HL Below the Surface Evaluating Risk of Relapse in Hodgkin Lymphoma

Hodgkin Lymphoma (HL): An Overview 2

HL Overview HL accounts for approximately 30% of all lymphomas 1 There will be an estimated 9050 cases of HL in the US in HL is composed of 2 subtypes that differ in their prevalence, clinical features, and cellular composition 1 : – Classical Hodgkin lymphoma (cHL) – Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) 3 References: 1. Swerdlow SH, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; American Cancer Society. Cancer Facts & Figures Atlanta, GA: American Cancer Society; 2015.

Features of HL Subtypes 4 cHLNLPHL Subtype prevalence 1 95%5% Malignant cell type 1,2 Reed-Sternberg cells (RS cells)Lymphocyte-predominant cells Typical immunophenotype* 2 CD15+, CD30+, PAX-5+ (weak), CD3-, CD20- (majority), CD45-, CD79a- CD20+, CD45+, CD79a+, BCL6+, PAX-5+, CD3-, CD15-, CD30- References: 1. Swerdlow SH, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, *An expanded panel of markers may be required, especially if equivocal diagnosis.

Frontline Treatment of HL 5

Clinical Staging: The First Step to Determining Treatment 1 Frontline treatment of HL is based on clinical staging The modified Ann Arbor staging system is most commonly used 6 StageDefinition IInvolvement of a single lymph node region or lymphoid structure (eg, spleen, thymus, Waldeyer ring) IIInvolvement of 2 or more lymph node regions on the same side of the diaphragm; the number of atomic sites is indicated by suffix (eg, II 3 ) IIIInvolvement of lymph node regions or structures on both sides of the diaphragm III 1 With or without splenic, hilar, celiac, or portal nodes III 2 With para-aortic, iliac, or mesenteric nodes IVInvolvement of extranodal site(s) beyond those designated E (E = involvement of a single extranodal site, or contiguous or proximal to known nodal site of disease) Ann Arbor Staging Classifications Reference: 1. Swerdlow SH, et al, eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer; 2008.

Treatment Recommendations by Stage 1 Using the Ann Arbor criteria, patients are classified into 3 groups with specific treatment recommendations 7 StageGroupTreatment Stage I-II with no unfavorable factors* Early-stage favorable Combined modality therapy (ABVD plus involved-site radiotherapy, or Stanford V) or chemotherapy alone with ABVD Stage I-II with any of the unfavorable factors* Early-stage unfavorable Chemotherapy (ABVD or Stanford V or BEACOPP plus ABVD) followed by consolidative involved-site radiotherapy Stage III-IVAdvanced stage Chemotherapy with ABVD or Stanford V or escalated- dose BEACOPP Adapted from NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ). ABVD = adriamycin, bleomycin, vinblastine, and dacarbazine; BEACOPP = bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone. *Unfavorable factors for early-stage disease include: bulky disease, B symptoms, >3 nodal sites of disease, and erythrocyte sedimentation rate >50 mm/h. Reference: 1. NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, 2015.

Outcomes After Frontline HL Therapy HL is curable in most patients, with the majority being effectively treated with frontline therapy 1 8 References: 1. NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Quddus F, et al. Cancer J. 2009;15(2): ■ Nevertheless, up to 10% of patients are refractory to frontline therapy 2 ■ As many as 30% of patients will eventually relapse 2

Challenges Remain in the Frontline Setting Older patients have a poorer risk profile and do not tolerate intensive therapy as well as younger patients 1,2 Young patients have high survival rates but may suffer long-term health complications from chemotherapy and/or radiotherapy 3 Patients treated for HL before age 21 are more likely than the general population to die from 4 : Clinical trials are focused on maintaining efficacy while minimizing the intensity of treatment 1,2 – This focus facilitates treatment of older patients and avoids late, potentially fatal toxic effects for young patients 9 References: 1. Engert A, et al. J Clin Oncol. 2005;23(22): Punnett A, et al. Semin Radiat Oncol. 2010;20(1): NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Aleman BMP, et al. J Clin Oncol. 2003;21(18): Cardiovascular Disease ~14 times more likely Solid Tumors ~15 times more likely

Relapsed/Refractory HL 10

Relapsed and Refractory HL 1 Patients whose disease relapses within 1 year of initial remission are at significant risk for: 11 Poor response to salvage therapy Shortened duration of second remission Shortened overall survival Reference: 1. Longo DL, et al. J Clin Oncol. 1992;10(2):

Treatment of Relapsed/Refractory HL Most patients will receive salvage chemotherapy followed by autologous stem cell transplant (ASCT), which has been established as the standard of care based on 2 randomized, phase 3 trials (British National Lymphoma Investigation and the German Hodgkin Study Group/European Group for Blood and Marrow Transplantation) 1,2 The selection of salvage chemotherapy regimens depends on the pattern of relapse and the agents previously used 1 Achieving complete remission (CR) with salvage therapy improves outcomes post-transplant 3,4 12 References: 1. NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Kuruvilla J, et al. Blood. 2011;117(16): Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Sureda A, et al. J Clin Oncol. 2001;19(5): Josting A, et al. Ann Oncol. 2002;13(10): Moskowitz CH, et al. Blood. 2001;97(3): Aparicio J, et al. Ann Oncol. 1999;10(5): Bartlett NL, et al. Ann Oncol. 2007;18(6): Kuruvilla J, et al. Cancer. 2006;106(2): Salvage RegimenNRR (%)CR (%) DHAP ICE ESHAP GVD GDP DHAP: dexamethasone, cisplatin, and cytarabine. ICE: ifosfamide, carboplatin, and etoposide. ESHAP: etoposide, methylprednisolone, high-dose cytarabine, and cisplatin. GVD: gemcitabine, vinorelbine, and pegylated liposomal doxorubicin. GDP: gemcitabine, dexamethasone, and cisplatin.

Risk Factors for Relapse in Patients With HL Undergoing ASCT 13

Many Prognostic Factors Are Predictive of Post-ASCT Outcome Several studies have developed prognostic models to risk-stratify patients undergoing ASCT 1 14 Risk factors that may help predict post-ASCT outcomes Disease refractory to frontline therapy 2-4 Positive FDG-PET scan pre-ASCT Relapse <12 months after frontline therapy 2,3,5-7 Bulky disease pre-ASCT 2,8 Extranodal disease at pre-ASCT relapse 2,5-8 Advanced disease at relapse 3,5 B symptoms at pre-ASCT relapse 3,5-7,9,10 Anemia pre-ASCT 3,5 Lack of chemoresponsiveness pre-ASCT 2,9,10 >1 relapse or >2 prior regimens 3,9 Residual disease at time of ASCT 9 Although these factors may allow estimations of a patient’s prognosis, few therapeutic strategies incorporate a risk-adapted approach to the management of patients undergoing ASCT. 14 As advances continue in the treatment of HL, utilization of clinical prognostic factors may help identify a group of patients who are at high risk of relapse pre-ASCT. 15 References: 1. NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Sureda A, et al. Ann Oncol. 2005;16(4): Josting A, et al. J Clin Oncol. 2010;28(34): Moskowitz AJ, et al. Br J Haematol. 2009;146(2): Josting A, et al. J Clin Oncol. 2002;20(1): Reece DE, et al. Blood. 1994;83(5): Moskowitz CH, et al. Blood. 2001;97(3): Smith SD, et al. Br J Haematol. 2011;153(3): Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Fermé C, et al. J Clin Oncol. 2002;20(2): Moskowitz AJ, et al. Blood. 2010;116(23): Smeltzer JP, et al. Biol Blood Marrow Transplant. 2011;17(11): Devillier R, et al. Haematologica. 2012;97(7): Kuruvilla J, et al. Blood. 2011;117(16): Colpo A, et al. Oncologist. 2012;17(1):80-90.

Patients With More Prognostic Risk Factors Have a Poorer Outcome Although there is no consensus on which model or factors best predict outcomes, studies show that there is a cumulative risk effect 1,2 15 Prognostic modelEstimated PFS Majhail et al 1 5-Year 1 Low risk (0-1 factors)67% (95% CI, 55%-79%) Intermediate risk (2 factors)37% (95% CI, 22%-52%) High risk (3 factors)9% (95% CI, 0%-20%) Hahn et al 2 4-Year 2 Low risk (score=0)71% (63%-78%) Intermediate risk (score=1-3)60% (53%-66%) High risk (score=4-6)42% (36%-49%) Majhail et al identified B symptoms at pretransplantation relapse, transplantation in CR, and chemosensitive disease at the time of ASCT as significant prognostic factors for progression-free survival (PFS). 1 Hahn et al identified Karnofsky performance <90, chemotherapy resistance pre-AHCT, 3+ chemotherapy regimens pre-AHCT, and extranodal disease as prognostic factors. Each factor was given a weighted score based on relative risk estimates, and the total sum score was used to stratify patients into 3 risk groups. 2 References: 1. Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Hahn T, et al. Biol Blood Marrow Transplant. 2013;19(12):

Probability of PFS (N=141) 1 Probability of PFS (N=728) 2 Cumulative Effect of Multiple Risk Factors Kaplan-Meier estimates from both Majhail et al and Hahn et al show that both models predict cumulative risk of relapse, or worse outcomes, based on increased effect of prognostic factors 1,2 16 Figure from Majhail et al 1 : probability of PFS based on a prognostic model using low-risk (0-1 adverse prognostic factors), intermediate-risk (2 adverse prognostic factors), or high-risk (3 adverse prognostic factors) groups. Figure from Hahn et al 2 : probability of PFS across 3 risk groups based on a weighted score of various risk factors. References: 1. Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Hahn T, et al. Biol Blood Marrow Transplant. 2013;19(12):

Prognosis Following Relapse After ASCT 17

Prognosis Following ASCT in HL Approximately 50% of patients will relapse within 5 years after ASCT 1,2 – The majority of relapses (71%) occur within 1 year 3 Among those who relapse after ASCT, prognosis has traditionally been poor % will die within 2 years 4 68% will die within 5 years years median survival 3 References: 1. Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Sureda A, et al. Ann Oncol. 2005;16(4): Arai S, et al. Leuk Lymphoma. 2013;54(11): Martinez C, et al. J Clin Oncol. 2010;28(suppl):8060.

Patients Who Relapse Within 1 Year Have a Significantly Poorer Prognosis 1 Post-progression survival was just 0.98 years for patients who relapsed within 1 year of ASCT – For those who remained in remission past 1 year, survival was 2.26 years (P<0.0001) 19 Reference: 1. Arai S, et al. Leuk Lymphoma. 2013;54(11): Post-progression survival by time to relapse after transplant (N=756) Adapted from Arai S, 2013.

RIC-Allogenic Transplant May Be an Option for Patients Who Relapse Following ASCT Reduced-intensity conditioning (RIC)-allogenic transplant has a 5-year overall survival rate of 28% 1 Nonrelapse mortality rates following RIC-allogenic transplant are high at approximately 24% 1 – According to the NCCN Guidelines ®, this approach remains investigational and is included as a category 3 recommendation* 2 20 References: 1. Sureda A, et al. J Clin Oncol. 2008;26(3): NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Non-relapse mortality after RIC-allogenic stem-cell transplant 1 Adapted from Sureda A, *Category 3: based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. 2

Summary 21

Identifying the Risk Factors Can Change the Way You See Your HL Transplant Patients Although HL is curable in a majority of patients with frontline therapy, up to 10% of patients are refractory to frontline therapy and as many as 30% of patients will eventually relapse 1,2 Up to half of patients will relapse after ASCT, and for these patients prognosis has historically been poor 3-6 Several studies have developed prognostic models to risk-stratify patients undergoing ASCT 1 – Although there is no consensus on which model or factors best predict outcomes, studies show that there is a cumulative risk effect 4,7 22 References: 1. NCCN Guidelines ® : Hodgkin Lymphoma (V2.2015). nccn.org/professionals/physician_gls/pdf/hodgkins.pdf. Accessed April 22, Quddus F, et al. Cancer J. 2009;15(2): Longo DL, et al. J Clin Oncol. 1992;10(2): Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Sureda A, et al. Ann Oncol. 2005;16(4): Arai S, et al. Leuk Lymphoma. 2013;54(11): Hahn T, et al. Biol Blood Marrow Transplant. 2013;19(12):

Risk Factors That May Help Predict Post-ASCT Outcomes Disease refractory to frontline therapy 1-3 Relapse <12 months after frontline therapy 1,2,4-6 Extranodal disease at pre-ASCT relapse 1,4-7 B symptoms at pre-ASCT relapse 2,4-6,8,9 Lack of chemoresponsiveness pre-ASCT 1,8,9 Residual disease at time of ASCT 8 Positive FDG-PET scan pre-ASCT Bulky disease pre-ASCT 1,7 Advanced disease at relapse 2,4 Anemia pre-ASCT 2,4 >1 relapse or >2 prior regimens 2,8 23 References: 1. Sureda A, et al. Ann Oncol. 2005;16(4): Josting A, et al. J Clin Oncol. 2010;28(34): Moskowitz AJ, et al. Br J Haematol. 2009;146(2): Josting A, et al. J Clin Oncol. 2002;20(1): Reece DE, et al. Blood. 1994;83(5): Moskowitz CH, et al. Blood. 2001;97(3): Smith SD, et al. Br J Haematol. 2011;153(3): Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Fermé C, et al. J Clin Oncol. 2002;20(2): Moskowitz AJ, et al. Blood. 2010;116(23): Smeltzer JP, et al. Biol Blood Marrow Transplant. 2011;17(11): Devillier R, et al. Haematologica. 2012;97(7):

What Is Next for Risk Assessment in Relapsed/Refractory HL? As advances continue in the treatment of HL, utilization of clinical prognostic factors may help identify a group of patients who are at risk of relapse pre-ASCT 2 24 Prognostic models…need to be explored further and validated so that patients at very high risk for relapse after ASCT can be identified before ASCT and enrolled in clinical trials investigating more aggressive and novel therapies. In summary, there is a need for a risk-adapted approach to determining appropriate therapeutic strategies for patients with [primary refractory and relapsed] HL. —Majhail et al, References: 1. Majhail NS, et al. Biol Blood Marrow Transplant. 2006;12(10): Colpo A, et al. Oncologist. 2012;17(1): Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2015 Seattle Genetics, Inc., Bothell, WA All rights reserved. Developed in USA. USM/BVM/2015/0031 ‘‘ ‘‘