a cme-certified oncology exchange program
DESCRIPTION
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. Anas Younes , M.D. Chief, Lymphoma Service Memorial Sloan Kettering Cancer Center New York - PowerPoint PPT PresentationTRANSCRIPT
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A CME-certified Oncology Exchange Program
Jointly provided by Potomac Center for Medical Education and RockpointeSupported by an educational grant from Seattle Genetics, Inc.
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Faculty
Anas Younes, M.D.Chief, Lymphoma ServiceMemorial Sloan Kettering Cancer CenterNew York
Jeremy S. Abramson, M.D.Director, Center for LymphomaMassachusetts General Hospital Cancer Center
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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.
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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
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Hodgkin LymphomaIntroduction and
Initial Therapy
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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
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CD30CD15
CD3 EBER
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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?
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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
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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
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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.
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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%
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Pathologic Classification
• Nodular lymphocyte predominant HL
CD20
• Classical HL– Nodular sclerosis– Mixed cellularity– Lymphocyte rich– Lymphocyte depleted
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NS
MC
LR
LD
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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
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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
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Nodular LP vs Classical HL: GHSG Trials HD4-HD12
Nogova, et al. JCO 2008
Freedom from Treatment Failure Overall Survival
NLPHL
CHLNLPHL
CHL
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Initial Treatment of Classical Hodgkin Lymphoma (cHL)
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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
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MOPP versus ABVD for Advanced HL
Canellos, et al. NEJM. 1992
Failure-free Survival
5 year FFS
MOPP-ABVD 65%ABVD 61%MOPP 50%
5 year OS
MOPP-ABVD 75%ABVD 73%MOPP 66%
Overall Survival
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Treatment Intensification: Escalated BEACOPP versus ABVD
Viviani, et al. NEJM. 2011
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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.
5y FFP (%) 5y OS (%)
IPS N Original BCCA Original BCCA
0 57 84 88 89 98
1 195 77 84 90 97
2 195 67 80 81 91
3 155 60 74 78 88
4 88 51 67 61 85
≥5 50 42 62 56 67
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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
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Treatment of Limited Stage cHL
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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
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Ferme et al. N Engl J Med 2007; 357: 1916-27.
Combined Modality Therapy is Superior to Radiation Alone in Early Favorable Disease
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Combined Modality Therapy allows Reducing Chemotherapy Cycles and Radiation Field
Ferme et al. N Engl J Med 2007; 357: 1916-27.
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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
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Beware the Late Effects of Therapy
Aleman, et al. Blood 2007, 109(5): 1878-1886.
All Cardiac EventsAngina Pectoris
Myocardial Infarction
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30 Gy IF 30 Gy IF20 Gy IF 20 Gy IF
CS I - II without risk factors*
ABVDABVD
ABVDABVD
ABVDABVDABVDABVD
ABVDABVDABVDABVD
German Hodgkin Study Group : HD10 trial
• No risk factors: Large mediastinal mass, extranodal disease, >3 nodal regions, elevated ESR
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Less is more: The GHSG HD10 trial
Engert et al. N Engl J Med 2010; 363(7): 640-652.
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ABVDx2+STNI ABVDx4-6
Unfavorable (N = 276)
35Gy STNI ABVDx4-6
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
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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)
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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
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Can Interim PET Scans be Used to Direct use of Radiation Therapy?
Arm events HR CI P
Standard 1/188 1.00
Experimental 9/193 9.36 2.45-35.73 .017
Arm events HR CI P
Standard 7/251 9.36
Experimental 16/268 2.42 1.35-4.36 .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 BEACOPPesc + INRT 30 Gy (+ 6 Gy)
2 ABVD
4 ABVD
2 ABVD
2 ABVD
2 ABVD
2 ABVD
PET
PET
PET
PET
R
H10F
-
+
R
H10U
-
+
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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
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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
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The Challenge of Treating Older Adults with Hodgkin Lymphoma
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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=0.002 P<0.0001
<60 yr≥ 60 yr
90%
58%
YearYear
Prob
abilit
y
Prob
abilit
y
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Limited Stage HL in Older Adults (GHSG HD10-HD11: ABVD x4 + IFRT)
Boll et al. J Clin Oncol , 2013, 31(12): 1522-1529.
Overall Survival Progression-free Survival
Time to HL death Time to HL treatment failure
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Chicago Elderly HL Prognostic Model
0 30 60 90 120 150 1800
25
50
75
1000 Prognostic factor(s)1 Prognostic factor(s)2 Prognostic factor(s)
Time in Months
Per
cen
t su
rviv
al
Event-free survival
Adverse Risk factors:1) ADL loss2) >70 years
Bleomycin lung toxicity 32% (Mortality: 25%)
Overall survival
0 30 60 90 120 150 1800
25
50
75
1000 Prognostic factor(s)1 Prognostic factor(s)2 Prognostic factor(s)
Time in Months
Per
ce
nt
su
rviv
al
Evens, et al. Blood 2013, 122(21).
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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
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Targeted Therapy and New Treatment Approaches
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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%.
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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
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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.
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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:
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ABVD
Relapse/Refractory
ICEDHAP
Response No Response
ASCT
Response
GVDIGEV
Brentuximab Vedotin
Cure
No Response/Relapse
Brentuximab Vedotin
No Response
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Results of Salvage Pre-transplant Regimens in cHL
ESHAP
GDP
GVD
DHAP
ICE
Dexa-BEAM
MINE
ASHAP
mini-BEAM
IGEV
0 20 40 60 80 100
PRCR
% response rate
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Moskowitz C H et al. Blood 2001;97:616-623
ICE + ASCT
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GVD = gemcitabine, vinorelbine, and pegylated liposomal doxorubicinBartlett 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
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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+ -
-
+
PET
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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.
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TTR N Median OS (y)>12 m 172 4.6 6-12 m 165 2.4 4-6 m 204 1.5 0-3 m 215 0.7
Overall Survival by Time to RelapseAfter 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
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Targeted Therapy in Hodgkin Lymphoma
Lee & Younes, Hematology 2013: 394-399.
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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
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Summary Results of Phase I/II Clinical Trials Targeting CD30
Younes, A: Curr Opin Oncol. 2011, 23(6): 587-593.
Drug Disease Antibody type PhaseNumber of evaluable patients
PR CR %PR + CR
MDX-060 HL, ALCL Humanized I HL = 63ALCL = 9
22
20
6%22%
SGN-30 HL, ALCL Chimeric I 24 0 0 0
SGN-30 HL, ALCL Chimeric II HL = 38ALCL = 41
05
02
017%
Xmab2513 HL Humanized I 13 1 0 7%
131I-Ki4 HL Murine I 22 5 1 27%
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Brentuximab Vedotin (SGN-35) Structure
Katz J, JanikJ, and Younes A . Clin Cancer Res 2011; 17: 6428-6436
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Investigator Assessment IRF Assessment
86% of patients achieved tumor reductions 83% of patients achieved tumor reductions
Phase-I Brentuximab Vedotin in Relapsed HLTreatment Response
Younes et al. N Engl J Med 2010; 363(19): 1812-1821.
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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 – BEAMASCT – HDAC-inhibitor
• SGN-35 2.7 mg/kg x 8 cycles– Best clinical response: CR– CT 93% reduction, PET-– PET negative
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Brentuximab Vedotin: Pivotal Phase II trialMaximum 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*)
Tum
our s
ize
(% c
hang
e fr
om b
asel
ine)
100
50
0
–50
–100
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Brentuximab Vedotin: Pivotal Phase II trialPFS Results By Best Response
• Phase II pivotal study of brentuximab vedotin in 102 patients with relapsed/refractory HL post ASCT: PFS by best response
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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
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OS from ASCT by BV
Karuturi, M et al ASH 2012
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Brentuximab VedotinInitial treatment vs retreatment
HL sALCL
N= 58 N=8N=102 N=15
Bartlet et al , ASCO 2012
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Proposed Algorithm for Treating Patients post ASCT
Relapse from CRRetreat with BV then allo-SCT
ASCT
<CR/Relapse
Brentuximab Vedotin
CRContinue BV
to8-16
doses
<CRConsider allo
SCT
Continue
BV until
disease progression
CR
Observe (Role of adjuvant BV?)
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Rationale for Using HDAC Inhibitors in HL
Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013
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Baseline31 year old femaleExtensive Prior TherapyRegimen Best ResponseABVD PRXRT Not EvalDHAP PRAuto Transplant Not EvalIGEV ProgressionDHAP ProgressionFludarabine/ Melphalan ProgressionAllo Transplant ProgressionDonor lymphocyte ProgressionMOPP Not EvalESHAP ProgressionIEV Progression
2 months
Mocetinostat in Relapsed Hodgkin Lymphoma
Younes et al Lancet Oncology 2012
CT (– 52% = PR)
PET
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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.
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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
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International Panobinostat Phase II Study in Relapsed HL
Younes A,Soreda A,, et al. JCO 2012
-100
-75
-50
-25
0
25
50
75
100
Be
st %
Ch
an
ge
in S
PD
Fro
m B
ase
line
(ind
ex
lesi
on
s o
nly
)
ActiveDiscontinued
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements
5 patients with SPD < 50% had new lesions at Eval 1
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements
5 patients with SPD < 50% had new lesions at Eval 1
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements
5 patients with SPD < 50% had new lesions at Eval 1
PR
PD
4 patients - SD (0%)
6 patients - off AE prior to Eval 11 patient - withdrew consent prior to Eval 11 patient - pending Eval 1 measurements
5 patients with SPD < 50% had new lesions at Eval 1
71% of patients with tumor reduction
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Phase I Panobinostat (LBH589) + ICE
LBH
ICE
PET/CT
Transplant
Dose Level LBH589 (Panobinostat) Dose mg
N
-1 10 0
0 20 6
1 30 14
Evaluable patients : N=21ORR : 86%, CR: 71% and all proceeded to ASCT
Results:
Oki Y, et al ASH 2013.
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S6K1 4EBP1
mTORC1
PI 3-kinase
AKT
CD19
BCRGPCRRTK TNFR
BADGSK3FOXOp53
SurvivalProliferationGrowthMetabolismApoptosisMotility
IdelalisibIPI-145
BKM-120XL-147
GDC-0941GSK1059615
EverolimusTemsirolimusRidaforolimus
AZD8055
MK-2206XL-418VQD002
BEZ-235BGT226XL765
PI3K Pathway Inhibitors
Younes a, ASH 2013
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Pathway Drug Target% Response Rate in Different Histologies
DLBCL FL MCL SLL/CLL T-Cell HL
PI3K/AKT/mTOR
Everolimus mTOR 30% 50% 32% 18% 63% 42%
Temsirolimus mTOR 36% 56% 38% 10% - -
Idelalisib PI3K-δ - 57% 67% 72% - 12%
IPI-145 PI3K-γδ 0% 67%* 67% 54% 33% 33%
BAY80-6946 PI3K-αδ 13% 40% 71% 43% 50% -
Activity of PI3K/mTOR Inhibitors in Lymphoma
Updated from Younes A & Berry D. Nature Rev Clin Oncol 2012
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Targeting PD1-PDL1
McDermott et al, Cancer Medicine 2013; 2(5): 662–673.
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SourceTarget molecule
PD-1 PD-L1/PDL2
Merck MK-3475(humanized IgG4)
CureTech/Teva CT-011 (humanized IgG1)
AmpliImmune/GSK AMP-224(PD-L2/IgG1 fusion protein
BMS MDX-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
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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.
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Single Agent Activity of New Agents in Post SCT Relapsed cHLComparison to multiagent chemotherapy GVD
Betlevi and Younes, Hematology Am Soc Hematol Educ Program. 2013
% R
espo
nse
rate
GVD
Brentuxim
ab Vedotin
Retreatm
ent BV
Evero
limus + Pan
obino...
Evero
limus
Panobinostat
Mocetinosta
t
Lenalid
omide
Vorinostat
SGN300
20
40
60
80
100 CR PR
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Brentuximab-Vedotin Combination Strategies
BrentuximabVedotin
HDACi
PI3Ki/mTORi
Chemotherapy
PD1/PDL1MoAb