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Treatment of DLBCL

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Treatment of DLBCL Andy Davies Chair UK National Caner Research Institute High-Grade Lymphoma Sub-Group ESMO Preceptorship Programme: Lymphoma Lugano Nov 2018 1 DISCLOSURE OF INTEREST Celgene: Research funding; Advisory Board; Honorarium Roche : Advisory Boards; Honorarium; Research support Gilead : Advisory Boards; Honorarium; Research support Takeda : Advisory Boards; Honorarium; Research support, Travel to scientific conferences CTI : Advisory Boards; Honorarium; Travel to scientific conferences GSK : Research support Bayer : Research support Janssen : Honorarium; Research support Karyopharma : Advisory Board; Research support Pfizer : Research support; Honorarium Acerta Pharma : Research funding and Advisory Board Kite Pharma: Advisory Board DLBCL Haematological Malignancies Research Network 2017 DLBCL is a curable disease Overall survival: UK R-CHOP 14 vs 21 1.0 2-year OS: 81% (95% CI: 78%-84%) 0.8 0.6 0.4 0.2 Events Totals 150 1080 0.0 0 6 12 18 24 30 36 42 48 PATIENTS at Risk Months from randomisation 1080 834 621 434 278 134 61 8 0 Cunningham, J Clin Oncol (2009) 27:15s, Real World Data Haematological Malignancies research Network 2017 CHOP PLUS RITUXIMAB VS. CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE LARGE-B- CELL LYMPHOMA CHOP CHEMOTHERAPY PLUS RITUXIMAB COMPARED WITH CHOP ALONE IN ELDERLY PATIENTS WITH DIFFUSE LARGE-B-CELL LYMPHOMA BERTRAND COIFFIER , M.D., E RIC LEPAGE , M.D., P H.D., J OSETTE BRIÈRE , M.D., R AOUL HERBRECHT , M.D., H ERVÉ TILLY , M.D., R EDA BOUABDALLAH , M.D., P IERRE MOREL , M.D., E RIC VAN DEN NESTE , M.D., G ILLES SALLES , M.D., P H.D., PHILIPPE GAULARD , M.D., F ELIX REYES , M.D., AND CHRISTIAN GISSELBRECHT , M.D. The benefit of rituximab is maintained over time GELA LNH-98.5 10-year follow-up 1.00 0.75 0.50 0.25 Overall survival Overall 0.00 0 2 4 6 8 10 12 Time (years) Arm A: CHOP Arm B: CHOP + Rituximab Coiffier B et al. Blood 2010;116:2040-2045 We are going to talk about: • Risk adapted approach to DLBCL management. • Tailoring therapy according to genotypes/phenotypes of DLBCL that have been explored to date. • Is the Cell-of-Origin classification ready for therapeutic stratification? We are NOT going to talk about: • Approaches to particular anatomical sites (eg CNS, testis, bone..). • Management of limited stage disease. • The difficult problem of elderly patients with DLBCL, where physiology may reduce tolerability of immunochemotherapy. • Those patients where co-morbidities may require modification of our standard approaches. Revision to WHO classification 2016 Diffuse large B-cell (NOS) Germinal Centre B-cell type Activated B-cell type T-cell/histiocyte rich large B-cell Primary DLBCL of central nervous system Primary cutaneous DLBCL leg type EBV+ DLBCL, NOS EBV+ mucocutaneous ulcer Primary mediastinal lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Plasmablastic lymphoma High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement Swerdlow et al. Blood 2016 There is clear heterogeneity in clinical outcomes IPI Age greater than 60 years Stage III or IV disease Elevated serum LDH ECOG > 2 More than 1 extranodal site Age adjusted IPI Stage LDH Performance status Ziepert at al. J Clin Oncol 28:2373-2380. ESMO Guidelines Young (age <61) aaIPI=0 no bulk aaIPI=1/aaIPI=0 +bulk aaIPI>2 R-CHOP 21 x6 R-ACVBP + consolid. R-CHOP 21 x8 R-CHOP 21 x6 + IFRT R-CHOP 14 x6 +Rx2 (to bulk) R-CHEOP14 x6 R-ACVBP + HDT R-CHOP14 +HDT Clinical trial Tilly et al. 2015 Annals of Oncol, 26,116–125 No clear standard in this group Is there much yet to be achieved with conventional chemotherapy ? Probably not….. Intensified regimens…might they hold the answer? Fisher RI, et al . N Engl J Med1993; 328:1002– 006. Dose Density: UK R-CHOP14 vs. 21 n=540 R-CHOP21 CHOP21 × 8 cycles × Newly Rituximab 8 cycles diagnosed R CD20+ve DLBCL n=540 R-CHOP14 CHOP14 × 6 cycles Stratified by Rituximab × 8 cycles • IPI (0-1, 2, 3, 4-5) Lenograstim Day 4-12 • Age ≤60 vs. >60 • Treatment centre 1080 patients; 119 sites Recruitment March 2005 - Nov 2008 Cunningham, D, et al. Lance t 2013; 381:1817–1826. R-CHOP14 vs 21: no difference in outcome Progression -free survival Overall survival Cunningham, D, et al. Lance t 2013; 381:1817–1826. R-CHOP14 vs 21: no subgroup could be identified Cunningham, D, et al. Lance t 2013; 381:1817–1826. Other ways of improving dose intensity: GELA LNH03-2B Young (age 18-59) aa IPI 1 n=380 Median age 47 55% stage III/IV, 44% bulk Recher C, et al Lancet 2011: 378:1858-18676. Improved outcome in R-ACVBP arm Recher C, et al Lancet 2011: 378:1858-18676. ► Improvement in EFS, PFS and OS ► Outcome of R-CHOP x 8 arm inferior to those observed in MInT with R-CHOP x 6 ► Excess utilisation of healthcare resource ► Excess of toxicity R-ACVBP R-CHOP Toxicity (grade >3) Neutropenia 78% 64% Anemia 35% 5% Thrombocytopenia 30% 3% Febrile neutropenia 38% 9% Toxic deaths (n) 3 2 Recher C, et al Lancet 2011: 378:1858-1867. Phase III Randomized Study of R-CHOP vs. DA-EPOCH-R and Molecular Analysis of Untreated Large B-Cell Lymphoma: CALGB/Alliance 50303 Wyndham H. Wilson, Sin-Ho Jung, Brandelyn N. Pitcher, Eric D.Hsi, Jonathan Friedberg, Bruce Cheson, Nancy L. Bartlett , Scott Smith, Nina Wagner-Johnston, Brad S. Kahl, Louis M. Staudt, Kristie A. Blum, Jeremy Abramson, Oliver W. Press, Richard I. Fisher, Kristy L. Richards, Heiko Schoder, Julie E. Chang, Andrew D. Zelenetz, John P. Leonard Abstract 469, American Society of Hematology, Dec 4, 2016 50303 Event Free Survival 0.6 0.8 Probability event free event Probability Median follow-up 5.0 y HR=1.14 (0.82-1.61) R-CHOP p = 0.4386 DA-EPOCH-R 0.0 0.2 0.4 0 1 2 3 4 5 Years from Study Entry Arm N Events 3 Y (95% CI) 5 Y (95% CI) R-CHOP 233 64 0.81 (0.75-0.85) 0.69 (0.62-0.75) DA-EPOCH-R 232 70 0.79 (0.73-0.84) 0.66 (0.59-0.72) Increasing dose intensity…High dose therapy Greb A, et al. Cancer Treat Rev 2007; 33: 338–346 Survival Rates among All Eligible Patients Who Underwent Randomization. …may improve PFS for poorer prognosis patients (not OS) All patients high or high-intermediate IPI PFS OS Similar findings in Italian DLCL04 Study Chiappella Lancet Oncol 2017 Stiff PJ et al. N Engl J Med 2013;369:1681-1690 Intensification of therapy based in interim PET… PETAL Trial Aggressive lymphoma (DLBCL n=606) R-CHOP-14 x2 Interim PET negative positive A2 A1 R-CHOP14 x4 B1 B2 R-CHOP14 x4 + Rx2 R-CHOP14 x6 B-ALL Duehrsen et al. Blood 128:1857 We should be capitalising on biological insights Integrative Genetic and Clinical Analysis through Whole Exome Sequencing in 1001 Diffuse Large B Cell Lymphoma (DLBCL) Patients Reveals Novel Disease Drivers and Risk Groups Zhang et al ASH 2016 and Reddy Cell 2017 Overall survival of R-CHOP-treated patients in Lunenburg analysis Salles G et al. Blood 2011;117:7070-7078 Application of complex models of biological heterogeneity Wright, George et al. (2003) Proc. Natl. Acad. Sci. USA 100, 9991-9996 But how to distinguish phenotype? ► Getting it right is important when looking prospectively at therapy, not prognosis ► The immunophenotype is not that good: ► CD10+ (about 1/3), Mum-1-: Almost all GCB ► CD10- (2/3) hard to distinguish ABC from GCB on immuno’s ► Bcl-6 is a difficult stain ► Discordance with mRNA (~20%) ► Conflicting IHC datasets ► Lunenberg project demonstrates poor correlation between centres (technical and interpretative) Hans, C. P. et al. Blood 2004;103:275-282 Lots of different IHC Algorithms… Rita Coutinho et al. Clin Cancer Res 2013;19:6686-6695 Other emerging platforms Deeper biological insights A Reddy et al., 2017; R Schmitz et al., 2018 B Chapuy et al., 2018 Cell, 171:481-494 N Engl J Med;378:1396-1407. Nat Med; 24:679–690 A new taxonomy MCD/Cluster 5 ABC N1 BN2/Cluster 1 DLBL UNC Cluster 2 GCB Cluster 4 Cluster 3/EZB Microenvironment Surface markers EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab CD20 CD80 GA-101 • HeaderT-cell exhaustion First level bold bullet: text… Anti CD40 moAb • Dacetuzumab ActionableFirst level mutations bold old bullet • Anti CD22 - SecondCD79a/b level bullet Epratuzumab EZH2 Inotuzumab Ozogamicin AEB071 E7438- Third level bullet Pathways polatuzumab - Third level bullet mTOR inhibitors HDAC inhibitors Proteosome inhibitors Everolimus Second level bullet Vorinostat - Bortezomib Temsirolimus Panobinostat - PI3K inhibitors Bcl-2 family Idelalisib PKC inhibitors • Header Copanlisib Enzastaurin inhibitors Duvelisib • First levelABT-263 bullet: text… TGR-1202 Aurora kinase Survivin inhibitors Btk inhibitors inhibitors YM155 Ibrutinib ONO/GS-4059 Nedd8-activating ACP-196 References… Syk inhibitors enzyme inhibitors …Footnote Fostamatinib Hsp 90 inhibitors MLN4924 entosplentib KW 2478 Microenvironment Surface markers EXAMPLE HEADER UPPERCASE TEXT… CD22 Anti CD20 moAb Lenalidomide Ofatumumab CD20 CD80 GA-101 • HeaderT-cell exhaustion First level bold bullet: text… Anti CD40 moAb • Dacetuzumab ActionableFirst level mutations bold old bullet • Anti CD22 - SecondCD79a/b level bullet Epratuzumab EZH2 Inotuzumab Ozogamicin AEB071 E7438- Third level bullet Pathways polatuzumab - Third level bullet mTOR inhibitors HDAC inhibitors Proteosome inhibitors Everolimus Second level bullet Vorinostat - Bortezomib Temsirolimus Panobinostat - PI3K inhibitors Bcl-2 family Idelalisib PKC inhibitors • Header Copanlisib Enzastaurin inhibitors Duvelisib • First levelABT-263 bullet: text… TGR-1202 Aurora kinase Survivin inhibitors Btk inhibitors inhibitors YM155 Ibrutinib ONO/GS-4059 Nedd8-activating ACP-196 References… Syk inhibitors enzyme inhibitors …Footnote Fostamatinib
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  • Novel Drugs in the Pipeline

    Novel Drugs in the Pipeline

    Institute of Biomedical University of Salamanca Cancer Research Center Research of Salamanca Novel Drugs in the pipeline Enrique M. Ocio University Hospital & Cancer Research Center University of Salamanca Spain Disclosures Type Company Amgen; Celgene; Novartis; BMS, Janssen, Honoraria Takeda Celgene; Amgen; Novartis, Takeda, Abbvie, Consultancy Pharmamar, Seattle Genetics Array Pharmaceuticals; Mundipharma; Celgene; Research Funding Amgen, Sanofi, MSD Treatment of MM 1844 1960 1970 1980 1990 2000 2003 2004 2013 2015 2018 Mr. Melphalan McBean (1958, Blokhin) HD chemo 1844 Ann NY Acad Sci ASCT Bortezomib Lenalidomide Melphalan Glucocorticoids Thalidomide Panobinostat (1969) Daratumumab Elotuzumab Ixazomib Combination chemo Vincristine Doxorubicin Carfilzomib Dexamethasone Pomalidomide Chemotherapy Era Targeted Therapy Era Do we need other agents with novel MoA? New drugs and mechanisms of action in MM CS-1 Elotuzumab CDK 1, 2, 5, 9 Dinaciclib / TG02 CD38 Daratumumab / Isatuximab FGFR3 Dovitinib / AB1010 / MFGR 1877S CD138 nBT062-DM4 cKit /PDGFR Imatinib / Dasatinib MoAb CD56 Lorvotuzumab VEGF-R Bevacizumab CD40 Dacetuzumab / Lucatumumab IGF-1R AVE1642 / CP-751, 851 BAFF Tabalumab Kinase Inh. EGF-R Cetuximab KiR IPH2101 PKC Enzastaurin PD1/PDL1 Pembrolizumab / Nivolumab / Pidilumab BTK Ibrutinib IL-6 Siltuximab Cell cycle Inh. Lymph. Ras NK cell KSP Inh Filanesib Aurora K Inh MLN8237 Raf PI3K CDK 4/6 Inh Seleciclib IMIDs MEK Akt Thalidomide Lenalidomide Alkylators Pomalidomide mTORC1 mTORC2 Melphalan Cyclophosphamide MAPK Bendamustine Melflufen Signaling Pathways TH-302 AKT Perifosine / Afuresertib mTORC1 Everolimus / Temsirolimus mTOR C1/C2 MLN0128 / INK128 Other DNA damaging Farn Transf Tipifarnib Proteasome Inh. p38/MAPK inh SCIO-469 DNA Damaging Zalypsis DACi p38/JNK act Aplidin Bortezomib MEK Selumetinib PARP Inhibitor Veliparib Panobinostat Carfilzomib Hsp-90 Inh.