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A CME-certified Oncology Exchange Program Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from.

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Presentation on theme: "A CME-certified Oncology Exchange Program Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from."— Presentation transcript:

1 A CME-certified Oncology Exchange Program Jointly provided by Potomac Center for Medical Education and Rockpointe Supported by an educational grant from Seattle Genetics, Inc.

2 Faculty Anas Younes, M.D. Chief, Lymphoma Service Memorial Sloan Kettering Cancer Center New York Jeremy S. Abramson, M.D. Director, Center for Lymphoma Massachusetts General Hospital Cancer Center

3 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.

4 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

5 Hodgkin Lymphoma Introduction and Initial Therapy

6 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



9 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?

10 Case 1: How will you treat this patient? 1.ABVD x 6 cycles followed by 30 Gy radiation 2.ABVD x 4 cycles followed by 30 Gy radiation 3.ABVD x 2 cycles followed by 20 Gy radiation 4.ABVD x 4-6 cycles without radiation 5.Escalated BEACOPP +/- radiation

11 Case 1: What if this patient was 73 years old instead of 23? 1.ABVD x 4 cycles followed by 30 Gy radiation 2.ABVD x 2 cycles followed by 20 Gy radiation 3.ABVD x 4-6 cycles without radiation 4.AVD x 4-6 cycles (omit bleomycin) +/- radiation 5.ChlVPP +/- radiation

12 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.

13 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%

14 Pathologic Classification Nodular lymphocyte predominant HL CD20 Classical HL –Nodular sclerosis –Mixed cellularity –Lymphocyte rich –Lymphocyte depleted


16 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

17 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

18 Nodular LP vs Classical HL: GHSG Trials HD4-HD12 Nogova, et al. JCO 2008 Freedom from Treatment FailureOverall Survival NLPHL CHL NLPHL CHL

19 Initial Treatment of Classical Hodgkin Lymphoma (cHL)

20 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

21 MOPP versus ABVD for Advanced HL Canellos, et al. NEJM. 1992 Failure-free Survival 5 year FFS MOPP-ABVD65% ABVD61% MOPP50% 5 year OS MOPP-ABVD75% ABVD73% MOPP66% Overall Survival

22 Treatment Intensification: Escalated BEACOPP versus ABVD Viviani, et al. NEJM. 2011

23 Risk Factors in Advanced Stage CHL Age ≥45 Male Gender Stage IV Hemoglobin <10.5 g/dL Leukocytosis >15k/mm 3 Lymphopenia <600/mm 3 or 8% Hypoalbuminemia <4.6 Moccia, et al. JCO 2012; 30(27): 3383-3388. 5y FFP (%)5y OS (%) IPS N OriginalBCCAOriginalBCCA 05784888998 119577849097 219567808191 315560747888 4 51676185 ≥55042625667

24 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

25 Treatment of Limited Stage cHL

26 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

27 Ferme et al. N Engl J Med 2007; 357: 1916-27. Combined Modality Therapy is Superior to Radiation Alone in Early Favorable Disease

28 Combined Modality Therapy allows Reducing Chemotherapy Cycles and Radiation Field Ferme et al. N Engl J Med 2007; 357: 1916-27.

29 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

30 Beware the Late Effects of Therapy Aleman, et al. Blood 2007, 109(5): 1878-1886. All Cardiac Events Angina Pectoris Myocardial Infarction

31 30 Gy IF 20 Gy IF CS I - II without risk factors* ABVD German Hodgkin Study Group : HD10 trial No risk factors: Large mediastinal mass, extranodal disease, >3 nodal regions, elevated ESR

32 Less is more: The GHSG HD10 trial Engert et al. N Engl J Med 2010; 363(7): 640-652.

33 ABVDx2+STNIABVDx4-6 Unfavorable (N = 276) 35Gy STNIABVDx4-6 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

34 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)

35 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

36 Can Interim PET Scans be Used to Direct use of Radiation Therapy? ArmeventsHRCI P Standard1/1881.00 Experimental9/1939.36 2.45- 35.73.017 ArmeventsHRCI P Standard7/2519.36 Experimental16/2682.421.35-4.36.026 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 ABVD 4 ABVD 2 ABVD PET PETPET PETPET R H10 F - + R H10 U - +

37 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

38 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

39 The Challenge of Treating Older Adults with Hodgkin Lymphoma

40 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=0.002P<0.0001 <60 yr ≥ 60 yr 90% 58% Year Probability

41 Limited Stage HL in Older Adults (GHSG HD10-HD11: ABVD x4 + IFRT) Boll et al. J Clin Oncol, 2013, 31(12): 1522-1529. Overall SurvivalProgression-free Survival Time to HL deathTime to HL treatment failure

42 Chicago Elderly HL Prognostic Model Event-free survival Adverse Risk factors: 1)ADL loss 2)>70 years Bleomycin lung toxicity 32% (Mortality: 25%) Overall survival 0306090120150180 0 25 50 75 100 0 Prognostic factor(s) 1 Prognostic factor(s) 2 Prognostic factor(s) Time in Months Percent survival Evens, et al. Blood 2013, 122(21).

43 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

44 Targeted Therapy and New Treatment Approaches

45 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%.

46 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

47 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.

48 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:

49 ABVD Relapse/Refractory ICE DHAP Response No Response ASCT Response GVD IGEV Brentuximab Vedotin Cure No Response/Relapse Brentuximab Vedotin No Response

50 Results of Salvage Pre-transplant Regimens in cHL % response rate

51 Moskowitz C H et al. Blood 2001;97:616-623 ICE + ASCT

52 GVD = gemcitabine, vinorelbine, and pegylated liposomal doxorubicin Bartlett 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

53 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 +- - +

54 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.

55 TTRN Median OS (y) >12 m172 4.6 6-12 m 1652.4 4-6 m 2041.5 0-3 m 2150.7 Overall Survival by Time to Relapse After 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

56 Targeted Therapy in Hodgkin Lymphoma Lee & Younes, Hematology 2013: 394-399.

57 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 1992 (Cell): Durkop and Stein: Molecular cloning of CD30 = TNF receptor family member

58 Summary Results of Phase I/II Clinical Trials Targeting CD30 Younes, A: Curr Opin Oncol. 2011, 23(6): 587-593. DrugDiseaseAntibody typePhase Number of evaluable patients PR CR%PR + CR MDX-060HL, ALCLHumanizedI HL = 63 ALCL = 9 2222 2020 6% 22% SGN-30HL, ALCLChimericI240 00 SGN-30HL, ALCLChimericII HL = 38 ALCL = 41 0505 0202 0 17% Xmab2513HLHumanizedI131 07% 131I-Ki4HLMurineI225 127%

59 Brentuximab Vedotin (SGN-35) Structure Katz J, JanikJ, and Younes A. Clin Cancer Res 2011; 17: 6428-6436

60 Investigator Assessment IRF Assessment 86% of patients achieved tumor reductions83% of patients achieved tumor reductions Phase-I Brentuximab Vedotin in Relapsed HL Treatment Response Younes et al. N Engl J Med 2010; 363(19): 1812-1821.

61 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 –BEAM  ASCT –HDAC-inhibitor SGN-35 2.7 mg/kg x 8 cycles –Best clinical response: CR –CT 93% reduction, PET- –PET negative

62 Brentuximab Vedotin: Pivotal Phase II trial Maximum 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*) Tumour size (% change from baseline) 100 50 0 –50 –100

63 Brentuximab Vedotin: Pivotal Phase II trial PFS Results By Best Response Phase II pivotal study of brentuximab vedotin in 102 patients with relapsed/refractory HL post ASCT: PFS by best response

64 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

65 OS from ASCT by BV Karuturi, M et al ASH 2012

66 Brentuximab Vedotin Initial treatment vs retreatment HL sALCL N= 58N=8 N=102N=15 Bartlet et al, ASCO 2012

67 Proposed Algorithm for Treating Patients post ASCT Relapse from CR Retreat with BV then allo-SCT ASCT { "@context": "", "@type": "ImageObject", "contentUrl": "", "name": "Proposed Algorithm for Treating Patients post ASCT Relapse from CR Retreat with BV then allo-SCT ASCT

68 Rationale for Using HDAC Inhibitors in HL Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013

69 Baseline 31 year old female Extensive Prior Therapy Regimen Best Response ABVDPR XRT Not Eval DHAPPR Auto TransplantNot Eval IGEVProgression DHAPProgression Fludarabine/ MelphalanProgression Allo Transplant Progression Donor lymphocyte Progression MOPPNot Eval ESHAPProgression IEVProgression 2 months Mocetinostat in Relapsed Hodgkin Lymphoma Younes et al Lancet Oncology 2012 CT (– 52% = PR) PET

70 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.

71 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

72 International Panobinostat Phase II Study in Relapsed HL Younes A,Soreda A,, et al. JCO 2012 71% of patients with tumor reduction

73 Phase I Panobinostat (LBH589) + ICE LBH ICE PET/CT Transplant Dose LevelLBH589 (Panobinostat) Dose mg N 100 0206 13014 Evaluable patients : N=21 ORR : 86%, CR: 71% and all proceeded to ASCT Results: Oki Y, et al ASH 2013.

74 S6K14EBP1 mTORC1 PI 3-kinase AKT CD19 BCR GPCR RTK TNFR BAD GSK3 FOXO p53 Survival Proliferation Growth Metabolism Apoptosis Motility Idelalisib IPI-145 BKM-120 XL-147 GDC-0941 GSK1059615 Everolimus Temsirolimus Ridaforolimus AZD8055 MK-2206 XL-418 VQD002 BEZ-235 BGT226 XL765 PI3K Pathway Inhibitors Younes a, ASH 2013

75 PathwayDrugTarget % Response Rate in Different Histologies DLBCLFLMCLSLL/CLLT-CellHL PI3K/AKT/ mTOR Everolimus mTOR30%50%32%18%63%42% Temsirolimus mTOR36%56%38%10%-- Idelalisib PI3K-δ-57%67% 72 % -12% IPI-145 PI3K-γδ0%67%*67%54%33% BAY80-6946 PI3K-αδ13%40%71%43%50%- Activity of PI3K/mTOR Inhibitors in Lymphoma Updated from Younes A & Berry D. Nature Rev Clin Oncol 2012

76 Targeting PD1-PDL1 McDermott et al, Cancer Medicine 2013; 2 (5): 662–673.

77 Source Target molecule PD-1PD-L1/PDL2 MerckMK-3475 (humanized IgG4) CureTech/TevaCT-011 (humanized IgG1) AmpliImmune/GSKAMP-224 (PD-L2/IgG1 fusion protein BMSMDX-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

78 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.

79 Single Agent Activity of New Agents in Post SCT Relapsed cHL Comparison to multiagent chemotherapy GVD Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013 % Response rate

80 Brentuximab-Vedotin Combination Strategies Brentuximab Vedotin HDACi PI3Ki/ mTORi Chemo therapy PD1/PDL1 MoAb

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