndash3678 2009

[22] D Laszlo G Andreola L Rigacci et al ldquoRituximab and sub-cutaneous 2-chloro-21015840-deoxyadenosine as therapy in untreatedand relapsedWaldenstromsmacroglobulinemiardquoClinical Lym-phoma Myeloma and Leukemia vol 11 no 1 pp 130ndash132 2011

[23] A Tedeschi G Benevolo M Varettoni et al ldquoFludarabine pluscyclophosphamide and rituximab inwaldenstrommacroglobu-linemia an effective butmyelosuppressive regimen to be offeredto patients with advanced diseaserdquo Cancer vol 118 no 2 pp434ndash443 2012

[24] S P Treon J D Soumerai A R Branagan et al ldquoThalidomideand rituximab inWaldenstrommacroglobulinemiardquo Blood vol112 no 12 pp 4452ndash4457 2008

[25] S P Treon J D Soumerai A R Branagan et al ldquoLenalidomideand rituximab in Waldenstroms macroglobulinemiardquo ClinicalCancer Research vol 15 no 1 pp 355ndash360 2009

[26] S P Treon L Ioakimidis J D Soumerai et al ldquoPrimarytherapy of Waldenstrom macroglobulinemia with bortezomibdexamethasone and rituximab WMCTG clinical trial 05-180rdquoJournal of Clinical Oncology vol 27 no 23 pp 3830ndash3835 2009

[27] I M Ghobrial F Hong S Padmanabhan et al ldquoPhase II trial ofweekly bortezomib in combination with rituximab in relapsedor relapsed and refractory Waldenstrom macroglobulinemiardquoJournal of Clinical Oncology vol 28 no 8 pp 1422ndash1428 2010

[28] M J Rummel N Niederle G Maschmeyer et al ldquoBen-damustine plus rituximab versus CHOP plus rituximab asfirst-line treatment for patients with indolent and mantle-celllymphomas an open-label multicentre randomised phase 3non-inferiority trialrdquo The Lancet vol 381 no 9873 pp 1203ndash1210 2013

[29] MAGertz ldquoWaldenstrommacroglobulinemia 2013 update ondiagnosis risk stratification and managementrdquo The AmericanJournal of Hematology vol 88 no 8 pp 703ndash711 2013

[30] P G Gobbi R Bettini CMontecucco et al ldquoStudy of prognosisin Waldenstroms macroglobulinemia a proposal for a simplebinary classification with clinical and investigational utilityrdquoBlood vol 83 no 10 pp 2939ndash2945 1994

[31] P Morel M Monconduit D Jacomy et al ldquoPrognostic factorsin Waldenstrom macroglobulinemia a report on 232 patientswith the description of a new scoring system and its validationon 253 other patientsrdquo Blood vol 96 no 3 pp 852ndash858 2000

[32] P Morel A Duhamel P Gobbi et al ldquoInternational prognosticscoring system for Waldenstrom macroglobulinemiardquo Bloodvol 113 no 18 pp 4163ndash4170 2009

[33] R Garcıa-Sanz S Montoto A Torrequebrada et al ldquoWalden-strommacroglobulinaemia presenting features and outcome ina series with 217 casesrdquo British Journal of Haematology vol 115no 3 pp 575ndash582 2001

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom