Hodgkin LymphomaAndrew M. Evens, DO, MSc

October 19th, 2019Professor of Medicine, Rutgers RWJ Medical SchoolAssociate Director (Clinical Services), Rutgers CINJ

Director, Lymphoma ProgramMedical Director, Oncology Service Line, RWJBH

New Brunswick, New Jersey

Presentation Overview• Hodgkin Lymphoma (HL) Overview • Milestones, Epidemiology and Incidence• Diagnosis and Workup/Stage• Treatment Approaches• Survivorship• Precision Medicine• Summary• Questions

Hodgkin Lymphoma: Overarching Goals

Efficacy

ToxicityCure, less progression or relapse, less

treatment Acute and late toxicity (morbid & mortal); QOL

Lymphoma Overview• Lymphomas are cancers of immune

system, and are the most common blood cancers

HODGKIN LYMPHOMANON-HODGKIN LYMPHOMA

B-cell 85-90%T-cell 10%NK-cell 1-2%Histiocyte

Hodgkin Disease• MILESTONES

– 1832: original description by Thomas Hodgkin – 1856: Samuel Wilks reported 15 cases– 1872: Langhans describes histology– 1898: Sternberg describes malignant cell– 1902: Dorothy Reed description

•Clusters reported

•About 8,000 new cases per year

•Family association (horizontal)

•Certain socioeconomic groups

•Bi-modal: young adults (20-35 years) and older adults (>60-70 years)

•Males:females = 1.5:1

Epidemiology and Incidence

Age at Diagnosis for Hodgkin and Non-Hodgkin Lymphoma

Cas

es/1

00,0

00

~74,200 NHL cases/year

~8,110 HL cases/year

NHL

HL

Age at diagnosis (y)Data for diagnoses from 1997 to 2001.Jemal et al. CA Cancer J Clin. 2011

Chart1

00

55

1010

1515

2020

2525

3030

3535

4040

4545

5050

5555

6060

6565

7070

7575

8080

8585

NHL

Hodgkin's

0.5

0.1

0.8

0.4

1.2

1.2

1.6

3

2.3

4.1

3.5

4.2

5.7

3.7

7.9

3.3

11.2

2.8

15.5

2.3

21.8

2.4

32.3

2.5

43

2.9

60.9

3.3

80.4

3.7

99.2

3.9

104.6

3.8

100.4

3.3

Sheet1

0510152025303540455055606570758085

NHL0.50.81.21.62.33.55.77.911.215.521.832.34360.980.499.2104.6100.4

Hodgkin's0.10.41.234.14.23.73.32.82.32.42.52.93.33.73.93.83.3

North45.946.94543.9

SEER Stat Database: Incidence-SEER 18 regs public use (2006-2015), NCI, DCCPS, Surveillance Research Program, Cancer Statistics Branch, Accessed February 9th, 2019

US Age-Specific SEER Incidence Rates

Katanoda, K. et al. Jpn J Clin Oncol. 2008 38:391-393

Time trends in age-standardized HD incidence rate: 18 cancer registries in East Asia, Europe and USA, males

Reed Sternberg cells (owl eyes)

CD15 and CD30 staining

Hodgkin Lymphoma WHO Classification 2008

NS65%

LRCHD2%

LD0.8%

LPHDN-D-Mix

3%

I. Classical Hodgkin’s Disease II. Lymphocyte PredominantHodgkin’s Disease

MC25%

III. Gray Zone Lymphoma(features intermediate b/t

cHL and DLBCL)

Hodgkin lymphoma cases may be divided into 3 groups on the basis of age and EBV status

Armstrong et al., 1998

The Lost B-cell Identity of Reed-Sternberg Cells

Germinal center B cell HRS cell

Evens et al. Nat Clin Pract Oncol 2008.

Cell-surface receptors and intracellular mediators induce pro-proliferative and anti-apoptotic H-RS cell phenotype

CD40and CD30

CD40L and CD30L

CD95/Fas

FasL

activeCaspase-8

effectorCaspases

No Apoptosis/Increased Proliferation

Mitochondria

TRAILRANK

LMP-1/2

Dutton et al Proc Natl Acad Sci U S A. 2004 Mathas et al. J Exp Med. 2004.

NFĸB

c-FLIP

XIAP

• Superficial lymph nodes–often painless

– Cervical 60-70%

– Axillary 10-15%

– Inguinal 6-12%

Clinical Features

- B-symptoms– Fever (over 101 Fahrenheit)– Night sweats (drenching)– Weight loss (>10% baseline over 6

months)– Pruritis– Painful nodes on alcohol ingestion– Fatigue, malaise

Constitutional Symptoms

• Symptoms related to mass of lymph nodes causing compression

–Cough–Shortness of breath–Chest pain–Abdominal symptoms (uncommon)–Superior vena cava syndrome (rare)–Spinal cord compression (rare)

Other Symptoms

•Splenomegaly•Hepatomegaly•Anemia•Leukocytosis•Eosinophilia•Lymphopenia•Elevated sedimentation rate (ESR)

Hodgkin Disease: Signs

Approach to Hodgkin Lymphoma

• The majority of patients will be cured!

• Patients are staged with PET/CT scan, and may require bone marrow biopsy (not always)

• Prior to chemotherapy, heart and lung function should be assessed

• Treatment is guided in part by stage

Chemotherapy for HL

• Single agent chemotherapies had low response rates and low cure

• MOPP developed at National Cancer Institute in 1964– 54% freedom from progression at 10 years– Sterilizing and risk leukemia

• ABVD developed (Milan Cancer Instit) in 1973– Not sterilizing and no leukemia

• Other: Stanford V, BEACOPP

Approach to Hodgkin Lymphoma

• Choice of therapy has to maximize chance for cure and minimize short- and long- term toxicity

• Limited stage disease (>90-95%cured )– Chemotherapy (usually ABVD) with low dose

radiation or– Chemotherapy alone

• Advanced stage disease (80-85% cured)– Combination chemotherapy (usually ABVD)

Brentuximab Vedotin Mechanism of Action

Brentuximab vedotin (SGN-35) ADC (Adcetris)monomethyl auristatin E (MMAE), antitubulin agentprotease-cleavable linkeranti-CD30 monoclonal antibody

ADC binds to CD30

MMAE disruptsMicrotubule network

ADC-CD30 complex traffics to lysosome

MMAE is released

Apoptosis

G2/M cellcycle arrest

• Defined: age ≥ 60 years• Under-represented in clinical trials:

Relapsed Hodgkin Lymphoma• Goal is still CURE

• Optimal approach is usually high-dose chemotherapy with autologous stem cell transplantation for eligible patients

• For patients who have relapsed after transplant, or who are not eligible for transplant, brentuximab vedotin (Adcetris) is now available

Immune checkpoint blockade: PD-1 and PD-L1 inhibition

- PD-1 cell surface marker on T-immune cells- Interacts with its ligands (PD-L1) initiating

inhibitor signal (T-cell exhaustion)- Tumor cells co-opt this pathway- PD-1 inhibitors block this pathway

FDA: Relapsed after transplant

Nivolumab 2016; Pembrolizumab

2017

470 pts

Newly diagnosed Stage III-IV

Hodgkin lymphoma (ages >11)

RANDOMIZE

Nivolumab + AVD6 cycles

Nivolumab 240mg days 1,15Doxorubicin 25mg/m2 days 1,15Vinblastine 6mg/m2 days 1,15

Dacarbazine 375mg/m2 days 1,15

Brentuximab vedotin + AVD

6 cyclesBV 1.2mg/kg days 1,15

Doxorubicin 25mg/m2 days 1,15Vinblastine 6mg/m2 days 1,15

Dacarbazine 375mg/m2 days 1,15

470 pts

1:1

Stratification:• Age• IPS

• ISRT eligible

New North American Cooperative Group Study for Advanced Stage Hodgkin Lymphoma: S1826

Cancer Survivorship• From Cancer Patient to Cancer Survivor:

Institute of Medicine (IOM) had as its 3rdrecommendation: “Health care providers should use systematically developed evidence-based clinical practice guidelines, assessment tools, and screening instruments to help identify and manage late effects of cancer and its treatment. Existing guidelines should be refined and new evidence-based guidelines should be developed.”Institute of Medicine: From cancer patient to cancer survivor: Lost in transition. Washington, DC, National Academies Press, 2005

Late Effects of Treatment

• Radiation– Cardiac damage (early atherosclerosis,

valve disease)– Secondary tumors (breast cancer in

women 10 years later)– Lhermitte’s syndrome– Transverse myelitis– Pneumonitis– Hypothyroidsm

Late Effects of Treatment

• Chemotherapy– Cardiomyopathy (adriamycin)– Acute leukemia (from 2 to 10 years after

treatment)– Nerve irritation– Sterility– Pulmonary injury (bleomycin) – Second malignancies

Strategies to ‘reduce’ therapy in good prognosis HL and ‘improve’ in

higher risk HL• Decreased reliance on chemotherapy

(dosing and overall)• Integration of novel (targeted)

therapeutics• Refinement of radiation (method,

dose + field size)• Utilize functional imaging: PET (i.e.,

response-adapted therapy)• Examination of host genetics• Incorporation of biologic findings

(tissue/biomarkers)

EFRT

INRT

IFRT

Courtesy of J. Yahalom, MSKCC

• Definition (quantitative)• EG: ΔSUV-max and MTV (volume in mL) of tumor

tissue demonstrating FDG uptake (segmentation technique/3D software); and tumor heterogeneity

• Total lesion glycolysis (TLG): integrate volume and glycolytic activity (TLG = MTV x SUV-mean)

Metabolic lymphoma burden

Lin C et al. J Nuc Med. 2007Wahl RL et al. J Nuc Med. 2009Casasnovas RO, et al. Blood. 2011 Kostakoglu L et al. Leuk Lymph. 2012

Lymphoma-associated macrophages

Steidl C, et al. NEJM, 2010

? Target the soil (vs the seeds)

Overall Summary• Increased knowledge re: the cause(s)

of HL• Early-stage HL: vast majority cured

– Minimization of acute and late toxicities (primary and secondary interventions)

• Advanced-stage HL– Goal is cure

• Current/future: biomarkers, FDG-PET, and novel targeted therapy

• Survivorship!!

Questions?

Thank you!

Slide Number 1Presentation OverviewHodgkin Lymphoma: Overarching GoalsLymphoma OverviewSlide Number 5Slide Number 6Age at Diagnosis for Hodgkin and Non-Hodgkin LymphomaSlide Number 8Slide Number 9Slide Number 10Slide Number 11Slide Number 12Hodgkin Lymphoma �WHO Classification 2008Hodgkin lymphoma cases may be divided into 3 groups on the basis of age and EBV statusSlide Number 15Slide Number 16Slide Number 17Slide Number 18Slide Number 19Slide Number 20Approach to Hodgkin LymphomaChemotherapy for HLApproach to Hodgkin LymphomaSlide Number 24Slide Number 25Relapsed Hodgkin LymphomaSlide Number 27New North American Cooperative Group Study for Advanced Stage Hodgkin Lymphoma: S1826Cancer SurvivorshipSlide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Overall SummaryQuestions?