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.
Faculty AnasYounes, M.D.Chief, Lymphoma ServiceMemorial Sloan Kettering Cancer CenterNew York Jeremy S. Abramson, M.D. Director, Center for Lymphoma Massachusetts General Hospital Cancer Center
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.
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
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
CD15 CD30 EBER CD3
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?
Case 1: How will you treat this patient? • ABVD x 6 cycles followed by 30 Gy radiation • ABVD x 4 cycles followed by 30 Gy radiation • ABVD x 2 cycles followed by 20 Gy radiation • ABVD x 4-6 cycles without radiation • Escalated BEACOPP +/- radiation
Case 1: What if this patient was 73 years old instead of 23? • ABVD x 4 cycles followed by 30 Gy radiation • ABVD x 2 cycles followed by 20 Gy radiation • ABVD x 4-6 cycles without radiation • AVD x 4-6 cycles (omit bleomycin) +/- radiation • ChlVPP +/- radiation
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.
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%
Nodular lymphocyte predominant HL CD20 Pathologic Classification • Classical HL • Nodular sclerosis • Mixed cellularity • Lymphocyte rich • Lymphocyte depleted
LR NS LD MC
Preparation for chemotherapy Echocardiogram Pulmonary Function Tests, with DLCO Fertility considerations 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
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 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
Nodular LP vs Classical HL: GHSG Trials HD4-HD12 Freedom from Treatment Failure Overall Survival NLPHL CHL NLPHL CHL Nogova, et al. JCO 2008
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
MOPP versus ABVD for Advanced HL Overall Survival Failure-free Survival 5 year OS MOPP-ABVD 75% ABVD 73% MOPP 66% 5 year FFS MOPP-ABVD 65% ABVD 61% MOPP 50% Canellos, et al. NEJM. 1992
Treatment Intensification: Escalated BEACOPP versus ABVD Viviani, et al. NEJM. 2011
Risk Factors in Advanced Stage CHL • Age ≥45 • Male Gender • Stage IV • Hemoglobin <10.5 g/dL • Leukocytosis >15k/mm3 • Lymphopenia <600/mm3 or 8% • Hypoalbuminemia <4.6 Moccia, et al. JCO 2012; 30(27): 3383-3388.
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
Risk Stratification: Adverse factors in Limited Stage Disease EORTC GHSG Large mediastinal mass Extranodal disease >3 nodal regions Elevated ESR • Large mediastinal mass • Age >50 • >4 involved sites • ESR> 30 with B sx OR >50 without B sx
Combined Modality Therapy is Superior to Radiation Alone in Early Favorable Disease Ferme et al. N Engl J Med 2007; 357: 1916-27.
Combined Modality Therapy allows Reducing Chemotherapy Cycles and Radiation Field Ferme et al. N Engl J Med 2007; 357: 1916-27.
Beware the Late Effects of Therapy Breast Cancer Incidence Ng et al. J ClinOncol 2002, 20(8): 2101-2108; De Bruin et al. J ClinOncol 2009 , 27(26): 4239-4246.
Beware the Late Effects of Therapy Angina Pectoris All Cardiac Events Myocardial Infarction Aleman, et al. Blood 2007, 109(5): 1878-1886.
German Hodgkin Study Group : HD10 trial • No risk factors: Large mediastinal mass, extranodal disease, >3 nodal regions, elevated ESR CS I - II withoutriskfactors* ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD ABVD 30 Gy IF 20 Gy IF 30 Gy IF 20 Gy IF
Less is more: The GHSG HD10 trial Engert et al. N Engl J Med 2010; 363(7): 640-652.
Chemotherapy alone for Limited-stage cHL • Study excluded patients with bulk • (M:T ratio >.33 or disease >10cm) • Unfavorable = ESR ≥ 50 mm/hr, age ≥ 40, > 3 sites, MC/LD Stage I/II HL (N = 399) Favorable (N = 123) Unfavorable (N = 276) 35Gy STNI ABVDx4-6 ABVDx2+STNI ABVDx4-6 Primary endpoint: 12 year overall survival
Chemotherapy Alone Versus Radiation-containing Therapy at 12 Years • OS at 12-years • ABVD 94% • XRT/CMT 87% (HR 0.4; p=0.04) • 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.
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
Can Interim PET Scans be Used to Direct use of Radiation Therapy? H10 F 1 ABVD + INRT 30 Gy (+ 6 Gy) H10 U 2 ABVD PET R R PET - 2 ABVD 2 ABVD - + 2 BEACOPPesc + INRT 30 Gy (+ 6 Gy) + 2 ABVD + INRT 30 Gy (+ 6 Gy) 2 ABVD PET PET 4 ABVD 2 ABVD 2 BEACOPPesc + INRT 30 Gy (+ 6 Gy) Raemaekers, et al. J ClinOncol, 2014, 32: 1-8.
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
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
Advanced Stage HL in Older Adults (E2496: ABVD/Stanford V) Overall survival Failure-free survival 90% 58% 74% 48% Probability Probability P=0.002 P<0.0001 Year Year <60 yr ≥ 60 yr • 24% of older patients developed bleomycin lung toxicity • Treatment-related mortality: 9.3% vs. 0.3%, p<0.001) Evens et al. BJH, 2013, 161(1): 76-86.
Limited Stage HL in Older Adults (GHSG HD10-HD11: ABVD x4 + IFRT) Overall Survival Progression-free Survival Time to HL death Time to HL treatment failure Boll et al. J ClinOncol , 2013, 31(12): 1522-1529.
100 0 Prognostic factor(s) 1 Prognostic factor(s) 2 Prognostic factor(s) 75 Percent survival 50 25 0 0 30 60 90 120 150 180 Time in Months Chicago Elderly HL Prognostic Model • Adverse Risk factors: • ADL loss • >70 years Event-free survival Overall survival Bleomycin lung toxicity 32% (Mortality: 25%) Evens, et al. Blood 2013, 122(21).
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
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%.
Case 2: You Would Recommend: • Brentuximabvedotinx 16 doses followed by ASCT • ICE x 2-3 cycles followed by ASCT • BEACOPP X 6 cycles • DHAP x 2-3 cycles followed by ASCT • GND x 2-3 cycles followed by ASCT
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.
Case 2: You Would Recommend: • Brentuximabvedotin x 16 doses followed by allogeneic stem cell transplant • Brentuximabvedotin up to 16 doses, unless disease progression or prohibitive toxicity • Brentuximabvedotinx 4 then PET/CT. If CR continue for at least 8 doses and a maximum of 16 doses, followed by observation • Clinical trial
ABVD Relapse/Refractory ICE DHAP No Response Response GVD IGEV BrentuximabVedotin Response No Response Cure ASCT BrentuximabVedotin No Response/Relapse
Results of Salvage Pre-transplant Regimens in cHL % response rate