Hodgkin’s Disease an Update. Is more always better?

Jeffrey Schriber, M.D.

Medical Director

Cancer Transplant Institute

Virginia G. Piper Cancer Center

Statistics at a Glance Percent Surviving 5

Years

85.3%

2004-2010

Estimated New Cases in 2014

9,190

% of All New Cancer Cases

Prevalence

0.6%185,000

Estimated Deaths in 2014

1,180

% of All Cancer Deaths

0.2%

New Cases, Deaths and 5-Year Relative Survival

Year 1975 1980 1985 1990 1994 1998 2002 2006

5-Year Relative Survival

69.9% 73.4% 78.7% 81.0% 83.0% 84.9% 85.1% 88.3%

Percent of New Cases by Age Group: Hodgkin Lymphoma

Median Age At

Diagnosis

39

Percent of Deaths by Age Group: Hodgkin Lymphoma

Median Age At Death

65

Symptoms

• Painless swelling of lymph nodes

• Fever

• Night Sweats

• Weight Loss

• Itching

• Loss Appetite

Testing

• History /Physical

• LDH

• PET

• BM (not so much now)

• Biopsy

Hodgkin Lymphoma (HL)

• >95% of HL isCD30-positive1

• CD68 and CD163 may have prognostic significance

• Lymphoid neoplasm defined by the presence of Reed-Sternberg (RS) cellsin a reactive infiltrate2,3

9

Reproduced with permission from Mani H et al, 20095

References: 1. Diehl V et al. In: DeVita VT Jr et al, eds. Cancer: Principles and Practice of Oncology. Vol 2. 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2008:2167-2220. 2. Pileri SA et al. J Clin Pathol. 2002;55(3):162-176. 3. Stein H et al. In: Swerdlow SH et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC; 2008:326-329. 4. American Cancer Society. Cancer Facts & Figures 2011. Atlanta, GA: American Cancer Society; 2011. 5. Mani H et al. Clin Lymphoma Myeloma. 2009;9(3):206-216.

Early Stage Hodgkin’s

• Favorable

– Clinical Stage I-II without risk factors

• Unfavorable

– Risk Factors present

• B Symptoms

• Elevated ESR > 50

• Mediastinal Mass

• > 3 Nodal Sites

Approximate Cumulative Risk of Recurrent Hodgkin's Lymphoma, Second Malignant Conditions, and Cardiovascular Events among Patients Receiving Both Radiotherapy and

Chemotherapy for Early-Stage Hodgkin's Lymphoma

Armitage JO. N Engl J Med 2010;363:653-662

Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression.

Meyer RM et al. N Engl J Med 2012;366:399-408

Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression among Patients with an Unfavorable Risk Profile.

Meyer RM et al. N Engl J Med 2012;366:399-408

12-Year Outcomes in Study Patients, According to Treatment Strategy.

Meyer RM et al. N Engl J Med 2012;366:399-408

Causes of Death, According to Treatment Strategy and Risk Profile.

Meyer RM et al. N Engl J Med 2012;366:399-408

Early Stage Hodgkin’s

• Treatment continues to improve• New Options are evolving and several options

currently available• Use of early response to PET may help• Chemo ( ABVD or Stanford V) with XRT (involved

site)• ABVD alone• Balance Up front benefit with Long term toxicity

Kaplan-Meier analysis of the probability of (A) freedom from treatment failure and (B) overall survival in each treatment arm.

Engert A et al. JCO 2009;27:4548-4554

©2009 by American Society of Clinical Oncology

Original Article

ABVD versus BEACOPP for Hodgkin's Lymphoma When High-Dose Salvage Is

Planned

Simonetta Viviani, M.D., Pier Luigi Zinzani, M.D., Alessandro Rambaldi, M.D., Ercole Brusamolino, M.D., Alessandro Levis, M.D., Valeria Bonfante, M.D., Umberto Vitolo, M.D., Alessandro Pulsoni, M.D., Anna Marina Liberati, M.D., Giorgina

Specchia, M.D., Pinuccia Valagussa, B.S., Andrea Rossi, M.D., Francesco Zaja, M.D., Enrico M. Pogliani, M.D., Patrizia Pregno, M.D., Manuel Gotti, M.D., Andrea

Gallamini, M.D., Delia Rota Scalabrini, M.D., Gianni Bonadonna, M.D., Alessandro M. Gianni, M.D., for the Michelangelo Foundation, the Gruppo Italiano di Terapie

Innovative nei Linfomi, and the Intergruppo Italiano Linfomi

N Engl J MedVolume 365(3):203-212

July 21, 2011

Study Overview

• BEACOPP combination chemotherapy was compared with ABVD

chemotherapy in advanced Hodgkin's disease.

• BEACOPP therapy was associated with higher initial rates of complete

response and freedom from relapse but also with more short-term and

long-term toxic effects.

Randomization, Treatment, and Follow-up.

Viviani S et al. N Engl J Med 2011;365:203-212

Kaplan–Meier Curves for Freedom from First Progression and Event-free Survival.

Viviani S et al. N Engl J Med 2011;365:203-212

Kaplan–Meier Curves for Freedom from Second Progression and Overall Survival.

Viviani S et al. N Engl J Med 2011;365:203-212

Outcomes and Important Adverse Events Associated with Initial Treatment, According to Regimen.

Viviani S et al. N Engl J Med 2011;365:203-212

Salvage Therapy and Outcome of Overall Intended Treatment.

Viviani S et al. N Engl J Med 2011;365:203-212

Conclusions

• Treatment with BEACOPP, as compared with ABVD, resulted in better

initial tumor control, but the long-term clinical outcome did not differ

significantly between the two regimens.

Advanced Stage Hodgkin’s

• Chemotherapy treatment of Choice• Choice depends on where you are• BEACOPP (Germany) ABVD/ Stanford V (USA)• Use of early response to PET may help• Balance Up front benefit with Long term toxicity• Look at totality of care

Cytotoxic agentThe synthetic microtubule-disrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death

ADCETRIS is a CD30-Directed Antibody-Drug Conjugate

ADCETRIS consists of three components:

LinkerA synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell

AntibodyThe antibody, brentuximab, specific for CD30

Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012.

Nonclinical Data Suggest a Multistep Process for ADCETRIS

Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012.

Efficacy Results (relapsed HL after ASCT)

Duration of response was calculated from the date of first response to the date of progression.

N = 102

Response (%)

95% CIDuration of response, in months

Median (95% CI) Range

CR 32 23, 42 20.5 (12.0, NE*) 1.4 to 21.9+

PR 40 32, 49 3.5 (2.2, 4.1) 1.3 to 18.7

ORR 73 65, 83 6.7 (4.0, 14.8) 1.3 to 21.9+

Median duration of treatment: 27 weeks

Summary

• Rare Cancer• Highly Curable• Staging Critical to understanding Treatment options• Early Disease less may be more • Advanced Disease PET may prove helpful• Salvage with Transplant • New Therapy including Brentuximab may change

Options

Original Article

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma

Andreas Engert, M.D., Annette Plütschow, Ph.D., Hans Theodor Eich, M.D., Andreas Lohri, M.D., Bernd Dörken, M.D., Peter Borchmann, M.D., Bernhard Berger, M.D.,

Richard Greil, M.D., Kay C. Willborn, M.D., Martin Wilhelm, M.D., Jürgen Debus, M.D., Michael J. Eble, M.D., Martin Sökler, M.D., Antony Ho, M.D., Andreas Rank, M.D., Arnold Ganser, M.D., Lorenz Trümper, M.D., Carsten Bokemeyer, M.D., Hartmut

Kirchner, M.D., Jörg Schubert, M.D., Zdenek Král, M.D., Michael Fuchs, M.D., Hans-Konrad Müller-Hermelink, M.D., Rolf-Peter Müller, M.D., and Volker Diehl, M.D.

N Engl J MedVolume 363(7):640-652

August 12, 2010

Study Overview

• Investigators examined whether the intensity of treatment can be

reduced in patients with early-stage Hodgkin's lymphoma without

compromising antitumor efficacy.

• In a comparison of two with four cycles of ABVD chemotherapy plus

either 20 or 30 Gy of involved-field radiation therapy, no significant

differences were noted in disease-free or overall survival between the

most and the least intensive regimens.

Numbers of Patients Randomly Assigned to Treatment Groups and Included in Analyses

Engert A et al. N Engl J Med 2010;363:640-652

Freedom from Treatment Failure and Overall Survival

Engert A et al. N Engl J Med 2010;363:640-652

Baseline Characteristics of the Patients According to Treatment Group

Engert A et al. N Engl J Med 2010;363:640-652

Adverse Events According to Treatment Group

Engert A et al. N Engl J Med 2010;363:640-652

Efficacy Outcomes According to Treatment Group

Engert A et al. N Engl J Med 2010;363:640-652

Conclusions

• In patients with early-stage Hodgkin's lymphoma and a favorable

prognosis, treatment with two cycles of ABVD followed by 20 Gy of

involved-field radiation therapy is as effective as, and less toxic than,

four cycles of ABVD followed by 30 Gy of involved-field radiation

therapy.

• Long-term effects of these treatments have not yet been fully assessed.

17%

41%

38%

4%

Percent of Cases by Stage

Localized (17%) Con-fined to Primary Site

Regional (41%) Spread to Regional Lymph Nodes

Distant (38%) Cancer Has Metastasized

Unknown (4%) Unstaged

5 – Year Relative Survival

Localized Regional Distant Unstaged0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%90.8% 92.1%

76.2%80.7%

Stage

Per

cen

tage

(A) Freedom from progression and (B) overall survival according to International Prognostic Score (IPS) factors (n = 740).

Moccia A A et al. JCO 2012;30:3383-3388

©2012 by American Society of Clinical Oncology

(A) Freedom from progression and (B) overall survival according to International Prognostic Score (IPS) factors for patients age ≤ 65 years (n = 686).

Moccia A A et al. JCO 2012;30:3383-3388

©2012 by American Society of Clinical Oncology

Original Article

ABVD Alone versus Radiation-Based Therapy in Limited-Stage Hodgkin's

Lymphoma

Ralph M. Meyer, M.D., Mary K. Gospodarowicz, M.D., Joseph M. Connors, M.D., Robert G. Pearcey, M.D., Woodrow A. Wells, M.D., Jane N. Winter, M.D., Sandra J. Horning, M.D., A. Rashid Dar, M.D., Chaim Shustik, M.D., Douglas A. Stewart, M.D., Michael Crump, M.D., Marina S. Djurfeldt, M.Sc., Bingshu E. Chen, Ph.D., Lois E. Shepherd, M.D., for the NCIC Clinical Trials Group and the Eastern Cooperative

Oncology Group

N Engl J MedVolume 366(5):399-408

February 2, 2012

Study Overview

• In patients with limited-stage Hodgkin's disease, ABVD chemotherapy

alone resulted in a higher rate of long-term (12-year) survival than

either radiation therapy alone or radiation therapy plus ABVD

chemotherapy, with significantly fewer late treatment-related deaths.

Second Cancers and Cardiac Events, According to Treatment Strategy.

Meyer RM et al. N Engl J Med 2012;366:399-408

Conclusions

• Among patients with Hodgkin's lymphoma, ABVD therapy alone, as

compared with treatment that included subtotal nodal radiation therapy,

was associated with a higher rate of overall survival owing to a lower

rate of death from other causes.