REVIEW

Hodgkin Lymphoma Current Status and Clinical Trial

Recommendations

Catherine S Diefenbach Joseph M Connors Jonathan W FriedbergJohn P Leonard Brad S Kahl Richard F Little Lawrence BaizerAndrew M Evens Richard T Hoppe Kara M Kelly Daniel O PerskyAnas Younes Lale Kostakaglu Nancy L BartlettAffiliations of authors NYU Perlmutter Cancer Center New York NY (CSD) BC Cancer Agency Centre for Lymphoid Cancer Vancouver BC Canada (JMC) WilmotCancer Center and Division of HematologyOncology University of Rochester Medical Center Rochester NY (JWF) Department of Medicine Weil Cornell UniversityNew York NY (JPL) Oncology Division Department of Medicine Washington University St Louis MO (BSK NLB) Division of Cancer Treatment and Diagnosis (RFL)and Coordinating Center for Clinical Trials (LB) Tufts Cancer Center and Division of HematologyOncology Tufts University School of Medicine Boston MA (AME)Stanford Cancer Institute Stanford University Medical School Stanford CA (RTH) Division of Pediatric HematologyOncologyStem Cell Transplant ColumbiaUniversity Medical Center New York NY (KMK) Department of Medicine University of Arizona Cancer Center Tucson AZ (DOP) Lymphoma Service Memorial SloanKettering Cancer Center New York NY (AY) Department of Radiology Mount Sinai Hospital New York NY (LK)

Correspondence to Catherine Diefenbach MD NYU Perlmutter Cancer Center 240 East 38th Street 19th Floor New York NY 10016 (e-mailcatherinediefenbachnyumcorg)

Abstract

The National Clinical Trials Network lymphoid malignancies Clinical Trials Planning Meeting (CTPM) occurred in Novemberof 2014 The scope of the CTPM was to prioritize across the lymphoid tumors clinically significant questions and to fosterstrategies leading to biologically informed and potentially practice changing clinical trials This review from the Hodgkinlymphoma (HL) subcommittee of the CTPM discusses the ongoing clinical challenges in HL outlines the current standard ofcare for HL patients from early to advanced stage and surveys the current science with respect to biomarkers and thelandscape of ongoing clinical trials Finally we suggest areas of unmet need in HL and elucidate promising therapeuticstrategies to guide future HL clinical trials planning across the NCTN

Despite the overall favorable outcomes for most patients withHodgkin lymphoma (HL) the young median age at diagnosis re-sults in unique treatment challenges and consequencesAmong patients with early-stage and advanced disease who arecured serious acute and long-term treatment-related toxicitiesremain a concern For HL with relapsed or refractory diseasethe loss of young lives and the treatment-related morbidity as-sociated with high-dose therapy increase the societal burden ofthis disease In a cost-per-death analysis of malignanciesthroughout Europe HL had the second highest ldquocost per deathrdquoor lost productivity cost due to premature cancer-related mor-tality after melanoma (1) The top priority in HL remains im-provement of cure rates however true success will only comewith treatments that do not impair the long-term quality of life

of HL survivors or result in life-threatening or life-altering acuteor late effects

BackgroundDisease Progress Summary

Epidemiology and Burden of Disease

Hodgkin Lymphoma is the most common lymphoma affectingthe young population with approximately 9200 estimated newcases of HL in the United States in 2014 (2) The incidence of HL isbimodal with the highest incidence at age 15 to 34 years and asecond peak in those older than age 60 years Higher HL-specificsurvival is observed for children and adolescents than for adults

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Received April 20 2016 Revised June 24 2016 Accepted September 26 2016

Published by Oxford University Press 2016 This work is written by US Government employees and is in the public domain in the US

1 of 12

JNCI J Natl Cancer Inst (2017) 109(4) djw249

doi 101093jncidjw249First published online December 31 2016Review

(five-year survival rate frac14 96 SE frac14 04 vs 88 SE frac14 03P lt 001 calculated by Kaplan-Meier analysis and two-sidedlog-rank test to compare survival curves) (3) Approximately25 of patients experience a relapse or are found to have dis-ease refractory to initial therapy While 90 of early-stage HLpatients are cured with conventional treatment only 70 of ad-vanced-stage patients are cured with standard therapeuticapproaches For HL patients with relapsed disease only half arecured with standard salvage therapies (4)

Over the past 30 years data regarding the late effects of ther-apy specifically cardiovascular toxicity and risk of second can-cers have led to treatment modifications of radiation dose andfield size This has led to risk reduction of therapy-related causesof death However long-term complications of therapy remain aclinically significant concern over the lives of this predominantlyyoung patient population In addition to second cancers cardiacand peripheral vascular disease and pulmonary disease less se-rious but potentially life-altering effects of infertility and sexualdysfunction neurocognitive dysfunction chronic fatigue andthyroid disease are associated with current therapeutics used forHL (5ndash10) Of particular concern are the adolescent and youngadult (AYA) patients who commonly present with bulky medias-tinal disease which currently is optimally treated with combinedmodality therapy (CMT) including radiotherapy (RT)Unfortunately treatment of the developing breast with RT indu-ces a statistically significant increased risk of secondary breastcancer In addition to current efforts to develop treatmentapproaches that minimize late effects improved surveillance ofHL survivors also has the potential to save lives

Current Standard of Care Disease Management

The management of early-stage nonbulky favorable HL (lt3 sitesof disease no extranodal disease no bulky adenopathy ESR lt 50

and Erythrocyte Sedimentation Rate (ESR) lt 30 if B symptoms) orintermediate HL (large mediastinal mass extranodal diseasehigh erythrocyte sedimentation rate or gt 3 nodal sites) remainsbased on the chemotherapy regimen of doxorubicin bleomycinvinblastine and dacarbazine (ABVD) This became the standardof care (SOC) in this group of patients more than 30 years agowhen its superiority to mechlorethamine vincristine procarba-zine and prednisone (MOPP) chemotherapy was demonstrated(11) Current SOC in early-stage disease has been informed bylarge European and North American cooperative group trials fo-cusing on how to minimize toxicity while maximizing curabilitythese trials have attempted to address the optimal number ofchemotherapy cycles the dose of radiotherapy and the compari-son of combined modality therapy (CMT) vs chemotherapy alone(12ndash15) Current SOC includes either CMT consisting of short-course ABVD (ie 2 to 4 cycles) followed by RT (20 to 30 Gy) basedin part on the HD10 and HD11 trials (1316) or ABVD chemother-apy (ie 4 to 6 cycles) as monotherapy The latter was based ini-tially on smaller studies that showed equivalent five-year overallsurvival (OS) rates and was recently confirmed with the long-term follow-up of the large phase III NCI Canada (NCIC) HD6 trial(1718) In the most recent clinical trials of CMT the radiationfields were ldquoinvolved fieldrdquo (IFRT) however with accurate PET-CT imaging radiation fields have been further reduced to ldquoin-volved siterdquo irradiation which has been adopted in the UnitedStates as the standard (19) Radiation dose varies from 20ndash30 Gydepending on the absence or presence of various unfavorableprognostic factors

The results of the UK RAPID trial which compared chemo-therapy alone with chemotherapy followed by involved field ra-diation suggest a modest improvement in PFS with theaddition of IFRT in patients who are 18F-fluorodeoxyglucosepositron emission tomography (PET)ndashnegative after three cyclesof ABVD (absolute increase frac14 38 relative reduction in risk ofprogression frac14 47) but per protocol analysis there was there

Table 1 SOC regimens in upfront therapy

Disease setting Treatment regimen Trials

Stage IndashIIA favorable (lt3 sites of disease no extrano-dal disease nonbulky adenopathy ESR lt 50 andESR lt 30 if B symptoms)

ABVD for 2 cycles followed by 20 Gy of IFRT HD10 (13)

ABVD for 3ndash6 cycles

HD13 (73)

HD6 (1477)RAPID (20)H10 (21)

Stage IndashII nonbulky unfavorable (extranodal diseasehigh erythrocyte sedimentation rate or 3 nodalsites B symptoms)

ABVD for 4 cycles plus 30 Gy IFRT HD11 (16)BEACOPP for 2 cyclesthorn ABVD for 2 cycles thorn 30 Gy IFRT HD14 (24)ABVD x 3ndash6 RAPID (20)

H10 (21)HD6 (76)CALGB 50401 (77)

Stage IndashII bulky (mediastinal mass ratio gt 13or mass gt 10 cm)

ABVD for 4ndash6 cycles plus 30 Gy IFRT HD11 (16)E2496 (25)H10 (21)

BEACOPP for 2 cyclesthorn ABVD for 2 cycles thorn 30 Gy IFRT HD 14 (24)Advanced disease (stage IIIndashIV) ABVD x 6 cycles CALGB 8952 (26)

LY09 Trial (27)EORTC (28)

escBEACOPP x 6 cycles HD12 (29)ABVD for 2 cycles followed by escBEACOPP x 6 in PETthorn GITIL HD0607 (78)

ABVD frac14 doxorubicin bleomycin vinblastine dacarbazine BEACOPP frac14 bleomycin etoposide doxorubicin cyclophosphamide vincristine procabazine prednisone

CALGB frac14 Cancer and Leukemia Group B EORTC = European Organization for the Research and Treatment of Cancer ESR = erythrocyte sedimentation rate GITIL =

Gruppo Italiano Terapie Innovative nei Linfomi IFT frac14 involved field radiotherapy PET frac14 positron emission tomography RAPID = Randomized Phase III Trial to

Determine the Role of FDGndashPET Imaging in Clinical Stages IAIIA Hodgkinrsquos Disease

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2 of 12 | JNCI J Natl Cancer Inst 2017 Vol 109 No 4

was no difference in OS (20) The EORTC H10 reported a pre-planned interim futility analysis of 1137 early-stage HL patientswho were PET negative after two cycles of ABVD who were ran-domly assigned between involved node radiotherapy or no RTOn the basis of this analysis CMT resulted in fewer early pro-gressions in early-stage III HL although outcome was excellentin both arms In the favorable subgroup 858 had a negativeearly PET scan (standard arm 1 event vs experimental arm 9events) in the unfavorable subgroup 748 had a negative earlyPET scan (standard arm 7 events vs experimental arm 16events) The independent data monitoring committee con-cluded it was unlikely that the trial would show noninferiorityin the final results for the experimental arm and advised stop-ping random assignment for early PET-negative patients (21)These studies suggest that to date early interim PET appears tobe prognostic but has not yet proven to be predictive in answer-ing whether the omission of radiation in PET-negative patientscan result in an equivalent failure-free survival (FFS) Despitethe fact that PET has not been predictive for acute disease con-trolFFS longer follow-up is needed to determine whether it willmake a difference for late events and late effects With a goal ofminimizing therapy for early-stage HL the recently publishedHD13 trial investigated whether the omission of dacarbazine orbleomycin from ABVD-based CMT reduced the efficacy of theregimen and concluded that the SOC for these favorable-riskearly-stage patients should remain short-course ABVD-basedCMT because omission of either (or both) drug resulted in in-creased risk of relapse (22) Data from the de-escalation arms ofthe response-adapted therapy based on interim FDG-PET scansin an advanced Hodgkin lymphoma study (RATHL) presented atthe 13th International Conference on Malignant Lymphoma in2015 demonstrated that in 984 HL patients stage IIndashIV who wereFDG-PET negative after two cycles of ABVD outcomes wereequivalent in patients who received four subsequent cycles ofABVD or AVD (PFS frac14 854 vs 844 OS frac14 97 vs 975) (23)These preliminary data suggest that in patients who have acomplete response by PET after two cycles of therapy it may besafe to omit the bleomycin from the subsequent four cycles oftherapy

For HL patients with early-stage bulky disease ABVD-basedCMT is SOC in the United States (eg ABVD x 4ndash6 cycles followedby RT) In Europe as an alternative intensified chemotherapyregimens such as bleomycin etoposide adriamycin cyclophos-phamide oncovin procarbazine and prednisone (BEACOPP)standard dose or escalated either alone or combined withABVD are based on data that demonstrate superior FFTF for thehigh-dose regimen but with a cost of increased toxicity and todate no difference in OS One thousand five hundred twenty-eight patients with early-stage unfavorable HL received ABVDfor four cycles or escalated doses of BEACOPP for two cycles plusABVD for two cycles All patients received 30 Gy IFRT The free-dom from treatment failure favored the aggressive chemother-apy arm with a difference of 72 at five years but there wasno difference in OS and increased toxicity was seen in the ag-gressive chemotherapy arm (24) In some centers end-of-treat-ment PETCT rather than degree of pretreatment bulk is usedto determine the need for RT which results in fewer patients re-ceiving RT Large phase III cooperative group clinical trials com-paring alternate regimens such as Stanford V (Intergroup trialE2496) and BEACOPP chemotherapy (HD11) failed to consistentlydemonstrate superiority to ABVD (1625) for these patients SeeTable 1 for SOC regimens for upfront therapy

For patients with locally extensive and advanced-stage HLthe SOC in the United States was defined as ABVD

chemotherapy more than 20 years ago based on phase III US co-operative group studies (26ndash29) In the German HodgkinLymphoma Study Group (GHSG) escalated BEACOPP is the SOCfor these patients based on the HD9 and HD12 studies (30)Preliminary data from the phase II S0816 US intergroup studyexploring response-adapted therapy showed that for patientswho were PETCT positive after two cycles of ABVD and weresubsequently escalated to BEACOPP the two-year PFS was 64(95 confidence interval [CI] frac14 50 to 75) suggesting a benefitfor escalating therapy in the PETCT-positive group (31) Thetwo-year PFS in the interim PETCT-negative group was 82(95 CI frac14 77 to 86) suggesting an opportunity for improve-ment even in early complete responders The HD0801 studyalso suggests a potential benefit with escalation of therapy foradvanced-stage HL patients who remain PET positive after twocycles of ABVD 519 advanced-stage HL patients were treatedwith ABVD and patients who were PET positive after two cyclesreceived intensified therapy and autologous stem cell trans-plant With two years of follow-up the PFS for the PET-positivegroup was equivalent to that of the PET-negative patients sug-gesting that early intensification may improve the durable com-plete response rate for interim PET-positive patients (32)

Hodgkin lymphoma patients with relapsed or refractory dis-ease both in the pretransplant setting and relapsing after autol-ogous stem cell transplant (ASCT) continue to represent a highpriority for study and innovation For patients with progressionafter primary treatment with multi-agent chemotherapy thestandard treatment approach commonly consists of second-line chemotherapy followed by ASCT which results in a cure ofabout 50 of such patients (33) Several studies have shownthat achieving a complete response (CR) prior to ASCT is associ-ated with better long-term disease control and cure Yet the CRrate for both standard chemotherapy regimens such as ifosfa-mide carboplatin and etoposide (ICE) as well as novel thera-pies such as brentuximab vedotin (BV) is approximately 34(95 CI frac14 252 to 444) indicating that many patients likelyproceed to transplant with suboptimal disease control (34) In asingle-institution study patients in first relapse were treatedsequentially with BV with a 27 CR rate (95 CI frac14 13 to 30)followed by augmented ICE chemotherapy for the patients whodid not achieve a CR yielding a 76 CR rate (95 CI frac14 62 to89) for the patients treated on the sequential combination (35)This may represent a strategy for patients with chemotherapy-sensitive disease however whether this sequential approachresults in improved long-term disease control vs ICE inductionalone requires validation in larger multicenter studies and moremature outcome data Additionally combinations that includenovel agents with high activity such as the checkpoint inhibi-tors nivolumab now FDA approved for HL relapsed or prog-ressed after ASCT and post-transplantation BV andpembrolizumab may obviate the need for such sequentialtherapies

The phase III AETHERA trial investigating BV maintenancein the post-ASCT setting demonstrated an increase in PFS com-pared with patients who received placebo (median of 43 monthsvs 24 months respectively hazard ratio frac14 057 95 CI frac14 62 to89 P frac14 001 calculated by stratified COX regression modelswith one-sided alpha level of 025) albeit with a higher inci-dence of therapy-related toxicities (36) Long-term survival anal-ysis is needed to evaluate whether this may influence thenatural history of disease for these patients and how this willinform the design of future studies Beyond these indicationsthere is no clear SOC in the relapsed patient population and todate there have been no large US cooperative group trials

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C S Diefenbach et al | 3 of 12

beyond small phase II studies examining new agents and novelcombinations

Chemotherapeutic agents used for the initial treatment of pe-diatric HL are similar to those used in adults however because ofthe recognition of the elevated risk for long-term effects in theyounger population (37) pediatric cooperative group studies havedeveloped different strategies from the adult cooperative groupsinvestigating hybrid regimens using lower cumulative doses ofalkylators doxorubicin and bleomycin especially for low-risk(stages IndashIIA no bulk no B symptoms) and intermediate-risk (allstage I and II patients not classified as early stage stage IIIA andvariably stage IVA) disease No single standard of care regimen ex-ists and trials differ by the use of chemotherapy regimens of vary-ing dose intensity as well as the criteria for omission ofradiotherapy In general pediatric radiotherapy approaches utilizelower doses (15ndash25 Gy) and smaller fields (involved field or node)resulting in lower exposure to heart and lung compared with thatadministered in adult trials (38) The German Society of PediatricOncology now in conjunction with other European pediatric on-cology centers (Euronet consortium) has investigated vincristineetoposide prednisone doxorubicin (OEPA) for low risk and OEPAwith cyclophosphamide vincristine prednisone dacarbazine(COPDac) for intermediate- and high-risk groups with involvedfield radiotherapy utilized for all except the 30 of low-risk pa-tients achieving a CR to two cycles of chemotherapy (39) In NorthAmerica the Childrenrsquos Oncology Group has primarily evaluateddoxorubicin bleomycin vincristine etoposide prednisone cyclo-phosphamide (ABVE-PC) and its derivatives across the risk groupswith radiotherapy omission in more recent trials in early-respond-ing low- and intermediate-risk groups (40ndash43)

Recent Progress in Biological Understanding of HL

Hodgkin lymphoma has a unique biology whereby the malig-nant Hodgkin Reed-Sternberg (HRS) cells are few in number(generally less than 1 of the total tumor bulk) and are sur-rounded by non-neoplastic immune cells in the tumor microen-vironment including T-cells B-cells macrophages mast cellsand eosinophils Recent advances in biology of HL have eluci-dated the key role of the cross-talk between the HRS cells andthe immune cells of the tumor microenvironment in promotinglymphomagenesis Tumor-associated macrophages (TAMs)and specifically increased TAM expression of CD68 by immu-nohistochemistry (IHC) have been demonstrated to be associ-ated with an inferior outcome in HL including outcome aftersalvage chemotherapy with autologous transplantation (4445)Patient samples from the phase III cooperative group trial ofStanford V vs ABVD (E2496) were used to validate the initialCD68 results and confirmed a statistically significantly inferiorOS in the 38 of patients with high CD68 expression (46) Geneexpression profiling of microdissected HRS cells demonstratedthat a macrophage-like signature (CSFIR) is statistically signifi-cantly associated with treatment failure and in combinationwith CD68 IHC is an independent predictor for inferior progres-sion-free survival in an independent set of 132 patients (47)More recently using NanoString technology a 23-gene outcomepredictor in advanced-stage HL patients has been developedfrom 290 patients on the E2496 study that may identify patientsat increased risk of death independently of IPS and CD68 whentreated with standard-intensity firstline chemotherapy (48)

Other advances in the knowledge of HL biology include thediscovery of 9p241 amplification and high increased PD-1 li-gand expression by HRS cells the contribution of the Epstein-

Barr virus (EBV) to HL pathogenesis such as in influencing theexpression of inhibitory cytokines such as CXCL10 CCL5 andCCL3 and the role of the microenvironment in contributing toderegulation of signaling pathways such as nuclear factor kappaB (NFjB) and Janus kinase signal transducer and activation oftranscription signaling (JAK-STAT) (49ndash51) A prospective correl-ative study evaluating plasma EBV-DNA at several time pointsbefore during and after therapy on E2496 showed that the pres-ence of plasma EBV-DNA was associated with a statistically sig-nificantly worse failure-free survival (52) Recent data alsosuggest an association with inhibitory cytokines and chemo-kines such as thymus and activation-regulated chemokine(TARC) and the pretreatment cytokine profile with higher levelsof inhibitory cytokines such as IL-6 and IL-2R associated with ahigher risk of early relapse (53ndash56) and mutation of the b-2microglobulin gene (B2M) in primary HRS cells associated withNS subtype younger age and favorable survival (57)

These scientific advances in HL biology are exciting and clin-ically significant yet they must now be translated into clinicalbenefit or validated as truly predictive surrogate end pointsMoving forward the goal of HL-focused research should be totranslate these discoveries into improved risk stratificationtools and biologically based therapeutic strategies for high-riskdisease Through translational aims embedded within clinicaltrials it is also of fundamental importance to use patient-fo-cused research to further elucidate HL disease biology

Key Clinical Knowledge Gaps and UnmetClinical Needs

We believe that despite the curability of HL strong unmet needsremain in the management of HL that should be consideredhigh priorities for research in the cooperative group settingThese include

1) improved therapeutic strategies that maximize the CR ratefor patients treated for first relapse which is likely to be as-sociated with a higher cure rate for these patients

2) improving the ability to identify the 10 to 30 of patientswhose primary therapy will fail and developing more effec-tive treatments for these high-risk patients

3) improved therapies that prolong life for multiply relapsedpatients who are not cured with ASCT

4) identifying and eliminating ldquounnecessary therapyrdquo in low-risk patients in order to minimize long-term consequencesof ldquosuccessfulrdquo treatments (eg increased second cancersand arterial diseases preservation of quality of life (QOL)

In order to achieve the dual goals of cure and minimizationof therapeutic toxicity it is critical to identify subgroups of pa-tients for example the AYA and older populations who mightbenefit most from these novel treatment approaches and fromwhom if successful we would be able to extrapolate outcomesto a more generalized setting Major challenges and unmetneeds for the management of high-risk patients include im-proved risk stratification the sequencing of standard therapywith promising new agents and the role of consolidation strate-gies for the highest-risk patients

Current Landscape of Ongoing Clinical Trials

The current landscape of ongoing or completed trials with re-sults pending that may inform the SOC (Table 1) is described in

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Table 2 Selected open or recently completed phase III and phase II clinical trials in Hodgkin lymphoma

TitleFrontline Regimen Population

NCT numbersponsor

Estimatedenrollment

Start datecom-pletion date Preliminary data

ECHELON 1 ABVD vs AAVD Advanced stage(IIbndashIV)

01712490MillenniumPharmaceutic-als Inc

1240 November 2012ndashDecember 2015

Phase 1 AAVD3-y FFS frac14 96OSfrac14100

HD16 ABVD 2 thorn-20 Gy IFRT

Early stage with-out bulk(IandashIIb)

NCT00736320University ofCologne

1150 November2009ndashMay 2020

HD18 escBEACOPP x 2thorn PETthornescBEACOPP x6 vsescBEACOPP x6 thorn rituximabPET- escBEACOPP 4vs escBEACOPP 8

Advanced stageHL (IIB withbulky diseaseIII IV)

00515554University ofCologne

1500 May 2008ndashJuly2014

PETthorn 3-y interimanalysis PFS frac14914 forBEACOPP 93for R-BEACOPPOSfrac14965 vs944 at 3 y

BV andcombinationchemotherapy

ABVEPC vsABvVEPC thornresponse-di-rected ISRT

High-risk ad-vanced-stagepediatricclassical HL(2ndash18 y)

0216643 COG 600 March 2015ndashNovember2019

CALGBresponse-based therapyassessed byPET scan

ABVD thorn-BEACOPP thornradiation

Bulky stage I andstage II cHL

01118026 CALGB 123 September 2010ndashJuly 2017

BV thorn AVD BV 2 AVD thornBV x 4ndash6

Limited-stage HL 01534078 MassGeneralHospital

34 March 2012ndashApril2015

CRfrac14 88 PFS frac1490 OSfrac14 97at 14 mo grade3ndash4 neuropa-thy frac14 24

Sequential BVAVD

BV-AVD Elderly HL NCT01476410Northwestern

48 November 2011ndashMay 2016

Sequential BVAVD

BV thorn AVD and30 Gy IFRT

Early-stageunfavorableHL

01868451MemorialSloanKetteringCancer Center

30 May 2013ndashMay2016

BV thorn DTIC orbendamustine

BV thorn dacarbazineorbendamustine

Elderly (60 y andolder)

NCT01716806SeattleGenetics

70 October 2012ndashOctober 2018

Interim analysis100 ORR forbothcombinations

Response-ad-justed therapyfor Hodgkinlymphoma(RATHL)

2 cycles ABVDPET- ABVDvs AVD 4 PETthorn BEACOPP x 6vs escBEACOPP 4 thorn- IFRT

Advanced stage(IIB with bulkydisease III IV)

CRUK07033 1214 Median FU of363 mo PFS frac14854 ABVD vs844 AVDOSfrac1497ABVD vs 975AVD

AEPA (BV etoposideprednisonedoxorubicin) 2 CAPDac (cy-clophospha-mide BVprednisonedacarbazine) 4 with low-dose IFRT

Advanced-stagepediatric

01920932Pediatric HLConsortium(St Jude DFCIStanford)

77 August 2013ndashAugust 2021

(continued)

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C S Diefenbach et al | 5 of 12

Table 2 (continued)

TitleFrontline Regimen Population

NCT numbersponsor

Estimatedenrollment

Start datecom-pletion date Preliminary data

TargetedBEACOPPvariants

BrECADDBrECAPP

Newly diagnosedadvancedstage

German HodgkinLymphomaStudy Group

104 October 2012ndashMay 2014

BrECADD CRR frac1488 CRCRufrac14 88 and18 month PFSfrac14 89 BreCAPCRR frac14 86 CRCRufrac14 94 and18 month PFSfrac14 93

RelapsedBV first salvage BV HL in first relapse 01393717 City of

Hope MedicalCenter

57 October 2011ndashDecember 2015

ORR (CR thorn PR) frac1469 CRfrac14 33

E4412 BV thorn ipilimumaband nivolumab

Relapsed HL (firstor later)

NCT01896999ECOG 4412

70 Jan 2014ndashDecember 2017

Preliminary effi-cacy BV thorn ipili-mumab ORR frac1472 CRfrac14 50

BVbendamustine

BV thornbendamustine

Relapsed HLpre-ASCT

01874054 SeattleGenetics Inc01657331ColumbiaUniversity

5571

July 2012June 2013ndash

May 2015October 2015

CRfrac14 82 ORR frac1494 stem cellmobilizationand collectionwas adequate

BV thorngemcitabine

Pediatric andAYA HL in firstrelapse

01780662 COG 63 Phase 1 January2013 phase 2February 2015ndash2018

CheckMate Nivolumab Relapsed HL 0218738 Bristol-Myers Squibb

120 July 2014ndashMay2016

Interim report on80 patientsORR frac14 66(575 PR 88CR) six-moPFS frac14 77 (63)

Nivolumab Pediatric re-lapsed HL

02304458 COG 204 (multipletumor types)20 with HL

February 2015ndashNovember2016

Pembrolizumab RelapsedHL post-ASCT

02362997 Dana-Farber CancerInstitute

60 March 2015ndashMarch 2022

Phase 1ORR of 53in 15 patients(CRfrac14 20PRfrac14 33)

Keynote Pembrolizumab RR HL NCT02453594Merck

180 June 2015ndashMay2017

60 patients(cohorts 1 and2) cohort 1ORR frac14 70CRfrac14 20PRfrac14 50cohort 2ORR frac14 80CRfrac14 27PRfrac14 53 (64)

BV andnivolumab

BV thorn nivolumab Frontline elderlyHL

NCT02758717 75 May 2016ndashFebruary 2018

BV andnivolumab

BV thorn nivolumab 4 cycles

First relapse HL NCT02572167 60 October 2015ndashMay 2020

AAVD = brentuximab adriamcyin vinblastine dacarbazine ABVD = doxorubicin bleomycin vinblastine dacarbazine AEPA = brentuximab etoposide prednisone

adriamycin ASCT = autologous stem cell transplant BEACOPP frac14 bleomycin etoposide doxorubicin cyclophosphamide vincristine procabazine prednisone

BrECADD frac14 brentuximab vedotin etoposide cyclophosphamide doxorubicin dacarbazine and dexamethasone BreCAP = brentuximab cyclophosphamide adriamy-

cin prednisone BV frac14 brentuximab vedotin CALGB frac14 Cancer and Leukemia Group B CR frac14 complete response HL frac14 Hodgkin lymphoma IFRT frac14 involved field radio-

therapy ISRT frac14 involved site radiotherapy NCT frac14 National Center for Tumor Diseases ORR frac14 overall response rate OS frac14 overall survival PET frac14 positron emission

tomography PFS frac14 progression-free survival PR frac14 partial response RR frac14 relapsed or refractory

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Table 2 (continued)

TitleFrontline Regimen Population

NCT numbersponsor

Estimatedenrollment

Start datecom-pletion date Preliminary data

TargetedBEACOPPvariants

BrECADDBrECAPP

Newly diagnosedadvancedstage

German HodgkinLymphomaStudy Group

104 October 2012ndashMay 2014

BrECADD CRR frac1488 CRCRufrac14 88 and18 month PFSfrac14 89 BreCAPCRR frac14 86 CRCRufrac14 94 and18 month PFSfrac14 93

RelapsedBV first salvage BV HL in first relapse 01393717 City of

Hope MedicalCenter

57 October 2011ndashDecember 2015

ORR (CR thorn PR) frac1469 CRfrac14 33

E4412 BV thorn ipilimumaband nivolumab

Relapsed HL (firstor later)

NCT01896999ECOG 4412

70 Jan 2014ndashDecember 2017

Preliminary effi-cacy BV thorn ipili-mumab ORR frac1472 CRfrac14 50

BVbendamustine

BV thornbendamustine

Relapsed HLpre-ASCT

01874054 SeattleGenetics Inc01657331ColumbiaUniversity

5571

July 2012June 2013ndash

May 2015October 2015

CRfrac14 82 ORR frac1494 stem cellmobilizationand collectionwas adequate

BV thorngemcitabine

Pediatric andAYA HL in firstrelapse

01780662 COG 63 Phase 1 January2013 phase 2February 2015ndash2018

CheckMate Nivolumab Relapsed HL 0218738 Bristol-Myers Squibb

120 July 2014ndashMay2016

Interim report on80 patientsORR frac14 66(575 PR 88CR) six-moPFS frac14 77 (63)

Nivolumab Pediatric re-lapsed HL

02304458 COG 204 (multipletumor types)20 with HL

February 2015ndashNovember2016

Pembrolizumab RelapsedHL post-ASCT

02362997 Dana-Farber CancerInstitute

60 March 2015ndashMarch 2022

Phase 1ORR of 53in 15 patients(CRfrac14 20PRfrac14 33)

Keynote Pembrolizumab RR HL NCT02453594Merck

180 June 2015ndashMay2017

60 patients(cohorts 1 and2) cohort 1ORR frac14 70CRfrac14 20PRfrac14 50cohort 2ORR frac14 80CRfrac14 27PRfrac14 53 (64)

BV andnivolumab

BV thorn nivolumab Frontline elderlyHL

NCT02758717 75 May 2016ndashFebruary 2018

BV andnivolumab

BV thorn nivolumab 4 cycles

First relapse HL NCT02572167 60 October 2015ndashMay 2020

AAVD = brentuximab adriamcyin vinblastine dacarbazine ABVD = doxorubicin bleomycin vinblastine dacarbazine AEPA = brentuximab etoposide prednisone

adriamycin ASCT = autologous stem cell transplant BEACOPP frac14 bleomycin etoposide doxorubicin cyclophosphamide vincristine procabazine prednisone

BrECADD frac14 brentuximab vedotin etoposide cyclophosphamide doxorubicin dacarbazine and dexamethasone BreCAP = brentuximab cyclophosphamide adriamy-

cin prednisone BV frac14 brentuximab vedotin CALGB frac14 Cancer and Leukemia Group B CR frac14 complete response HL frac14 Hodgkin lymphoma IFRT frac14 involved field radio-

therapy ISRT frac14 involved site radiotherapy NCT frac14 National Center for Tumor Diseases ORR frac14 overall response rate OS frac14 overall survival PET frac14 positron emission

tomography PFS frac14 progression-free survival PR frac14 partial response RR frac14 relapsed or refractory

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Table 2 Current frontline phase III studies are primarily focusedon investigating the benefit of the addition of BV to standardchemotherapy with the exception of the German study HD18which examines whether to escalate or de-escalate therapywith BEACOPP based on PETCT data after two cycles of therapyIn a phase II study of 104 advanced-stage HL patients the inte-gration of BV into the BEACOPP regimen demonstrated equiva-lent PFS with decreased toxicity compared with standardBEACOPP and the regimen of BV etoposide cyclophosphamidedoxorubicin dacarbazine and dexamethasone (BrECADD) isplanned to be compared against BEACOPP in a phase III clinicaltrial (58) Existing phase II studies are similarly examining theaddition of BV to upfront treatment in specialized populationssuch as older patients and low-risk early-stage patients For HLpatients who have relapsed after ASCT and BC the checkpointinhibitor Nivolumab is now approved on the basis of the phaseII CheckMate registration study (NCT02181738) and the check-point inhibitor pembrolizumab remains under investigation inthe phase II registration study Keynote (NCT02453594) Currentphase II studies and early-phase studies for relapsed patientsinclude the combination of BV and bendamustine BV andcheckpoint inhibitor therapy BV and gemcitabine or BV withsequential chemotherapy for nonresponders both as pretrans-plant salvage or for multiply relapsed patients

The agents most likely to impact the next generation of clini-cal trials are the antibody-drug conjugate BV and the checkpointinhibitors nivolumab and pembrolizumab Clinically the successof the first antibody drug-conjugate BV targeting the TNF recep-tor superfamily member CD30 which is highly and differentiallyexpressed by HRS cells represents a striking recent advance inthe management of HL Brentuximab vedotin was FDA approvedin 2011 for the treatment of HL patients not eligible for ASCTbased on the pivotal phase II study who relapsed either afterASCT or after two lines of combination chemotherapy

Immune modulatory therapy in particular with checkpointinhibitors nivolumab and pembrolizumab appears extremelypromising in HL with extremely high response rates and littletoxicity In a phase I study of patients with relapsed HL treatedwith nivolumab at a dose of 3 mgkg every two weeks the ORRwas 87 (CR frac14 17 PR frac14 70 95 CI frac14 66 to 97) the remain-ing 13 had SD Progression-free survival (PFS) at 24 weeks was86 (95 CI frac14 62 to 95) (59) Similar data were reported forPD-1 inhibitor pembrolizumab at the 2014 American Society ofHematology (ASH) Annual Meeting in a similar population of re-lapsed HL patients with an ORR of 53 in 15 patients (CR frac14 20PR frac14 33 95 CIs were not reported) (60) The data for bothagents was updated at ASH 2015 and demonstrates that withlonger follow-up (86 weeks and 97 months respectively dura-ble responses persist in approximately 50 of patients) (6162)A preliminary report of the phase II studies for both checkpointinhibitors was reported at the 2016 American Society of ClinicalOncology Annual Meeting In the CheckMate study an interimanalysis of 80 patients with relapsed HL treated with Nivolumabshowed an ORR of 66 (PR frac14 575 CR frac14 88) with a six-month PFS of 77 (95 CIs were not reported) (63) The Keynotestudy presented data on the first two cohorts of the study pa-tients with relapsed or refractory HL after ASCT and subsequentBV therapy (cohort 1) and patients ineligible for ASCT becauseof chemoresistance and BV therapy failure (cohort 2 60 patientstotal) For cohort 1 the ORR was 70 (CR frac14 20 PR frac14 50) forcohort 2 the ORR was 80 (CR frac14 27 PR frac14 53 95 CIs werenot reported) (64) If this emerging data is confirmed by largerstudies checkpoint inhibitors have the potential to redefinetreatment paradigms in all aspects of HL management

Recommended Top Clinical Trial Questions

The following populations of patients have been identified asrepresenting the highest immediate priority for further study

bull Patients in first relapse or with primary refractory diseaseSuch patients still have the potential for cure but are at sub-stantial risk of dying from their disease with a cure rate ofapproximately 50 with current therapies For patients infirst relapse we suggest a multi-arm randomized phase IIdesign with ICE as the comparator arm PETCT CR as the pri-mary end point and one- to two-year PFS toxicity and bio-marker studies (eg TARC and gene signature) as secondaryend points Several recently described regimens incorporat-ing new agents would be appropriate to test in a randomizedstudy

bull Optimizing initial therapy for patients with bulky disease isalso a priority Incorporating highly active novel agents intofirstline therapy may allow elimination of RT in this popula-tion of primarily adolescents and young adults who are atstatistically significant risk for second cancers and cardio-vascular disease We suggest a trial that includes both pedi-atric and adult patients and uses early interim PETCT orend-of-treatment PETCT to determine the need for RTWhile a phase III study would be preferred small patientnumbers and difficulty accruing patients on previous adultstudies in this population may justify the use of a less strin-gent level of evidence to allow for a smaller randomizedcomparison employing larger alpha (and potentially biggertreatment effects) in the rare circumstances where nonran-domized data can be shown to be sufficient to produce prac-tice-changing evidence a single-arm design can be used

bull While optimizing upfront therapy for patients with ad-vanced disease remains an important priority the largephase III study currently ongoing comparing ABVD with AVDplus brentuximab and BrECADD with BEACOPP may definenew SOCs for this population Further studies in advanced-stage disease will need to await results of these studieshowever potential integration of checkpoint inhibitors intofrontline therapy is an intriguing option

bull Improving the outcome of special populations such as the el-derly and AYA are high priorities but we agreed that large-scale clinical investigations are challenging for the US NCTNgroups given the modest patient numbers of these popula-tions treated at large academic centers

End Points for Clinical Trials in HL

For firstline therapy we recommend that a PFS-based end pointbe considered the primary end point in HL clinical trials Whilenot a surrogate for OS a PFS improvement that is sustainedover time would represent a major clinical benefit in HL avoid-ing the toxic effects of second-line therapy such as ASCT thepotential need for multiple lines of therapy and the decreasedQOL and increased risk of late complications related to undergo-ing repeated treatments In the older patient population with astatistically significantly inferior outcome and limited treat-ment options PFS may indeed be a surrogate for OS Quality-of-life end points should be considered secondary end points in HLclinical trials especially in the pediatric and AYA populationsas well as in studies for older patients If possible in a selectedsubset of patients long-term OS should be determined prospec-tively in order to capture the cumulative long-term toxicity oftreatment in this predominantly young patient population

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C S Diefenbach et al | 7 of 12

Interim PETCT has not been validated as a predictive or sur-rogate end point for clinical trials at this time and remains in-vestigational The possibility of end of treatment (EOT) PETCTserving as a surrogate for PFS remains an open question that re-quires further investigation For patients with relapsed HL PETCT-negative CR may be considered an end point for phase II tri-als of pretransplant salvage regimens and regimens for post-transplant failures with PFS and OS as secondary end points

While we recognize the importance of being conscientiousabout the cost of integrating novel targeted therapeutics intostandard HL regimens we would not at this time recommendthe exclusion of any potential regimen based solely on costHowever we recommend that prospective clinical trials includecost-effectiveness analyses (CEAs) for all regimens being studiedin randomized phase II or III trials as have been incorporated inthe ongoing COG high-risk phase III trial These analyses should

take into consideration the cost of the current therapy as well asbalance this with patient outcomes and potential cost savings re-lated to the elimination of future therapy or prolonged therapyWell-validated CEA measures have been studied and can form abasis for those planned for these trials (65)

Potential Surrogate Biomarkers and theIntegration of Biomarkers Into Future ClinicalTrials

While there have been many potential biomarker candidatesidentified in retrospective analyses there are no prospectivelyvalidated integral markers in HL for risk stratification or for useas a surrogate end point We unanimously agree with theNational Cancer Institute that this is a top priority but integralmarkers and surrogates are not likely to be identified without a

Table 3 Biomarkers in Hodgkin lymphoma

RecommendationsHistopathology Standard of care Integral Integrated Exploratory Validated

Identifieshigh-low-risk

groupsIdentifies

therapeutic target

Full diagnostic immunohis-tochemistry (includingCD30 CD15 CD20others)

Yes Yes No No Yes No Yes

Prognostic IHC-focused onHRS cells

No No No Yes No Yes Yes

EBV (80ndash84) BCL2 HLA II(85) BCL-XL (86) p53 (86)T-cell antigens (87)

Prognostic IHC focused onmicroenvironment

No No No Yes No Yes Yes

tumor-associate macro-phages (44ndash46) CD68 (88)FOXP3 (88) CD20 (88)FGF2 (89) Syndecan-1(89) CD163 (90)

CytokineschemokinesSerum TARC (9091) IL10

(92ndash94) sIL10R (93) IL6(93) TNF (93) sTNFR (93)sCD30 (9394) galectin-1(9596) CD482554 (94)

No No No Yes No Yes No

MolecularGene expression profile for

risk group (26-gene pre-dictor from Nanostring)(48)

No No Yes Yes No Yes No

Global microRNA levels in-cluding MIR21 MIR30EMIR30D and MIR92B(9798)

No No No Yes No Yes No

Host germline polymor-phisms and mutations

IL-10-specific polymor-phism 592AA (99)

No No No Yes No No No

IL-6-specific polymorphism174GG (99)

No No No Yes No No No

Germline NPAT mutation(100)

No No No Yes No No No

IHC frac14 immunohistochemistry

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large prospective trial incorporating these potential markersFor example multiple phase II studies have not been able to de-fine the utility of the interim PETCT We encourage the study ofsurrogate biomarkers both for risk stratification and prognosisin HL strongly recommend that translational aims focusing oncorrelative biomarkers be included in all future prospective clin-ical trials and would support this as the primary aim of thestudy At the present time however the only validated clinicalindex to assign upfront risk in HL is the International PrognosticScore (IPS) a retrospectively developed clinical model with aprimary end point of freedom from progression (FFP) (66) how-ever recent studies suggest that its predictive range may havenarrowed due to improved patient outcomes in the modern era(6768) Despite advances in knowledge of disease biology thereare insufficient data currently to support the use of any specificbiomarker to reliably identify high-risk subsets of patients fortreatment decision-making or prognostication during therapy

There is a myriad of potential markers in HL that are promis-ing and have been described as correlating with patient risk andor clinical outcome These are listed in Table 3 and can begrouped into the following categories 1) markers related toReed-Sternberg immunohistochemistry 2) assessment of mi-cro-environmental or circulating non-neoplastic cells cyto-kines and membrane-associated antigens 3) gene expressionand miRNA profiling reflecting the tumor microenvironmentand host germline polymorphisms and mutations To date thelargest group of these biomarkers includes those assessed byimmunohistochemistry and in the circulation yet to date noneof these markers have been validated in a large-scale prospec-tive randomized trial Several promising biomarkers includingthe chemokine TARC and the 23-gene signature which havecorrelated with disease outcome but remain to be validated inlarge-scale prospective clinical trials (48)

Potential integrated biomarker candidates as described inTable 3 include BCL-XL p53 BCL-2 on HRS cells tumor-associ-ated macrophages in the tumor microenvironment serum cyto-kines and chemokines such as serum TARC galectin-1 IL-10CD30 and gene expression profiling Potential biomarkers oflate effects include host polymorphisms and should be assem-bled from large databases (69)

With regards to imaging biomarkers the committee feelsthat important questions include improving the reproducibilityof PET and optimizing the timing for PET to best guide treat-ment response standardizing and optimizing response defini-tion (Deauville criteria may depend on treatment and extent ofdisease) elucidating the combined role of anatomic and func-tional volume imaging and evaluating metabolic volume as-sessment as a new tool to guide treatment decision-makingPossible areas for imaging biomarker research include investi-gation of the predictive value of combinatorial approaches ofPET and CT scan using both morphologic and metabolic changeduring therapy particularly in PET-2-positive HL and quantita-tive PET assessment at baseline and change in tumor metabo-lism during therapy It is imperative to adopt standardizedacquisition reconstruction and analysis protocols for the useof quantitative PET metrics Data suggest that quantitative PETmeasures mainly standardized uptake value (SUV) may beused to improve visual analysis for response assessment inDLBCL (70) however this has yet to be validated in HL

To further increase the interpretation accuracy and reproduc-ibility of PET results novel quantitative techniques beyond SUVwhich are currently under investigation may be integrated intotherapeutic protocols These include tumor functional volume

parameters (eg metabolically active tumor volume [MTV] and to-tal lesion glycolysis [TLG]) To date the bulk of the literature hasbeen published on DLBCL patients (71) In HL metabolic tumorvolumes may be relevant to patient management particularly inthe better definition of tumor bulk at baseline which is an im-portant prognostic factor The high reproducibility for volume-derived image indices suggests a potential superior role com-pared with SUVs (72ndash74) If these functional volume parametersare validated as independent or complementary prognostic fac-tors they may facilitate identification of patients at high risk oftreatment failure which may direct early treatment intensifica-tion More research on all of these areas is necessary to make thetranslation from research into clinical practice feasible

Given the ongoing evaluation of multiple biomarkers usingseveral different techniques (IHC gene expression profiling se-quencing NanoString imaging) not only in HL but in multiplelymphoma subtypes we believe the best approach for furtherstudy is a post hoc biomarker analysis as opposed to randomi-zation risk stratification response assessment or monitoringbased on these biomarkers at this time We recommend collect-ing tumor samples (peripheral blood bone marrow lymphnode) at baseline at interim response evaluation at completionof treatment in both PETCT-negative and PETCT-positive pa-tients and if feasible at relapse in those patients who achieveinitial PETCT negativity While biomarkers should be includedin every clinical study they should not at this time be used todetermine clinical outcome but rather analyzed after comple-tion of the trial with the eventual goal of using them for anadaptive trial design in future clinical trials We believe that the23-gene signature and the serum biomarker TARC should beprioritized for prospective investigation

Promising Novel Agents and IntegrationInto Current Standard Therapies

The integration of novel agents into treatment paradigms eitherto replace or augment current treatment strategies should be aprimary goal of future research in HL The emergence of biologi-cally derived targeted therapies and immunotherapies providesnew and exciting treatment options for patients

To date of these novel agents only BV has mature data andis FDA approved as a single agent Combination strategies goingforward will be extremely important as many of these agentsare well tolerated but have moderate single-agent activity in therelapsed setting

While the checkpoint inhibitors nivolumab and pembrolizu-mab are the most exciting novel agents there are many othernew therapies for HL under development Agents that appearpromising in combination strategies include immune modula-tory agents such as the checkpoint inhibitors ipilimumab nivo-lumab and pembrolizumab the novel alkylator bendamustineand mTOR inhibitors all of which have demonstrated encour-aging single-agent activity in small early-phase studies Otheragents that have shown more limited single-agent activity butmay in the future prove promising in combination include epi-genetic therapy such as the histone deacetylase inhibitor(HDACI) panobinostat agents targeting the NFjB or the JAK-STAT pathways PI3 Kinase inhibitors and other modulators ofthe tumor microenvironment macrophages and immune mi-lieu such as lenalidomide Many of these drugs have demon-strated synergistic effects with nonoverlapping toxicity in smallearly-phase studies such as the combination of lenalidomide

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C S Diefenbach et al | 9 of 12

with either mTOR inhibition or bendamustine Preliminarysafety and efficacy data from the ongoing early-phase clinicaltrial investigating the combination of brentuximab vedotin withthe immune checkpoint inhibitors ipilimumab and nivolumabdemonstrated that the combination of BV and ipilimumab wassafe and highly active with an ORR of 72 and a CR of 50 (95CIs were not reported) (75) Going forward the challenge will bechoosing which of these agents to combine and where in the se-quence of treatments (upfront vs first relapse vs relapsed aftertransplant) they should be integrated

Immunotherapy and targeted therapies have the potential tochange treatment paradigms for HL and potentially for other lym-phomas over the next decade For relapsed patients integratingthese agents into standard therapy and combining them withother novel agents may allow more patients to successfully betransplanted or control disease longer-term in patients who haverelapsed post-transplant For patients with high-risk or advanced-stage disease integrating these therapies into standard treatmentplatforms may cure more patients in the upfront setting avoidingthe excessive toxicity of current high-dose regimens For low-riskpatients substitution of immune and novel therapies for elementsof standard therapy may lower treatment-related toxicity and re-duce long-term complications For special populations such as thefrail and the elderly alternative treatment regimens may allowdisease control without cytotoxic chemotherapy

Clinical trials in first relapse should be planned as random-ized two- or three-arm studies using standard second-line ifos-famide carboplatin and etoposide chemotherapy as acomparator Based on current data combination strategies test-ing chemotherapy-immunotherapy platforms vs ICE with CR asa primary end point and employing a Simon 2 stage designwould allow a fast and efficient comparison between the noveland standard arms Comparing two novel arms against thestandard of care would allow the simultaneous evaluation oftwo promising approaches within one clinical trial

Final Recommendations and Conclusions

While relapsed HL subsequent to ASCT remains incurable and themanagement of high-risk and relapsed disease without excessivelong-term toxicity remains challenging there are more treatmentoptions currently available than ever previously Recent progressin novel therapeutics such as checkpoint inhibitors and advancesin biomarker discovery bring us to an exciting point in time As wemove forward the challenge will be how to thoughtfully and sci-entifically integrate these novel therapies to modify and reshapecurrent treatment paradigms potentially altering the landscapefor relapsed HL patients by providing long-term disease controland for newly diagnosed patients by providing therapies withequivalent or superior efficacy and less toxicity Improvements inrisk stratification will help to better tailor appropriate therapiesand therapeutic intensity in high-risk patients allowing avoidanceof toxic therapies for patients who do not require them and mayguide therapeutic selection for HL patients in relapse Going for-ward both relapsedrefractory patients and bulkyhigh-risk newlydiagnosed patients remain a high priority for clinical investigationClinical trials in this space should include novel targeted and im-munologic agents and novel design strategies such as an adaptivedesign for which the cooperative group setting is ideal

Funding

Partial support was from the Office of the DirectorCoordinating Center for Clinical Trials National CancerInstituteNational Institutes of Health

Notes

This manuscript resulted from a Clinical Trials PlanningMeeting in Lymphoma November 21 and 22 2014

The sponsors had no role in the writing of the review or thedecision to submit it for publication

References1 Hanly P Soerjomataram I Sharp L Measuring the societal burden of cancer

The cost of lost productivity due to premature cancer-related mortality inEurope Int J Cancer 2015136(4)E136ndashE145

2 National Cancer Institute Surveillance Epidemiology and End ResultsProgram (SEER) httpseercancergovstatfactshtmlhodghtml

3 Bazzeh F Rihani R Howard S et al Comparing adult and pediatric Hodgkinlymphoma in the Surveillance Epidemiology and End Results Program1988ndash2005 An analysis of 21 734 Cases Leuk Lymph 201051(12)2198ndash2207

4 Evens AM Hutchings M Diehl V Treatment of Hodgkin lymphoma The pastpresent and future Nat Clin Pract Oncol 20085(9)543ndash556

5 Koontz MZ Horning SJ Balise R et al Risk of therapy-related secondary leu-kemia in Hodgkin lymphoma The Stanford University experience over threegenerations of clinical trials J Clin Oncol 201331(5)592ndash598

6 De Bruin ML Sparidans J vanrsquot Veer MB et al Breast cancer risk in femalesurvivors of Hodgkinrsquos lymphoma Lower risk after smaller radiation vol-umes J Clin Oncol 200927(26)4239ndash4246

7 De Bruin ML Burgers JA Baas P et al Malignant mesothelioma after radia-tion treatment for Hodgkin lymphoma Blood 2009113(16)3679ndash3681

8 De Bruin ML Dorresteijn LD vanrsquot Veer MB et al Increased risk of stroke andtransient ischemic attack in 5-year survivors of Hodgkin lymphoma J NatlCancer Inst 2009101(13)928ndash937

9 Aleman BM van den Belt-Dusebout AW De Bruin ML et al Late cardiotoxic-ity after treatment for Hodgkin lymphoma Blood 2007109(5)1878ndash1886

10 Hodgson DC Late effects in the era of modern therapy for Hodgkin lym-phoma Hematology Am Soc Hematol Educ Program 20112011323ndash329

11 Bonadonna G Zucali R Monfardini S et al Combination chemotherapy ofHodgkinrsquos disease with adriamycin bleomycin vinblastine and imidazolecarboxamide versus MOPP Cancer 197536(1)252ndash259

12 Bonadonna G Bonfante V Viviani S et al ABVD plus subtotal nodal versusinvolved-field radiotherapy in early-stage Hodgkinrsquos disease Long-term re-sults J Clin Oncol 200422(14)2835ndash2841

13 Engert A Plutschow A Eich HT et al Reduced treatment intensity in pa-tients with early-stage Hodgkinrsquos lymphoma N Engl J Med 2010363(7)640ndash652

14 Meyer RM Gospodarowicz MK Connors JM et al ABVD alone versusradiation-based therapy in limited-stage Hodgkinrsquos lymphoma N Engl J Med2012366(5)399ndash408

15 Brusamolino E Lazzarino M Orlandi E et al Early-stage Hodgkinrsquos diseaseLong-term results with radiotherapy alone or combined radiotherapy andchemotherapy Ann Oncol 19945(suppl 2)101ndash106

16 Eich HT Diehl V Gorgen H et al Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorableHodgkinrsquos lymphoma Final analysis of the German Hodgkin Study GroupHD11 trial J Clin Oncol 201028(27)4199ndash206

17 Canellos GP Abramson JS Fisher DC et al Treatment of favorable limited-stage Hodgkinrsquos lymphoma with chemotherapy without consolidation by ra-diation therapy J Clin Oncol 201028(9)1611ndash1615

18 Meyer RM Gospodarowicz MK Connors JM et al Randomized comparison ofABVD chemotherapy with a strategy that includes radiation therapy in pa-tients with limited-stage Hodgkinrsquos lymphoma National Cancer Institute ofCanada Clinical Trials Group and the Eastern Cooperative Oncology Group JClin Oncol 200523(21)4634ndash4642

19 Specht L Yahalom J Illidge T et al Modern radiation therapy for Hodgkinlymphoma Field and dose guidelines from the international lymphomaradiation oncology group (ILROG) Int J Radiat Oncol Biol Phys 201489(4)854ndash862

20 Radford J Illidge T Counsell N et al Results of a trial of PET-directed ther-apy for early-stage Hodgkinrsquos lymphoma N Engl J Med 2015372(17)1598ndash1607

21 Raemaekers JM Andre MP Federico M et al Omitting radiotherapy in earlypositron emission tomography-negative stage III Hodgkin lymphoma is as-sociated with an increased risk of early relapse Clinical results of the pre-planned interim analysis of the randomized EORTCLYSAFIL H10 trial J ClinOncol 201432(12)1188ndash1194

22 Behringer K Goergen H Hitz F et al Omission of dacarbazine or bleomycinor both from the ABVD regimen in treatment of early-stage favourableHodgkinrsquos lymphoma (GHSG HD13) An open-label randomised non-inferiority trial Lancet 2015 Apr 11385(9976)1418ndash1427

23 Moskowitz CH Response-adapted therapy based on interim FDG-PET scansin advanced Hodgkin lymphoma First analysis of the safety of deescalationand efficacy of escalation in the international RATHL study (CRUK07033)Clin Adv Hematol Oncol 201513(8 suppl 9)6ndash7

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IEW

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24 von Tresckow B Plutschow A Fuchs M et al Dose-intensification in early un-favorable Hodgkinrsquos lymphoma Final analysis of the German Hodgkin StudyGroup HD14 trial J Clin Oncol 201230(9)907ndash913

25 Gordon LI Hong F Fisher RI et al Randomized phase III trial of ABVD versusStanford V with or without radiation therapy in locally extensive andadvanced-stage Hodgkin lymphoma An intergroup study coordinated by theEastern Cooperative Oncology Group (E2496) J Clin Oncol 201331(6)684ndash691

26 Duggan DB Petroni GR Johnson JL et al Randomized comparison of ABVDand MOPPABV hybrid for the treatment of advanced Hodgkinrsquos diseaseReport of an intergroup trial J Clin Oncol 200321(4)607ndash614

27 Johnson PW Radford JA Cullen MH et al Comparison of ABVD and alternat-ing or hybrid multidrug regimens for the treatment of advanced Hodgkinrsquoslymphoma Results of the United Kingdom Lymphoma Group LY09 Trial(ISRCTN97144519) J Clin Oncol 200523(36)9208ndash9218

28 Aleman BM Raemaekers JM Tirelli U et al Involved-field radiotherapy foradvanced Hodgkinrsquos lymphoma N Engl J Med 2003348(24)2396ndash2406

29 Canellos GP Anderson JR Propert KJ et al Chemotherapy of advancedHodgkinrsquos disease with MOPP ABVD or MOPP alternating with ABVD N Engl JMed 1992327(21)1478ndash1484

30 Borchmann P Haverkamp H Diehl V et al Eight cycles of escalated-doseBEACOPP compared with four cycles of escalated-dose BEACOPP followed byfour cycles of baseline-dose BEACOPP with or without radiotherapy in pa-tients with advanced-stage hodgkinrsquos lymphoma Final analysis of the HD12trial of the German Hodgkin Study Group J Clin Oncol 201129(32)4234ndash4242

31 Press OW Li H Schoder H et al US Intergroup Trial of response-adaptedtherapy for stage III to IV Hodgkin lymphoma using early interimfluorodeoxyglucose-positron emission tmography imaging SouthwestOncology Group S0816 J Clin Oncol 201634 in press

32 Zinzani PL Broccoli A Gioia DM et al Interim positron emission tomographyresponse-adapted therapy in advanced-stage Hodgkin lymphoma Final re-sults of the phase II part of the HD0801 study J Clin Oncol 201634(12)1376ndash1385

33 Schmitz N Pfistner B Sextro M et al Aggressive conventional chemotherapycompared with high-dose chemotherapy with autologous haemopoieticstem-cell transplantation for relapsed chemosensitive Hodgkinrsquos disease Arandomised trial Lancet 2002359(9323)2065ndash2071

34 Younes A Gopal AK Smith SE et al Results of a pivotal phase II study ofbrentuximab vedotin for patients with relapsed or refractory Hodgkinrsquos lym-phoma J Clin Oncol 201230(18)2183ndash2189

35 Moskowitz AJ Schoder H Yahalom J et al PET-adapted sequential salvagetherapy with brentuximab vedotin followed by augmented ifosamide carbo-platin and etoposide for patients with relapsed and refractory Hodgkinrsquoslymphoma A non-randomised open-label single-centre phase 2 studyLancet Oncol 201516(3)284ndash292

36 Moskowitz CH Nademanee A Masszi T et al Brentuximab vedotin as con-solidation therapy after autologous stem-cell transplantation in patientswith Hodgkinrsquos lymphoma at risk of relapse or progression (AETHERA) Arandomised double-blind placebo-controlled phase 3 trial Lancet 2015385(9980)1853ndash1862

37 Castellino SM Geiger AM Mertens AC et al Morbidity and mortality in long-term survivors of Hodgkin lymphoma A report from the Childhood CancerSurvivor Study Blood 20111171806ndash1816

38 Pieters RS Wagner H Baker S et al The impact of protocol assignment forolder adolescents with hodgkin lymphoma Front Oncol 20144317

39 Mauz-Korholz C Hasenclever D Dorffel W et al Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in girls have com-parable effectiveness in pediatric Hodgkinrsquos lymphoma The GPOH-HD-2002study J Clin Oncol 2010283680ndash3686

40 Schwartz CL Constine LS Villaluna D et al A risk-adapted response-basedapproach using ABVE-PC for children and adolescents with intermediate-and high-risk Hodgkin lymphoma The results of P9425 Blood 20091142051ndash2059

41 Keller FG Nachman J Constine L et al A phase III study for the treatment ofchildren and adolescents with newly diagnosed low risk Hodgkin lymphoma(HL) Blood 201011621

42 Tebbi CK Mendenhall NP London WB et al Response-dependent and re-duced treatment in lower risk Hodgkin lymphoma in children and adoles-cents results of P9426 A report from the Childrenrsquos Oncology Group PediatrBlood Cancer 201259(7)1259ndash1265

43 Friedman D Chen L Wolden S et al Dose-intensive response-based chemo-therapy and radiation therapy for children and adolescents with newly diag-nosed intermediate-risk hodgkin lymphoma A report from the ChildrenrsquosOncology Group Study AHOD0031 J Clin Oncol 2014 32(32)3651ndash3658

44 Steidl C Lee T Shah SP et al Tumor-associated macrophages and survival inclassic Hodgkinrsquos lymphoma N Engl J Med 2010362(10)875ndash885

45 Steidl C Farinha P Gascoyne RD Macrophages predict treatment outcome inHodgkinrsquos lymphoma Haematologica 201196(2)186ndash189

46 Tan KL Scott DW Hong F et al Tumor-associated macrophages predict infe-rior outcomes in classic Hodgkin lymphoma A correlative study from theE2496 Intergroup trial Blood 2012120(16)3280ndash3287

47 Steidl C Diepstra A Lee T et al Gene expression profiling of microdissectedHodgkin Reed-Sternberg cells correlates with treatment outcome in classicalHodgkin lymphoma Blood 2012120(17)3530ndash3540

48 Scott DW Chan FC Hong F et al Gene expression-based model usingformalin-fixed paraffin-embedded biopsies predicts overall survival inadvanced-stage classical Hodgkin lymphoma J Clin Oncol 201331(6)692ndash700

49 Kuppers R The biology of Hodgkinrsquos lymphoma Nat Rev Cancer 20099(1)15ndash27

50 Emmerich F Meiser M Hummel M et al Overexpression of I kappa B alphawithout inhibition of NF-kappaB activity and mutations in the I kappa B al-pha gene in Reed-Sternberg cells Blood 199994(9)3129ndash3134

51 Green MR Monti S Rodig SJ et al Integrative analysis reveals selective9p241 amplification increased PD-1 ligand expression and further induc-tion via JAK2 in nodular sclerosing Hodgkin lymphoma and primary medias-tinal large B-cell lymphoma Blood 2010116(17)3268ndash3277

52 Kanakry JA Li H Gellert LL et al Plasma Epstein-Barr virus DNA predicts out-come in advanced Hodgkin lymphoma Correlative analysis from a largeNorth American cooperative group trial Blood 2013121(18)3547ndash3553

53 van den Berg A Visser L Poppema S High expression of the CC chemokineTARC in Reed-Sternberg cells A possible explanation for the characteristic T-cell infiltratein Hodgkinrsquos lymphoma Am J Pathol 1999154(6)1685ndash1691

54 Buglio D Georgakis GV Hanabuchi S et al Vorinostat inhibits STAT6-mediated TH2 cytokine and TARC production and induces cell death inHodgkin lymphoma cell lines Blood 2008112(4)1424ndash1433

55 Weihrauch MR Manzke O Beyer M et al Elevated serum levels of CC thymusand activation-related chemokine (TARC) in primary Hodgkinrsquos diseasePotential for a prognostic factor Cancer Res 200565(13)5516ndash5519

56 Marri P Hodge LS Maurer MJ et al Prognostic significance of pretreatmentserum cytokines in classical Hodgkin lymphoma Clin Cancer Res 201319(24)6812ndash6819

57 Reichel J Chadburn A Rubinstein PG et al Flow sorting and exome sequenc-ing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cellsBlood 2015125(7)1061ndash1072

58 Borchmann P Eichenauer DA Pluetschow A et al Targeted Beacopp variantsin patients with newly diagnosed advanced stage classical Hodgkin lym-phoma Final analysis of a randomized phase II study Blood 2015126(23)580

59 Ansell SM Lesokhin AM Borrello I et al PD-1 blockade with nivolumab in re-lapsed or refractory Hodgkinrsquos lymphoma N Engl J Med 2015372(4)311ndash319

60 Moskowitz C et al PD-1 blockade with the monclonal antibody pembrolizu-mab in patients with classical Hodgkin lymphoma after brentuximabvedotin failure Preliminary results from a phase 1b study presented at the56th meeting of the American Society for Hematology December 2014 SanFranciso CA

61 Ansell S Armand P Timmerman JM et al Nivolumab in patients (Pts) withrelapsed or refractory classical Hodgkin lymphoma (RR cHL) Clinical out-comes from extended follow-up of a phase 1 study (CA209-039) Preliminaryresults presented at the 57th meeting of the American Society forHematology December 2015 Orlando FL

62 Armand P Shipp MA Ribrag V et al PD-1 blockade with pembrolizumab inpatients with classical Hodgkin lymphoma after brentuximab vedotin fail-ure Safety efficacy and biomarker assessment Preliminary results pre-sented at the 57th meeting of the American Society for HematologyDecember 2015 Orlando FL

63 Checkmate 205 Nivolumab (nivo) in classical Hodgkin lymphoma (cHL) afterautologous stem cell transplant (ASCT) and brentuximab vedotin (BV)ndashAphase 2 study Preliminary results presented at the meeting of the AmericanSociety for Clinical Oncology June 2016 Chicago IL

64 Pembrolizumab for relapsedrefractory classical Hodgkin lymphoma (RRcHL) phase 2 KEYNOTE-087 study Preliminary results presented at themeeting of the American Society for Clinical Oncology June 2016 Chicago IL

65 Saret CJ Winn AN Shah G et al Value of innovation in hematologic malig-nancies A systematic review of published cost-effectiveness analyses Blood2015125(12)1866ndash1869

66 Hasenclever D Diehl V A prognostic score for advanced Hodgkinrsquos diseaseInternational Prognostic Factors Project on Advanced Hodgkinrsquos Disease NEngl J Med 1998339(21)1506ndash1514

67 Moccia AA Donaldson J Chhanabhai M et al International Prognostic Scorein advanced-stage Hodgkinrsquos lymphoma Altered utility in the modern era JClin Oncol 201230(27)3383ndash3388

68 Diefenbach CS Li H Hong F et al Evaluation of the International PrognosticScore (IPS-7) and a Simpler Prognostic Score (IPS-3) for advanced Hodgkinlymphoma in the modern era Br J Haematol 2015171(4)530ndash538

69 Best T Li D Skol AD et al Variants at 6q21 implicate PRDM1 in the etiology oftherapy-induced second malignancies after Hodgkinrsquos lymphoma Nat Med201117(8)941ndash943

70 Itti E Meignan M Berriolo-Riedinger A et al An international confirmatorystudy of the prognostic value of early PETCT in diffuse large B-cell lym-phoma Comparison between Deauville criteria and DeltaSUVmax Eur J NuclMed Mol Imaging 201340(9)1312ndash1320

71 Adams HJ de Klerk JM Fijnheer R et al Prognostic superiority of the NationalComprehensive Cancer Network International Prognostic Index over pre-treatment whole-body volumetric-metabolic FDG-PETCT metrics in diffuselarge B-cell lymphoma Eur J Haematol 201594(6)532ndash539

72 Hatt M Cheze-Le Rest C Aboagye EO et al Reproducibility of 18F-FDG and3rsquo-deoxy-3rsquo-18F-fluorothymidine PET tumor volume measurements J NuclMed 201051(9)1368ndash1376

REV

IEW

C S Diefenbach et al | 11 of 12

73 Hatt M Cheze-le Rest C van Baardwijk A et al Impact of tumor size andtracer uptake heterogeneity in (18)F-FDG PET and CT non-small cell lung can-cer tumor delineation J Nucl Med 201152(11)1690ndash1697

74 van Velden FH Cheebsumon P Yaqub M et al Evaluation of a cumulativeSUV-volume histogram method for parameterizing heterogeneous intratu-moural FDG uptake in non-small cell lung cancer PET studies Eur J Nucl MedMol Imaging 201138(9)1636ndash1647

75 Diefenbach CS Hong F Cohen JB et al Preliminary safety and efficacy of thecombination of brentuximab vedotin and ipilimumab in relapsedrefractoryHodgkin lymphoma A trial of the ECOG-ACRIN Cancer Research Group(E4412) Blood 2015126(23)585

76 Behringer K Goergen H Hitz F et al Omission of dacarbazine or bleomycinor both from the ABVD regimen in treatment of early-stage favourableHodgkinrsquos lymphoma (GHSG HD13) An open-label randomised non-inferiority trial Lancet 2015385(9976)1418ndash1427

77 Hay AE Klimm B Chen BE et al An individual patient-data comparison ofcombined modality therapy and ABVD alone for patients with limited-stageHodgkin lymphoma Ann Oncol 201324(12)3065ndash3069

78 Gallamini A Patti C Viviani S et al Early chemotherapy intensification withBEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PETpositive after two ABVD courses Br J Haematol 2011152(5)551ndash560

79 Simon R Optimal two-stage designs for phase II clinical trials Controlled ClinTrials 1989101ndash10

80 Kanakry JA Ambinder RF EBV-related lymphomas new approaches to treat-ment Curr Treat Options Oncol 201314(2)224ndash236

81 Diepstra A van Imhoff GW Schaapveld M et al Latent Epstein-Barr virusinfection of tumor cells in classical Hodgkinrsquos lymphoma predicts adverseoutcome in older adult patients J Clin Oncol 200927(23)3815ndash3821

82 Keegan TH Glaser SL Clarke CA et al Epstein-Barr virus as a marker of sur-vival after Hodgkinrsquos lymphoma a population-based study J Clin Oncol 200523(30)7604ndash7613

83 Jarrett RF Stark GL White J et al Impact of tumor Epstein-Barr virus statuson presenting features and outcome in age-defined subgroups of patientswith classic Hodgkin lymphoma a population-based study Blood 2005106(7)2444ndash2451

84 Flavell KJ Billingham LJ Biddulph JP et al The effect of Epstein-Barr virusstatus on outcome in age- and sex- defined subgroups of patients withadvanced Hodgkinrsquos disease Ann Oncol 200314(2)282ndash290

85 Diepstra A van Imhoff GW Karim-Kos HE et al HLA class II expression byHodgkin Reed-Sternberg cells is an independent prognostic factor in classicalHodgkinrsquos lymphoma J Clin Oncol 200725(21)3101ndash3108

86 Montalban C Garcia JF Abraira V et al Influence of biologic markers on theoutcome of Hodgkinrsquos lymphoma a study by the Spanish HodgkinrsquosLymphoma Study Group J Clin Oncol 200422(9)1664ndash1673

87 Venkataraman G Song JY Tzankov A et al Aberrant T-cell antigen expres-sion in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival Blood 2013121(10)1795ndash1804

88 Greaves P Clear A Coutinho R et al Expression of FOXP3 CD68 and CD20at Diagnosis in the Microenvironment of Classical Hodgkin Lymphoma IsPredictive of Outcome J Clin Oncol 201331(2)256ndash262

89 Gharbaran R Goy A Tanaka T et al Fibroblast growth factor-2 (FGF2) andsyndecan-1 (SDC1) are potential biomarkers for putative circulating CD15thornCD30thorn cells in poor outcome Hodgkin lymphoma patients J Hematol Oncol2013662

90 Jones K Vari F Keane C et al Serum CD163 and TARC as disease responsebiomarkers in classical Hodgkin lymphoma Clin Cancer Res 201319(3)731ndash742

91 Sauer M Plutschow A Jachimowicz RD et al Baseline serum TARC levelspredict therapy outcome in patients with Hodgkin lymphoma Am J Hematol201388(2)113ndash115

92 Rautert R Schinkothe T Franklin J et al Elevated pretreatment interleukin-10 serum level is an International Prognostic Score (IPS)-independent riskfactor for early treatment failure in advanced stage Hodgkin lymphomaLeuk amp lymp 200849(11)2091ndash2098

93 Casasnovas RO Mounier N Brice P et al Plasma cytokine and soluble recep-tor signature predicts outcome of patients with classical Hodgkinrsquos lym-phoma a study from the Groupe drsquoEtude des Lymphomes de lrsquoAdulte J ClinOncol 200725(13)1732ndash1740

94 Axdorph U Sjoberg J Grimfors G et al Biological markers may add to pre-diction of outcome achieved by the International Prognostic Score inHodgkinrsquos disease Ann Oncol 200011(11)1405ndash1411

95 Ouyang J Plutschow A von Strandmann EP et al Galectin-1 serum levelsreflect tumor burden and adverse clinical features in classical Hodgkin lym-phoma Blood 2013121(17)3431ndash3433

96 Kamper P Ludvigsen M Bendix K et al Proteomic analysis identifies galec-tin-1 as a predictive biomarker for relapsedrefractory disease in classicalHodgkin lymphoma Blood 2011117(24)6638ndash6649

97 Sanchez-Espiridion B Martin-Moreno AM Montalban C et al MicroRNA sig-natures and treatment response in patients with advanced classicalHodgkin lymphoma British J Haematol 2013162(3)336ndash347

98 Navarro A Gaya A Martinez A et al MicroRNA expression profiling in clas-sic Hodgkin lymphoma Blood 2008111(5)2825ndash2832

99 Hohaus S Giachelia M Di Febo A et al Polymorphism in cytokine genesas prognostic markers in Hodgkinrsquos lymphoma Ann Oncol 200718(8)1376ndash1381

100 Saarinen S Aavikko M Aittomaki K et al Exome sequencing reveals germ-line NPAT mutation as a candidate risk factor for Hodgkin lymphoma Blood2011118(3)493ndash498

REV

IEW

12 of 12 | JNCI J Natl Cancer Inst 2017 Vol 109 No 4

• djw249-TF1
• djw249-TF3
• djw249-TF6

73 Hatt M Cheze-le Rest C van Baardwijk A et al Impact of tumor size andtracer uptake heterogeneity in (18)F-FDG PET and CT non-small cell lung can-cer tumor delineation J Nucl Med 201152(11)1690ndash1697

74 van Velden FH Cheebsumon P Yaqub M et al Evaluation of a cumulativeSUV-volume histogram method for parameterizing heterogeneous intratu-moural FDG uptake in non-small cell lung cancer PET studies Eur J Nucl MedMol Imaging 201138(9)1636ndash1647

75 Diefenbach CS Hong F Cohen JB et al Preliminary safety and efficacy of thecombination of brentuximab vedotin and ipilimumab in relapsedrefractoryHodgkin lymphoma A trial of the ECOG-ACRIN Cancer Research Group(E4412) Blood 2015126(23)585

76 Behringer K Goergen H Hitz F et al Omission of dacarbazine or bleomycinor both from the ABVD regimen in treatment of early-stage favourableHodgkinrsquos lymphoma (GHSG HD13) An open-label randomised non-inferiority trial Lancet 2015385(9976)1418ndash1427

77 Hay AE Klimm B Chen BE et al An individual patient-data comparison ofcombined modality therapy and ABVD alone for patients with limited-stageHodgkin lymphoma Ann Oncol 201324(12)3065ndash3069

78 Gallamini A Patti C Viviani S et al Early chemotherapy intensification withBEACOPP in advanced-stage Hodgkin lymphoma patients with a interim-PETpositive after two ABVD courses Br J Haematol 2011152(5)551ndash560

79 Simon R Optimal two-stage designs for phase II clinical trials Controlled ClinTrials 1989101ndash10

80 Kanakry JA Ambinder RF EBV-related lymphomas new approaches to treat-ment Curr Treat Options Oncol 201314(2)224ndash236

81 Diepstra A van Imhoff GW Schaapveld M et al Latent Epstein-Barr virusinfection of tumor cells in classical Hodgkinrsquos lymphoma predicts adverseoutcome in older adult patients J Clin Oncol 200927(23)3815ndash3821

82 Keegan TH Glaser SL Clarke CA et al Epstein-Barr virus as a marker of sur-vival after Hodgkinrsquos lymphoma a population-based study J Clin Oncol 200523(30)7604ndash7613

83 Jarrett RF Stark GL White J et al Impact of tumor Epstein-Barr virus statuson presenting features and outcome in age-defined subgroups of patientswith classic Hodgkin lymphoma a population-based study Blood 2005106(7)2444ndash2451

84 Flavell KJ Billingham LJ Biddulph JP et al The effect of Epstein-Barr virusstatus on outcome in age- and sex- defined subgroups of patients withadvanced Hodgkinrsquos disease Ann Oncol 200314(2)282ndash290

85 Diepstra A van Imhoff GW Karim-Kos HE et al HLA class II expression byHodgkin Reed-Sternberg cells is an independent prognostic factor in classicalHodgkinrsquos lymphoma J Clin Oncol 200725(21)3101ndash3108

86 Montalban C Garcia JF Abraira V et al Influence of biologic markers on theoutcome of Hodgkinrsquos lymphoma a study by the Spanish HodgkinrsquosLymphoma Study Group J Clin Oncol 200422(9)1664ndash1673

87 Venkataraman G Song JY Tzankov A et al Aberrant T-cell antigen expres-sion in classical Hodgkin lymphoma is associated with decreased event-free survival and overall survival Blood 2013121(10)1795ndash1804

88 Greaves P Clear A Coutinho R et al Expression of FOXP3 CD68 and CD20at Diagnosis in the Microenvironment of Classical Hodgkin Lymphoma IsPredictive of Outcome J Clin Oncol 201331(2)256ndash262

89 Gharbaran R Goy A Tanaka T et al Fibroblast growth factor-2 (FGF2) andsyndecan-1 (SDC1) are potential biomarkers for putative circulating CD15thornCD30thorn cells in poor outcome Hodgkin lymphoma patients J Hematol Oncol2013662

90 Jones K Vari F Keane C et al Serum CD163 and TARC as disease responsebiomarkers in classical Hodgkin lymphoma Clin Cancer Res 201319(3)731ndash742

91 Sauer M Plutschow A Jachimowicz RD et al Baseline serum TARC levelspredict therapy outcome in patients with Hodgkin lymphoma Am J Hematol201388(2)113ndash115

92 Rautert R Schinkothe T Franklin J et al Elevated pretreatment interleukin-10 serum level is an International Prognostic Score (IPS)-independent riskfactor for early treatment failure in advanced stage Hodgkin lymphomaLeuk amp lymp 200849(11)2091ndash2098

93 Casasnovas RO Mounier N Brice P et al Plasma cytokine and soluble recep-tor signature predicts outcome of patients with classical Hodgkinrsquos lym-phoma a study from the Groupe drsquoEtude des Lymphomes de lrsquoAdulte J ClinOncol 200725(13)1732ndash1740

94 Axdorph U Sjoberg J Grimfors G et al Biological markers may add to pre-diction of outcome achieved by the International Prognostic Score inHodgkinrsquos disease Ann Oncol 200011(11)1405ndash1411

95 Ouyang J Plutschow A von Strandmann EP et al Galectin-1 serum levelsreflect tumor burden and adverse clinical features in classical Hodgkin lym-phoma Blood 2013121(17)3431ndash3433

96 Kamper P Ludvigsen M Bendix K et al Proteomic analysis identifies galec-tin-1 as a predictive biomarker for relapsedrefractory disease in classicalHodgkin lymphoma Blood 2011117(24)6638ndash6649

97 Sanchez-Espiridion B Martin-Moreno AM Montalban C et al MicroRNA sig-natures and treatment response in patients with advanced classicalHodgkin lymphoma British J Haematol 2013162(3)336ndash347

98 Navarro A Gaya A Martinez A et al MicroRNA expression profiling in clas-sic Hodgkin lymphoma Blood 2008111(5)2825ndash2832

99 Hohaus S Giachelia M Di Febo A et al Polymorphism in cytokine genesas prognostic markers in Hodgkinrsquos lymphoma Ann Oncol 200718(8)1376ndash1381

100 Saarinen S Aavikko M Aittomaki K et al Exome sequencing reveals germ-line NPAT mutation as a candidate risk factor for Hodgkin lymphoma Blood2011118(3)493ndash498

REV

IEW

12 of 12 | JNCI J Natl Cancer Inst 2017 Vol 109 No 4

• djw249-TF1
• djw249-TF3
• djw249-TF6