A CME-certified Oncology Exchange Program

A CME-certified Oncology Exchange Program

Jointly provided by Potomac Center for Medical Education and RockpointeSupported by an educational grant from Seattle Genetics, Inc.

Faculty

Anas Younes, M.D.Chief, Lymphoma ServiceMemorial Sloan Kettering Cancer CenterNew York

Jeremy S. Abramson, M.D.Director, Center for LymphomaMassachusetts General Hospital Cancer Center

Off-label Discussion Disclosure

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the Food and Drug Administration. PCME does not recommend the use of any agent outside of the labeled indications. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications and warnings. The opinions expressed are those of the presenters and are not to be construed as those of the publisher or grantors.

Learning Objectives

• Assess emerging frontline approaches for patients with Hodgkin lymphoma

• Evaluate the efficacy and safety data for novel agents in patients with relapsed/refractory Hodgkin lymphoma

• Discuss strategies to mitigate adverse effects to improve long-term survival in Hodgkin lymphoma

Hodgkin LymphomaIntroduction and

Initial Therapy

Case Study 1

• M.C. is a 23 yo woman who presents with painless swelling of a right supraclavicular lymph node. She was otherwise asymptomatic with a normal physical examination

• A course of antibiotics was prescribed, without response

• An FNA was performed and interpreted as consistent wit a reactive lymphoid population

• An excisional lymph node biopsy was ultimately performed

CD30CD15

CD3 EBER

Staging and Pre-treatment Evaluation

• PET/CT showed non-bulky stage IIA disease

• CBC, CMP unremarkable• ESR 12 ml/hour• HIV negative• No bone marrow is performed• Echocardiogram and PFTs show

no organ dysfunction

• What is the optimal therapy for this patient?

Case 1: How will you treat this patient?

1. ABVD x 6 cycles followed by 30 Gy radiation



4. ABVD x 4-6 cycles without radiation

5. Escalated BEACOPP +/- radiation

Case 1: What if this patient was 73 years old instead of 23?1. ABVD x 4 cycles followed by 30 Gy radiation


3. ABVD x 4-6 cycles without radiation

4. AVD x 4-6 cycles (omit bleomycin) +/- radiation

5. ChlVPP +/- radiation

Epidemiology

• ~9200 cases/year in US• ~1200 deaths• Median age 35

– Bimodal distribution

• Slight male predominance• Incidence is stable

Siegel, et al. CA Cancer J Clin. 2014; 64(1): 9-29.

Clinical Presentation

• 70% present with painless lymph node enlargement

• Limited in 55%, Advanced in 45%

• 30% will have “B” symptoms

• Pruritus• Rare pain with alcohol

ingestion

• Sites of involvement– Nodal regions

• Cervical/Supraclavicular (L>R) 60-70%• Mediastinal 60%• Axillary 25-35%• Hilar nodes 15-35%• Para-aortic 30-40%• Iliac 15-20%• Inguinal 8-15%• Mesenteric 1-4%

– Other lymphoid organs• Spleen 30-35%• Waldeyer’s ring 1-2%

– Extranodal sites (10-15%)• Liver 2-6%• Bone marrow 2-8%• Other organs (lung, bone) 10%

Pathologic Classification

• Nodular lymphocyte predominant HL

CD20

• Classical HL– Nodular sclerosis– Mixed cellularity– Lymphocyte rich– Lymphocyte depleted

NS

MC

LR

LD

Initial Evaluation and Workup

• History• Physical exam• Staging studies

– PET/CT scan

– Bone marrow (Can usually be omitted based on PET findings)

• Labs– CBC with differential

– Erythrocyte Sedimentation Rate

– Albumin, LFTs, Ca++, HIV

• Preparation for chemotherapy– Echocardiogram

– Pulmonary Function Tests, with DLCO

– Fertility considerations

Nodular Lymphocyte-predominant HL

• 5% of Hodgkin lymphomas• Pathologically distinct from CHL• Clinically distinct from cHL

– Indolent natural history

– Male predominance (75%)

– Median age in 30s

– Increased risk among first degree family members

– Limited stage in 75%, usually peripheral

– Extranodal disease, B symptoms very uncommon

– ~12% rate of high-grade transformation at 10y

• Treatment– Radiation alone preferred for

limited stage: 10 year FFP ~ 80%– Advanced stage extrapolated from

cHL +/- rituximab• ABVD +/- rituximab

• R-CHOP

– Some suggest alkylators may be more effective (controversial)

– Rituximab alone is an effective option, particularly at relapse

– Late recurrences may occur

Nodular LP vs Classical HL: GHSG Trials HD4-HD12

Nogova, et al. JCO 2008

Freedom from Treatment Failure Overall Survival

NLPHL

CHLNLPHL

CHL

Initial Treatment of Classical Hodgkin Lymphoma (cHL)

Chemotherapy for cHL

• MOPP developed at National Cancer Institute in 1964– 54% freedom from progression at 10 years– Potentially sterilizing– Potentially leukemogenic

• ABVD developed at Milan Cancer Institute in 1973– Not sterilizing– Not associated with MDS or leukemia

DeVita NEJM ‘03

MOPP versus ABVD for Advanced HL

Canellos, et al. NEJM. 1992

Failure-free Survival

5 year FFS

MOPP-ABVD 65%ABVD 61%MOPP 50%

5 year OS

MOPP-ABVD 75%ABVD 73%MOPP 66%

Overall Survival

Treatment Intensification: Escalated BEACOPP versus ABVD

Viviani, et al. NEJM. 2011

Risk Factors in Advanced Stage CHL

• Age ≥45• Male Gender• Stage IV• Hemoglobin <10.5 g/dL• Leukocytosis >15k/mm3

• Lymphopenia <600/mm3 or 8%• Hypoalbuminemia <4.6

Moccia, et al. JCO 2012; 30(27): 3383-3388.

5y FFP (%) 5y OS (%)

IPS N Original BCCA Original BCCA

0 57 84 88 89 98

1 195 77 84 90 97

2 195 67 80 81 91

3 155 60 74 78 88

4 88 51 67 61 85

≥5 50 42 62 56 67

Advanced Stage disease

• ABVD x 6 cycles

• Outstanding questions– Selection of high-risk patients for treatment intensification– Role of PET-adapted therapy– Incorporation of novel agents

Treatment of Limited Stage cHL

Risk Stratification: Adverse factors in Limited Stage Disease

EORTC

• Large mediastinal mass

• Age >50

• >4 involved sites

• ESR> 30 with B sx OR >50 without B sx

GHSG

• Large mediastinal mass

• Extranodal disease

• >3 nodal regions

• Elevated ESR

Ferme et al. N Engl J Med 2007; 357: 1916-27.

Combined Modality Therapy is Superior to Radiation Alone in Early Favorable Disease

Combined Modality Therapy allows Reducing Chemotherapy Cycles and Radiation Field

Ferme et al. N Engl J Med 2007; 357: 1916-27.

Beware the Late Effects of Therapy

Ng et al. J Clin Oncol 2002, 20(8): 2101-2108; De Bruin et al. J Clin Oncol 2009 , 27(26): 4239-4246.

Breast Cancer Incidence

Beware the Late Effects of Therapy

Aleman, et al. Blood 2007, 109(5): 1878-1886.

All Cardiac EventsAngina Pectoris

Myocardial Infarction

30 Gy IF 30 Gy IF20 Gy IF 20 Gy IF

CS I - II without risk factors*

ABVDABVD

ABVDABVD

ABVDABVDABVDABVD

ABVDABVDABVDABVD

German Hodgkin Study Group : HD10 trial

• No risk factors: Large mediastinal mass, extranodal disease, >3 nodal regions, elevated ESR

Less is more: The GHSG HD10 trial

Engert et al. N Engl J Med 2010; 363(7): 640-652.

ABVDx2+STNI ABVDx4-6

Unfavorable (N = 276)

35Gy STNI ABVDx4-6

Favorable (N = 123)

Stage I/II HL (N = 399)

Chemotherapy alone for Limited-stage cHL

Primary endpoint: 12 year overall survival

• Study excluded patients with bulk– (M:T ratio >.33 or disease >10cm)

• Unfavorable = ESR ≥ 50 mm/hr, age ≥ 40, > 3 sites, MC/LD

Chemotherapy Alone Versus Radiation-containing Therapy at 12 Years

FFDP at 12-years• ABVD 87%• XRT/CMT 92% (HR 3.03; p=0.01)

Meyer, et al. N Engl J Med 2012; 366(5): 399-408.

OS at 12-years• ABVD 94%• XRT/CMT 87% (HR 0.4; p=0.04)

Are These Data Relevant in 2014?

NO• Subtotal nodal radiotherapy is not the modern standard of care and leads

to increased radiation exposure compared to current involved field/nodal techniques

• XRT likely didn’t cause late infections, Alzheimer’s disease or drowning

YES• Though we radiate lower volumes today, modern radiation in HL often

includes the breasts, lungs, skin/soft tissues, and coronary ostia.

• ABVD alone produced 12-year overall survival of 94%, which is excellent

• This OS and FFDP is virtually identical to the GHSG HD11 trial results at 5 years using modern CMT with IFRT in the same population

Can Interim PET Scans be Used to Direct use of Radiation Therapy?

Arm events HR CI P

Standard 1/188 1.00

Experimental 9/193 9.36 2.45-35.73 .017

Arm events HR CI P

Standard 7/251 9.36

Experimental 16/268 2.42 1.35-4.36 .026

Raemaekers, et al. J Clin Oncol, 2014, 32: 1-8.

1 ABVD + INRT 30 Gy (+ 6 Gy)

2 ABVD + INRT 30 Gy (+ 6 Gy)

2 BEACOPPesc + INRT 30 Gy (+ 6 Gy)

2 BEACOPPesc + INRT 30 Gy (+ 6 Gy)

2 ABVD

4 ABVD

2 ABVD

2 ABVD

2 ABVD

2 ABVD

PET

PET

PET

PET

R

H10F

-

+

R

H10U

-

+

Who Should Receive Radiation?Not one size fits all

• Current data support combined modality therapy for bulky limited stage disease

• For non-bulky patients, choice of therapy should be informed by patient age, tumor location and patient preference

• Further data anticipated regarding the role of PET-adapted therapy

Treatment of Limited Stage disease

• Favorable– ABVD x 2 cycles plus 20Gy IFRT– ABVD x 4-6 cycles without XRT (for selected patients)

• Unfavorable, non-bulky– ABVD x 4 cycles + 30 Gy IFRT– ABVD x 6 cycles without XRT (for selected patients)

• Unfavorable, bulky– ABVD x 6 cycles plus 30-36 Gy IFRT– ABVD x 4 cycles without XRT if interim PET negative (for selected patients)

• Major ongoing questions– PET-adapted therapy – Incorporation of novel agents

The Challenge of Treating Older Adults with Hodgkin Lymphoma

Advanced Stage HL in Older Adults (E2496: ABVD/Stanford V)

Failure-free survival Overall survival

Evens et al. BJH, 2013, 161(1): 76-86.

• 24% of older patients developed bleomycin lung toxicity• Treatment-related mortality: 9.3% vs. 0.3%, p<0.001)

74%

48%

P=0.002 P<0.0001

<60 yr≥ 60 yr

90%

58%

YearYear

Prob

abilit

y

Prob

abilit

y

Limited Stage HL in Older Adults (GHSG HD10-HD11: ABVD x4 + IFRT)

Boll et al. J Clin Oncol , 2013, 31(12): 1522-1529.

Overall Survival Progression-free Survival

Time to HL death Time to HL treatment failure

Chicago Elderly HL Prognostic Model

0 30 60 90 120 150 1800

25

50

75

1000 Prognostic factor(s)1 Prognostic factor(s)2 Prognostic factor(s)

Time in Months

Per

cen

t su

rviv

al

Event-free survival

Adverse Risk factors:1) ADL loss2) >70 years

Bleomycin lung toxicity 32% (Mortality: 25%)

Overall survival

0 30 60 90 120 150 1800

25

50

75

1000 Prognostic factor(s)1 Prognostic factor(s)2 Prognostic factor(s)

Time in Months

Per

ce

nt

su

rviv

al

Evens, et al. Blood 2013, 122(21).

Recommendations for Managing Older Adults with HL• Outcomes inferior to younger patients• Increased toxicity and treatment-related mortality• Take great caution regarding bleomycin lung toxicity and neutropenic

infections• Low threshold to omit bleomycin (AVD) • Short course therapy if possible• Consider myeloid growth factor support• Non-ABVD/AVD options include ChlVPP, CHOP• Clinical trials preferred• Ongoing studies examining incorporation of brentuximab vedotin into

frontline therapy

Targeted Therapy and New Treatment Approaches

Case Study 2

32 yo woman was diagnosed with stage IV cHL a year ago. She was treated with ABVD and achieved a complete response.

Today, she presents with fatigue and enlarged right cervical lymph node measuring 2 x 2 cm.

Imaging studies showed PET avid lesions above and below the diaphragm, with the largest nodal mass measuring 3 x 2 cm.

Bone marrow biopsy was negative. Echocardiogram showed LVEF of 60%.

Case 2: You Would Recommend:

1. Brentuximab vedotin x 16 doses followed by ASCT

2. ICE x 2-3 cycles followed by ASCT

3. BEACOPP X 6 cycles

4. DHAP x 2-3 cycles followed by ASCT

5. GND x 2-3 cycles followed by ASCT

Case 2 (continued)

• The patient received 3 cycles of ICE and achieved a CR. This was followed by stem cell collection, BEAM, and stem cell re-infusion (ASCT).

• One year later, she had enlarged nodes above and below the diaphragm, and a biopsy of a left inguinal node confirmed the presence of relapsed HL.

1. Brentuximab vedotin x 16 doses followed by allogeneic stem cell transplant

2. Brentuximab vedotin up to 16 doses, unless disease progression or prohibitive toxicity

3. Brentuximab vedotin x 4 then PET/CT. If CR continue for at least 8 doses and a maximum of 16 doses, followed by observation

4. Clinical trial

Case 2: You Would Recommend:

ABVD

Relapse/Refractory

ICEDHAP

Response No Response

ASCT

Response

GVDIGEV

Brentuximab Vedotin

Cure

No Response/Relapse

Brentuximab Vedotin

No Response

Results of Salvage Pre-transplant Regimens in cHL

ESHAP

GDP

GVD

DHAP

ICE

Dexa-BEAM

MINE

ASHAP

mini-BEAM

IGEV

0 20 40 60 80 100

PRCR

% response rate

Moskowitz C H et al. Blood 2001;97:616-623

ICE + ASCT

GVD = gemcitabine, vinorelbine, and pegylated liposomal doxorubicinBartlett N et al. Ann Oncol 2007; 18: 1071-1079.

GVD plus ASCT

Event-free Survival for Transplant-naive Patients

GVD after failing a prior transplant

MSKCC 11-142: Relapsed/refractory HL First TX following upfront therapy

Moskowitz, A et al ASH2013, Poster # 2099.

Further treatment according to treating

physician

Weekly BV x 2 cycles

Augmented ICE x2 cycles

HDT/ASCT

PET+ -

-

+

PET

Summary

• 80% CR rate achieved with PET adapted sequential therapy with BV and augmented ICE

• 30% patients avoided ICE salvage therapy

• Of 40 evaluable patients– 36 have completed ASCT– 3 will undergo ASCT shortly– 1 remains on treatment for persistent disease

Moskowitz, A et al ASH2013, Poster # 2099.

TTR N Median OS (y)>12 m 172 4.6 6-12 m 165 2.4 4-6 m 204 1.5 0-3 m 215 0.7

Overall Survival by Time to RelapseAfter Transplant

Horning S et al, Ann Oncol 2008:19 (suppl 4):Abstract 118; Arai S et al. Leukaemia and Lymphoma. 2013.

Date of Prep 09/10/13 EUCAN/ADC/2013-10029l

Targeted Therapy in Hodgkin Lymphoma

Lee & Younes, Hematology 2013: 394-399.

Younes A & Kadin M et al: J Clin Oncol, 21, 2003: 3526-3534.

1992 (Cell): Durkop and Stein:Molecular cloning of CD30 = TNF receptor family member

Summary Results of Phase I/II Clinical Trials Targeting CD30

Younes, A: Curr Opin Oncol. 2011, 23(6): 587-593.

Drug Disease Antibody type PhaseNumber of evaluable patients

PR CR %PR + CR

MDX-060 HL, ALCL Humanized I HL = 63ALCL = 9

22

20

6%22%

SGN-30 HL, ALCL Chimeric I 24 0 0 0

SGN-30 HL, ALCL Chimeric II HL = 38ALCL = 41

05

02

017%

Xmab2513 HL Humanized I 13 1 0 7%

131I-Ki4 HL Murine I 22 5 1 27%

Brentuximab Vedotin (SGN-35) Structure

Katz J, JanikJ, and Younes A . Clin Cancer Res 2011; 17: 6428-6436

Investigator Assessment IRF Assessment

86% of patients achieved tumor reductions 83% of patients achieved tumor reductions

Phase-I Brentuximab Vedotin in Relapsed HLTreatment Response

Younes et al. N Engl J Med 2010; 363(19): 1812-1821.

Phase I Brentuximab Vedotin in Relapsed HL

Younes A, et al. N Engl J Med 2010; 363(19): 1812-1821.

• 21-year-old female• HL diagnosed 2003

– ABVD + XRT to mediastinum – ICE – BEAMASCT – HDAC-inhibitor

• SGN-35 2.7 mg/kg x 8 cycles– Best clinical response: CR– CT 93% reduction, PET-– PET negative

Brentuximab Vedotin: Pivotal Phase II trialMaximum Tumor Reduction per IRF

Younes et al. J Clin Oncol, 2012, 30(18): 2183-2189.

Complete remission by PET

94% (96 of 102) of patients achieved tumor reduction

Individual patients (n=98*)

Tum

our s

ize

(% c

hang

e fr

om b

asel

ine)

100

50

0

–50

–100

Brentuximab Vedotin: Pivotal Phase II trialPFS Results By Best Response

• Phase II pivotal study of brentuximab vedotin in 102 patients with relapsed/refractory HL post ASCT: PFS by best response

Gopal A, et al ASH 2013

Three-year Follow-up Data and Characterization of Long-Term Remissions from an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Hodgkin Lymphoma

OS from ASCT by BV

Karuturi, M et al ASH 2012

Brentuximab VedotinInitial treatment vs retreatment

HL sALCL

N= 58 N=8N=102 N=15

Bartlet et al , ASCO 2012

Proposed Algorithm for Treating Patients post ASCT

Relapse from CRRetreat with BV then allo-SCT

ASCT

<CR/Relapse

Brentuximab Vedotin

CRContinue BV

to8-16

doses

<CRConsider allo

SCT

Continue

BV until

disease progression

CR

Observe (Role of adjuvant BV?)

Rationale for Using HDAC Inhibitors in HL

Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013

Baseline31 year old femaleExtensive Prior TherapyRegimen Best ResponseABVD PRXRT Not EvalDHAP PRAuto Transplant Not EvalIGEV ProgressionDHAP ProgressionFludarabine/ Melphalan ProgressionAllo Transplant ProgressionDonor lymphocyte ProgressionMOPP Not EvalESHAP ProgressionIEV Progression

2 months

Mocetinostat in Relapsed Hodgkin Lymphoma

Younes et al Lancet Oncology 2012

CT (– 52% = PR)

PET

Mocetinostat in Relapsed HL:Clinical Responses

85 mg

110 mg

58% of subjects experienced tumor reduction

Younes A, et al, Lancet Oncology, 2012, 12(13), 1222-1228.

Panobinostat in Patients with Relapsed/Refractory HL

Younes A, et al. Blood. 2009;114: Abstract 923.

Week

0 1 2 3 4 5 6

40 mg (fixed dose) orally, 3 times/week

Restage:If no PD Give Panobinostat

until PD or tox

International Panobinostat Phase II Study in Relapsed HL

Younes A,Soreda A,, et al. JCO 2012

-100

-75

-50

-25

0

25

50

75

100

Be

st %

Ch

an

ge

in S

PD

Fro

m B

ase

line

(ind

ex

lesi

on

s o

nly

)

ActiveDiscontinued

PR

PD

4 patients - SD (0%)

6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements

5 patients with SPD < 50% had new lesions at Eval 1

PR

PD




PR

PD




PR

PD




71% of patients with tumor reduction

Phase I Panobinostat (LBH589) + ICE

LBH

ICE

PET/CT

Transplant

Dose Level LBH589 (Panobinostat) Dose mg

N

-1 10 0

0 20 6

1 30 14

Evaluable patients : N=21ORR : 86%, CR: 71% and all proceeded to ASCT

Results:

Oki Y, et al ASH 2013.

S6K1 4EBP1

mTORC1

PI 3-kinase

AKT

CD19

BCRGPCRRTK TNFR

BADGSK3FOXOp53

SurvivalProliferationGrowthMetabolismApoptosisMotility

IdelalisibIPI-145

BKM-120XL-147

GDC-0941GSK1059615

EverolimusTemsirolimusRidaforolimus

AZD8055

MK-2206XL-418VQD002

BEZ-235BGT226XL765

PI3K Pathway Inhibitors

Younes a, ASH 2013

Pathway Drug Target% Response Rate in Different Histologies

DLBCL FL MCL SLL/CLL T-Cell HL

PI3K/AKT/mTOR

Everolimus mTOR 30% 50% 32% 18% 63% 42%

Temsirolimus mTOR 36% 56% 38% 10% - -

Idelalisib PI3K-δ - 57% 67% 72% - 12%

IPI-145 PI3K-γδ 0% 67%* 67% 54% 33% 33%

BAY80-6946 PI3K-αδ 13% 40% 71% 43% 50% -

Activity of PI3K/mTOR Inhibitors in Lymphoma

Updated from Younes A & Berry D. Nature Rev Clin Oncol 2012

Targeting PD1-PDL1

McDermott et al, Cancer Medicine 2013; 2(5): 662–673.

SourceTarget molecule

PD-1 PD-L1/PDL2

Merck MK-3475(humanized IgG4)

CureTech/Teva CT-011 (humanized IgG1)

AmpliImmune/GSK AMP-224(PD-L2/IgG1 fusion protein

BMS MDX-1106/BMS-936558(Fully human IgG4)

MDX-1105/BMS-936559 (Fully human IgG4)

Genentech/ROCHE MPDL3280A(Engineered IgG1)

PD1/PD-L1 Blocking Agents in Clinical Trials

Immune regulatory effects of panobinostat in patients with Hodgkin lymphoma through modulation of T-cell PD1 expression

Oki Y, …Younes A: Blood Cancer Journal (2014) 4, e236.

Single Agent Activity of New Agents in Post SCT Relapsed cHLComparison to multiagent chemotherapy GVD

Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013

% R

espo

nse

rate

GVD

Brentuxim

ab Vedotin

Retreatm

ent BV

Evero

limus + Pan

obino...

Evero

limus

Panobinostat

Mocetinosta

t

Lenalid

omide

Vorinostat

SGN300

20

40

60

80

100 CR PR

Brentuximab-Vedotin Combination Strategies

BrentuximabVedotin

HDACi

PI3Ki/mTORi

Chemotherapy

PD1/PDL1MoAb

A CME-certified Oncology Exchange Program

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