Hodgkin’s Disease an Update. Is more always better? Jeffrey Schriber, M.D. Medical Director Cancer Transplant Institute Virginia G. Piper Cancer Center

Percent Surviving 5 Years 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 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 is CD30-positive1 CD68 and CD163 may have prognostic significance Lymphoid neoplasm defined by the presence of Reed- Sternberg (RS) cells in a reactive infiltrate2,3 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 Figure 1 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. Figure 1 Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression. A total of 405 patients with stage IA or IIA nonbulky Hodgkin's lymphoma were randomly assigned to receive treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment that included subtotal nodal radiation therapy; 399 of the patients were included in the analyses. Among the 203 patients assigned to subtotal nodal radiation therapy, 64 had a favorable risk profile and received subtotal nodal radiation therapy alone and 139 had an unfavorable risk profile and received two cycles of ABVD plus subtotal nodal radiation therapy. At 12 years, the rate of overall survival (Panel A) was 94% among patients in the ABVD-only group and 87% among patients in the radiation-therapy group, and the rate of freedom from disease progression (Panel B) was 87% and 92% in the two groups, respectively. 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. Figure 2 Kaplan–Meier Estimates of Overall Survival and Freedom from Disease Progression among Patients with an Unfavorable Risk Profile. Patients with unfavorable clinical features were randomly assigned to receive ABVD alone or to receive combination treatment with two cycles of ABVD plus subtotal nodal radiation therapy. At 12 years, the rate of overall survival (Panel A) was 92% among patients who received ABVD alone as compared with 81% among those who received combination treatment, and the rate of freedom from disease progression (Panel B) was 86% and 94% in the two groups, respectively. Meyer RM et al. N Engl J Med 2012;366:399-408

12-Year Outcomes in Study Patients, According to Treatment Strategy. Table 1 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. Table 2 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. Kaplan-Meier analysis of the probability of (A) freedom from treatment failure and (B) overall survival in each treatment arm. P values were calculated with use of the log-rank test for all three pairwise differences between arms. Numbers at risk are the numbers of patients under observation. 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 Med Volume 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. Figure 1 Randomization, Treatment, and Follow-up. ABVD denotes doxorubicin, bleomycin, vinblastine, and dacarbazine, and BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. Viviani S et al. N Engl J Med 2011;365:203-212

Kaplan–Meier Curves for Freedom from First Progression and Event-free Survival. Figure 2 Kaplan–Meier Curves for Freedom from First Progression and Event-free Survival. The probability of freedom from first progression is shown in Panel A. Events of first progression were defined as progression while receiving treatment, a lack of complete remission at the end of treatment, relapse, or death from any cause. The probability of event-free survival is shown in Panel B. Events were defined as progression while receiving treatment, a lack of complete remission at the end of treatment, relapse, death from any cause, discontinuation of treatment owing to life-threatening toxic effects, and secondary leukemia. All efficacy outcomes were analyzed in the intention-to-treat population (all patients who underwent randomization). ABVD denotes doxorubicin, bleomycin, vinblastine, and dacarbazine, and BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. Viviani S et al. N Engl J Med 2011;365:203-212

Kaplan–Meier Curves for Freedom from Second Progression and Overall Survival. Figure 3 Kaplan–Meier Curves for Freedom from Second Progression and Overall Survival. The probability of freedom from second progression is shown in Panel A. Events of second progression were defined as progression during salvage treatment, lack of a complete remission at the end of salvage treatment, relapse after the second complete response, or death from any cause. The probability of overall survival is shown in Panel B. All efficacy outcomes were analyzed in the intention-to-treat population (all patients who underwent randomization). ABVD denotes doxorubicin, bleomycin, vinblastine, and dacarbazine, and BEACOPP bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone. Viviani S et al. N Engl J Med 2011;365:203-212

Outcomes and Important Adverse Events Associated with Initial Treatment, According to Regimen. Table 1 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. Table 2 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

ADCETRIS is a CD30-Directed Antibody-Drug Conjugate Confidential For training purposes only. Not for public dissemination ADCETRIS consists of three components: Cytotoxic agent The synthetic microtubule-disrupting agent, monomethyl auristatin E (MMAE, vedotin), that induces target cell death Antibody The antibody, brentuximab, specific for CD30 ADCETRIS is an antibody-drug conjugate directed at CD30. The components of ADCETRIS are: A CD30-specific antibody A microtubule-disrupting agent A protease-cleavable linker Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. Linker A synthetic protease-cleavable linker that covalently attaches MMAE to the CD30-directed antibody and releases the agent within the target cell Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012.

Nonclinical Data Suggest a Multistep Process for ADCETRIS Confidential For training purposes only. Not for public dissemination Nonclinical Data Suggest a Multistep Process for ADCETRIS ADCETRIS was designed to deliver an antineoplastic agent that results in apoptotic cell death selectively in CD30-expressing tumor cells. ADCETRIS was engineered to bind to CD30 on the cell surface. This slide describes how ADCETRIS targets CD30 and delivers the cytotoxic agent to kill the cell. Nonclinical data suggest anticancer activity of ADCETRIS is due to: 1. Binding of the ADC to CD30-expressing cells, followed by internalization of the ADC-CD30 complex 2. Release of MMAE via proteolytic cleavage 3. Binding of MMAE to tubulin, disrupting the microtubule network within the cell 4. Induction of cell cycle arrest, resulting in apoptotic death of the cells Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012.

Efficacy Results (relapsed HL after ASCT) Confidential For training purposes only. Not for public dissemination Efficacy Results (relapsed HL after ASCT) N = 102 Response (%) 95% CI Duration 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 This slide presents a summary of the efficacy results in relapsed HL after ASCT. Note the ORR of 73%, with a CR of 32% and a PR of 40%. Reference: ADCETRIS [Prescribing Information]. Bothell, WA: Seattle Genetics Inc; 2012. Duration of response was calculated from the date of first response to the date of progression.

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 Med Volume 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 Figure 1 Numbers of Patients Randomly Assigned to Treatment Groups and Included in Analyses. ABVD denotes doxorubicin, bleomycin, vinblastine, and dacarbazine, and IFRT involved-field radiation therapy. Engert A et al. N Engl J Med 2010;363:640-652

Freedom from Treatment Failure and Overall Survival Figure 2 Freedom from Treatment Failure and Overall Survival. Two pooled treatment groups were compared with respect to chemotherapy regimens (groups 1 and 2 vs. groups 3 and 4) (Panel A) and radiation therapy doses (groups 1 and 3 vs. groups 2 and 4) (Panel B). Groups 1 and 4 were also compared (Panel C). Group differences with respect to freedom from treatment failure and overall survival at 5 years were estimated on the basis of Kaplan–Meier analyses, and hazard ratios were calculated with the use of Cox regression analysis (i.e., the comparison of the chemotherapy groups was stratified according to radiation therapy group, and vice versa). (For definitions of study end points, see the , available with the full text of this article at NEJM.org.) Data for all patients were analyzed on the basis of the randomly assigned treatment groups (intention-to-treat principle). Data for overall survival were censored on the date when the information was last obtained; when the information lag exceeded 2 years, data on survival were obtained from registries, whenever possible. The median observation period for freedom from treatment failure was 79 months and that for overall survival was 91 months. The main analysis for the chemotherapy comparison included 1190 eligible patients who received at least 1 dose of the assigned study treatment. According to the protocol, 27 patients whose disease progressed or whose chemotherapy was discontinued before the start of radiation therapy were excluded from the main analysis for the radiation therapy comparison. (For methods and results of the sensitivity analyses, see the .) Engert A et al. N Engl J Med 2010;363:640-652

Baseline Characteristics of the Patients According to Treatment Group Table 1 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 Table 2 Adverse Events According to Treatment Group. Engert A et al. N Engl J Med 2010;363:640-652

Efficacy Outcomes According to Treatment Group Table 3 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.

5 – Year Relative Survival

(A) Freedom from progression and (B) overall survival according to International Prognostic Score (IPS) factors (n = 740). (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). (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 Med Volume 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. Table 3 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.