Treatment of Large Cell Lymphoma

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Andre Goy, MD, Chairman and Chief of Lymphoma, John Theurer Cancer Center at Hackensack University Medical Center - Treatment of Large Cell Lymphoma

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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Treatment of Large Cell Lymphoma

  1. 1. Treatment of Large Cell Lymphoma Andre Goy, MDChairman / Director John Theurer Cancer Center Lymphoma Program Head Professor of Medicine UMDNJ
  2. 2. Early Stage DLBCL
  3. 3. Early Stage DLBCL (SWOG) 8 CHOP vs 3 CHOP + IFXRT 200 pts per arm / stage I (2/3 pts) / stage II 1/3 pts 100 90 CHOP plus radiotherapy 80 70 60 % Survival 50 CHOP alone 40 30 20 P = 0.02 10 0 0 1 2 3 4 5 6 7 8 Year post randomization 5y OS 72% vs 82% for CMTMiller, NEJM July 1998
  4. 4. CHOP alone vs CHOP + IFXRT in Stage I-II DLBCL > 60y (GELA) 290 pts per arm / Med flup 7y PFS OS 5y NO difference / Prognostic factor: Stage II <Bonnet JCO, March 2007
  5. 5. Localized DLBCL Controversy on number of cycles and need for radiation consolidation Radiation improved local control and often > PFS Difference in OS debatedBindra & Yahalom, Expert Rev Anticancer Ther, 2011 Sep;11(9):1367-78.
  6. 6. MINT Trial – R-CHOP / CHOP for Young Patients with good-prognosis DLBCL 18–60 y with 0 or 1 risk factor according to the aa-IPI, stage II–IV disease or stage I-bulky 420 pts each arm / Median follow-up of 6 years Rituximab obviously improves all subgroups / Pts with IPI = 0, no bulk > 90%Pfreundschuh, Lancet Oct 2011
  7. 7. - R-Chemo is also > in early stage DLBCL- Impact of bulky disease is reduced byR-chemo but remains prognostic- Do we still need XRT in R-chemo era?
  8. 8. Can PET Scan Help? Stage I/II, no B symp, mass ≤10 cm (Vancouver) 65 patientsSehn L, ICML 2011, abst # 28
  9. 9. Can PET Scan Help? Stage I/II, no B symp, mass ≤10 cm (Vancouver) PET –ve excellent outcome / PET +ve high relapse rate of distant relapse  NEED other approaches Ongoing GELA study / PET to decide 6 vs 4 cyclesSehn L, ICML 2011, abst # 28
  10. 10. Issues with Early Stage DLBCL- Problem is series vary I, II and BULK or not- Most relapses are distant relapses Are late and distant relapses a reflection of inadequate systemic therapy?
  11. 11. GELA – ACBVP vs CHOP + IFRTPreviously untreated patients < 61 years old / Stage I or II aggressive lymphoma 320 pts each arm / No IPI risk factors / Median follow-up of 7.7 years 5y EFS 82% for chemo alone vs 74% for CMT / also > in PFS and OS (similar In bulky or non-bulky)Reyes, NEJM, March 2005
  12. 12. DLBCL – Early Stage- Very limited disease (stage I / non bulky):  R-CHOP x 3 w/wo XRT (3 +1 if PET –ve?)  R-CHOP (6/6 vs 4/6) FLYER study Germany- Stage I bulky / IE or II non bulky  R-CHOP x 6 / limit nb cycles + XRT?  6 R-CHOP-21 vs 6 R-CHOP-14(UNFOLDER)  6 v 4 R-CHOP if PET –ve (GELA)
  13. 13. Advanced Stage DLBCL
  14. 14. Established Superiority of R-CHOP vs CHOP MInT[1] British Columbia[2] 1.0 R- 1.0 0.8 Chemo Post-rituximab 0.8 0.6 0.6 GELA 0.4 Chemo 0.4 1.0 Pre-rituximab 0.2 0.2 P = .000000007 P=.0001 0 0.8 0 0 5 10 15 20 25 30 35 40 45 50 0.6 R-CHOP 0 1 2 3 4 Months Years 0.4 CHOP 0.2 RICOVER 60[5]1.0 ECOG 4494[3] P < .0001 0 R-CHOP-140.8 Maintenance 0 1 2 3 4 5 6 7 8 9 10 Years0.6 CHOP-140.4 Observation0.2 CHOP R-CHOP P = .0000250.0 0 1 2 3 4 5 0 5 10 15 20 25 30 35 40 45 Years Months Confirmed by multiple studies even in < 60y 1. Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391. 2. Sehn L, et al. ASH 2003. Abstract 88. 3. Habermann T, et al. J Clin Oncol. 2006;24:3121-3127. 4. Coiffier B, et al. ASCO 2007. Abstract 8009. 5. Pfreundschuh M, et al. Lancet Oncol. 2008;9:105-116.
  15. 15. R-CHOP-21 is The “Standard”How can we improve?
  16. 16. DLBCL: Current Challenges w/R-CHOP GELA 98-05 - median follow-up time of 10 years 80% of drop 1st 3 years 40% at 10 y still NED in R-CHOP ½ failures occur in 1st 12 to 18ms Poor outcome of early relapse (<1y)  target for improvement +++Coiffier et al, Blood June 2010
  17. 17. DLBCL: Strategies to improve / R-CHOP Nb cycles / 6 vs 8 cycles RICOVER trial (q2kws) Dose-intensity “More“ chemo R-CHOP-14 vs 21 Continuous infusion R-EPOCH Consolidation w/ DI / HDT-ASCT upfront Prediction response on PET Pts stratification ++ New combinations / R-CHOP + X Revisit maintenance strategies
  18. 18. Adjust Number of cycles: 6 vs 8 Cycles (R)-CHOP-14 (RICOVER)RICOVER Trial: 6 vs 8 CHOP-14 ± R in DLBCL > 60y (GHGLSG) / > 800 pts Regimen 6 cycles 8 cycles FFTF CHOP 53% 58% R-CHOP 70% 70% PFS according to mid-therapy restaging 100 90 CR CRu PR 80 70 60% 50 40 8 R-CHOP 14 8 R-CHOP 14 8 R-CHOP 14 30 6 R-CHOP 14 6 R-CHOP 14 6 R-CHOP 14 20 10 0 20 40 60 0 20 40 60 0 20 40 60 0 Months Months Months NO benefit from 8 cyclesSchubert J, et al. ASH 2007. Abstract 788Pfreundshuh M. Lancet Oncol. 2008;9:105-116. No benefit from XRTBulk in CR-CRu
  19. 19. R-CHOP-21 vs R-CHOP-14 UK NCRI Phase III Trial R-CHOP-21 CHOP-21: 8 cycles Newly diagnosed Rituximab x 8 CD20+ve R DLBCL R-CHOP-14 CHOP-14 x 6 Rituximab x 8 Stratified by age, IPI Lenograstim dasy 4-12 1080 pts, 540 / arm / 119 sites / May 2005 Nov 2008 Primary endpoints: OSCunningham D et al, , ASCO 2011, abst # 8000.
  20. 20. R-CHOP-21 vs R-CHOP-14 UK NCRI Phase III Trial Recruitment by age 450 52% 400 350 Patients recruited 300 250 200 150 100 50 0 <30 30-39 40-49 50-59 60-69 70-79 80+ Age range No difference clinical parameters btw both arms 2/3 stage III-IV / 50% bulkyCunningham D et al, , ASCO 2011, abst # 8000.
  21. 21. R-CHOP-21 (8) vs R-CHOP-14 (6) UK NCRI Phase III Trial DLBCL, age >18, Bulky IA (>10cm), IB, II, III, IV PFS OS ORR 88% for RCHOP-21 vs 90% for RCHOP-14 Radiological CR 47% in both arms No difference in ORR, CR rate, PFS or OSCunningham D et al, , ASCO 2011, abst # 8000.
  22. 22. R-CHOP-21 vs R-CHOP-14 UK NCRI Phase III Trial Higher % neutropenia and F/N in R-CHOP21 reflects the primary prophylaxis with G-CSF in R-CHOP14Cunningham D et al, , ASCO 2011, abst # 8000.
  23. 23. R-CHOP-21 vs R-CHOP-14 UK NCRI Phase III Trial OS by phenotype 1.0 0.9 0.8 Probability 0.7 0.6 0.5 0.4 p=0.2082 0.3 Events Totals 0.2 non GC 63 271 0.1 GC 53 289 0.0 0 1 2 3 4 5 6 No difference in bulky, IPI, KI-67 (MIB-1), LDH, etc..Cunningham D et al, , ASCO 2011, abst # 8000.
  24. 24. R-CHOP-21 vs R-CHOP-14 (8 cycles) GELA Trial Interim analysis • 60 to 80 y 200 pts • Stage II to IV • AA IPI 1,2 or 3 Med flup 39 ms Update ICML Lugano R-CHOP14 R-CHOP21 CR + CRu 71% 73% PR 16 % 12 % ORR 87 % 85 %Delarue et al, ASH 2009: abst # 406 Delarue, ICML 2011 abst # 124
  25. 25. R-CHOP-21 vs R-CHOP-14 (8 cycles) GELA Trial EFS OS 3y-EFS : 57% vs 60% 3y-OS : 70% vs 73% No benefit ORR, CR, EFS, PFS or OSDelarue, ICML 2011 abst # 124 Delarue et al, ASH 2009: abst # 406
  26. 26. Continuous Infusion – R-EPOCH Phase II Study of dose-adjusted R-EPOCH in DLBCL 72 pts stage II or more, med age 50, 40% had a high-intermediate or high IPI IPI score / PFS (P = .007) Risk 5y PFS Low-risk 91% Low-interm 90% High-interm 67% High risk 47% LNH98-5: R-CHOP high risk 5y EFS 47% Ongoing randomization R-CHOP-21 vs R-EPOCH (CALGB) w/ GEPWilson WH, et al. J Clin Oncol. 2008;26:2717-2724.
  27. 27. More Intensive Induction Regimens? LNH 03-2B Trial 380 pts / young pts IPI ≥ 1 MTX R-IFM-VP16 Ara-C R-ACVBP 14 0 2 4 6 10 14 24 Wks R 4 IT-MTX 0 3 6 9 12 15 18 21 Wks R-CHOP 21 *No radiotherapy in both arms NO ASCTRecher Blood Nov 2010 abst # 109
  28. 28. More Intensive Induction Regimens? LNH 03-2B Trial 3-y PFS 87% in R-ACVBP arm 3-y OS was 92% R-ACVBP vs 73% in R-CHOP arm and 84% (R-CHOP arm R-ACVBP significantly improves EFS, PFS, DFS and overall survivalRecher Blood Nov 2010 abst # 109
  29. 29. Consolidation w/ HDT – ASCTMeta analysis 15 large randomized studies with chemo vs ASCT in DLBCL frontline 2728 pts In pre rituximab era multiple studies conducted  NOT conclusive Greb, Cancer Treatment Reviews (2007) 33, 338-346
  30. 30. Consolidation w/ HDT – ASCT Upfront In Rituximab Era DLCL04 Trial R-CHOP-14 vs R-mega CHOP  consolidation or not w/HDT-ASCT / High risk DLBCL pts AAIPI 2-3 /188 pts / arm 2y PFS no HDT-ASCT: 59% 2y OS: no difference vs 72% for HDT-ASCTVitolo, ICML 2011 abst # 72
  31. 31. Consolidation w/ HDT – ASCT Upfront In Rituximab Era GOELAMS Trial 075 R-CHOP-14 x 8 vs HDT (CCEP/MC/DHAP) induction followed by BEAM ASCT / 340 pts 1,0 Cumulative Survival 0,8 0,6 R-CHOP 0,4 R-HDT p= 0.03 0,2 3y EFS R-CHOP 56 % 3y EFS R-HDT 41 % 0, 0 10 20 30 40 50 60 70 Months 3y PFS 81 % vs 79 % / No diff in OS or by IPILeGouill ASCO 2011 abst # 8003
  32. 32. Consolidation w/ HDT – ASCT Upfront In Rituximab Era DSHNHL Trial 8 CHOEP + 6 R vs 4 MegaCHOEP+ 6R MegaCHEOP increasing dose  3 ASCR / 130 pts /arm / young pts high risk R-MegaCHOEP not > (CR rate and PFS) and >> toxicitySchmitz, ICML 2011 abst # 73
  33. 33. Consolidation w/ HDT – ASCT Upfront In Rituximab Era S9704 Trial (SWOG + Canada) Bulky stage II, III, and IV H-Int / High IPI DLBCL Hypothesis: is HDT-ASCT > after 5 CHOP+/- R?Stiff, ASCO 2011 abst # 8001
  34. 34. Consolidation w/ HDT – ASCT Upfront In Rituximab Era S9704 Trial (SWOG + Canada) Bulky stage II, III, and IV H-Int/High IPI diffuse Outcome ASCT arm Conventional Hazard ration P-value % arm 2-year PFS 69 56 1.72 .005 2-year OS 74 71 1.24 .16 HDT-ASCT improved PFS even for pts who received R-CHOP but no diff OS (except in AN UNPLANNED subset analysis > for high risk pts)Stiff, ASCO 2011 abst # 8001
  35. 35. Consolidation w/ DI / HDT – ASCT Upfront??• Rituximab is likely to decrease potential differencesbetween conventional and high-dose regimens• Lack of impact on OS means it does not matter if ptsreceive HDT-ASCT HDT should not be part of routine upfront consolidation A subset of high risk pts might benefit from DI / HDT approaches upfront (difficult to identify)
  36. 36. Can we identify high risk patients upfront / early on??
  37. 37. Adjust Response Based on PET Can we use functional imaging to detect chemosensitivity in-vivo?
  38. 38. Early Interim PET in Lymphoma No event in PET-ve group PET after 4th cycle PET after 1st cycle PET+ve Interim- PET +Spaepen et al, Ann Oncol 13: 1356, Kostakoglu et al, Cancer 107: 2678, 2002 2006 PET after 3rd cycle PET after 2nd cycleMikhaeel et al, Ann Oncol 16: 1514, 2005 Haioun et al, Blood 106: 1376, 2005 Strong predictor if NEGATIVE Issues: consistency / false +ve / NEED BIOPSY ΔSUV (drop ≥70%) might be better predictor?
  39. 39. Early Interim PET in Lymphoma• Evidence that pts benefit from having their treatment adapted based on early FDG-Pet is limited and conflicting (need better standardization interpretation)• Most data so far „adjusting“ based on PET were pre Rituximab• Ongoing risk-adapted studies / still pending Ongoing studies FDG-PET remains investigationalHaouin, ICML 2011 abst # 139Moskowitz, ICML 2011 abst # 140 Djor, ICML 2011 abst # 132
  40. 40. Risk Adapted Therapy Patients stratification ++
  41. 41. CLINICAL Prognostic Factors – IPI (APLES) Risk Group Risk CR, 5-Yr OS, Factors, % % n Patients (all ages)  Low 0-1 87 73  Low intermediate 2 67 51  High intermediate 3 55 43  High 4-5 44 26 Patients 60 yrs of age or younger  Low 0 92 83  Low intermediate 1 78 69  High intermediate 2 57 46  High 3 46 32 Prognostic models CAN BE INFLUENCED by EVOLVING therapiesShipp et al, NEJM 1993
  42. 42. Revised IPI (R-IPI) 365 pts DLBCL R-CHOP PFS Overall Survival R-IPI cannot predict population < 50% OS @ 5y! IPI still debated in the R-chemo era Other factors: beta-2microglobulin, BM+, bulky NOT included!Sehn et al, Blood, 2007 Bari A et al, Ann Oncol 2010;21:1486-1491 Ziepert et al, JCO May 2010
  43. 43. Impact of biologicalheterogeneity of DLBCL
  44. 44. Cellular Origin of B-cell Lymphomas Classification of lymphomas based on B-cell differentiation steps and molecular (oncogenic) featuresKuppers et al, Nat Rev Cancer,
  45. 45. DLBCL Subtypes Resemble Stages of B-cell Differentiation and Activation 2 main molecular subtypes of DLBCL correspond to different cell of origin GC- ABC- DLBCL DLBCLAlizdeh et al, Nature 2000. Kuppers et al, Nat Rev Cancer,
  46. 46. Primary Mediastinal Large Cell lymphoma (PMBL) Have Distinct GEP A group of 46 genes allowed to separate PMBL signature overlaps PMBL from other DLBCL w/ classical Hodgkin lymphomaRosenwald et al, J Ex Med, Sept 2003
  47. 47. 3 Main Subtypes of DLBCL w/ Different OutcomeRosenwald et al, J Ex Med, Sept 2003
  48. 48. Distinction ABC / GC remains after R-CHOP in DLBCL Non GC subtype still worse outcomeRosenwald A, et al. N Engl J Med. 2002;346:1937-1947 Lenz et al, NEJM, Nov 2008
  49. 49. Definition of ABC and GC Subtypes by IHC Hans algorithm GCB GCB + - CD 10+ MUM-1 + - Bcl-6 + Non-GCB - Non-GCB GCB Non-GCB 76% 34% Choi model addition of GCET-1 (GC) and FOXP-1 (ABC)Hans, CP, et al. Blood. 2004;103:275-282. Choi et al, Clin CA Res, Nov 2009.
  50. 50. Stromal Signatures in DLBCL GEP on lymph node biopsies of 233 pts treated w/ R-CHOP Stroma 1: extra-cellular matrix, myeloid, macrophages Stroma 2: endothelial, angiogenesis signatureLenz G et al. N Engl J Med 2008;359:2313-2323 Also predictive for PFS
  51. 51. Evolving COMPLEXITYOf Signatures in DLBCL Other Mutations Genomic MicroRNAs (MYC, double- hit, CGH) Epigenetic SNPs (Histones, methylation)
  52. 52. GROWING awareness of molecular Heterogeneity of DLBCL BUTnot yet ready for routine clinical decisions
  53. 53. What Happen After R-CHOP(Relapse / refractory setting)?
  54. 54. Guideline Recommendations for Treatment of Relapsed DLBCL Second-line therapy in  Second-line therapy for candidates for high- patients who are not dose therapy + ASCT candidates for high-dose – DHAP ± rituximab therapy – ESHAP ± rituximab – Clinical trial – GDP ± rituximab – Rituximab – GemOx ± rituximab – CEPP ± rituximab – ICE ± rituximab – PEPC – miniBEAM ± rituximab – EPOCH ± rituximab – MINE ± rituximabNCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. v.1.2011.
  55. 55. PARMA Study: Bone Marrow Transplantation vs Salvage Chemotherapy Transplantation 100 100 Conventional treatment 80 80 EFS (%) OS (%) 60 60 40 40 20 20 P = .001 P = .038 0 0 0 15 30 45 60 75 90 0 15 30 45 60 75 90 Mos After Randomization Mos After Randomization All PRE rituximabPhilip T, et al. N Engl J Med. 1995;333:1540-1545.
  56. 56. CORAL – Relapse / Refractory DLBCL 2 questions: Salvage regimen and benefit of maintenance post ASCT R A Patients with A N Rituximab R-ICE relapsed/refract S D q2 m x 6 ory C O CD20+ DLBCL, T M R-DHAP I Observation < 65 years Z E N =400 patients OS PFS R-ICE and R-DHAP : similar activityC. Gisselbrecht et al. JCO Sept 2010
  57. 57. CORAL – Relapse / Refractory DLBCL Impact of prior Rituximab Impact of early relapse Prior rituximab exposure and relapse within 12 ms of diagnosis  3y PFS 23% after HDT-ASCTC. Gisselbrecht et al. JCO Sept 2010
  58. 58. BIO- CORAL Study Paired biopsies showed no diff in GC / non-GC over time and by GEP Hans algorythm GC Non GC R-ICE R-DHAP 52% 31% 27% 32% 3 years 3 years p = NS p = 0.04 p = NS Difference in outcome confirmed when based on GEP +++Thieblemont et al. ASH 2010, abt # 993
  59. 59. CORAL – Update on Maintenance post ASCT At 45 months, mobilization-adjusted ORR comparable after induction therapy • ORR 51.5% for R-ICE vs 56.5% for R-DHAP (NS) • EFS 29% vs 33% (NS) • OS 48% vs 51% (NS) Outcome R- No further P-value 4- years % maintenance treatment EFS 55 53 .7435 PFS 55 57 .8314 OS 64 67 .7547 R-maintenance is not superior to observation after salvage  ASCT (except in women > > PFS @2y and > OS for MR (p= 0.0066)Gisselbrecht ASC0 2011, abst # 8004
  60. 60. Effect of R-CHOP Induction DebatedMoore ICML 2011, abst # 76
  61. 61. Salvage after R-CHOP• Primary failures to R-CHOP do VERY POORLY +++• Early failures to R-CHOP do worse than late failures (>1y) but if chemosensitive should be transplanted• Need for new strategies / (new combinations / allogenic TH2)
  62. 62. Special Considerationsin the Treament of DLBCL
  63. 63. R-Mini-CHOP in > 80y Life expectancy of an 80y person is 9 years! >80 y - Stage I-X to IV  150 pts 51 males 99 females R-mini-CHOP:  38 GELA centers cyclophosphamide: 400 mg/m2 doxorubicine: 25 mg/m2  108 pts completed 6 cycles vincristine: 1 mg total dose D1  ORR 74% / CR-CRu 63% 6 cycles q21d / GCSF optional  2y OS 59% / PFS 48% Primary endpoint efficacy / OS  30 deaths: 1/3 tox / 1/3 NHL / 1/3 other Elderly w/ good PS can still do well with reduced dose R-CHOPSchmitz N, et al. ASH 2010. Abstract 112.
  64. 64. Location: Testes Lymphoma - IELSG-10 (CONSORT Trial) Fifty-three patients (22-79) with untreated stage I or II PTL R-CHOP-21 + IT MTX + XRT (controlateral testis) Cumulative incidence of CNS relapse at 5 years was only 6% (up to 35% in prior studies) Is IT only sufficient? Common brain parenchymal relapses > Outcome / historical controlsVitolo, JCO July 2011
  65. 65. CNS Disease in DLBCL CNS involvement in DLBCL  CNS disease developed in poor prognosis ++ 56 patients (2.5%) @ median: 7.0 mos; range, 0.2-85.0 mos Few data available on impact of systemic therapy on CNS events in DLBCL  CNS disease reduced in patients with IPI 0 or 1 receiving 2797 patients ≥ 60 yrs DLBCL rituximab in the DSHNHL and MInT trials – 2196 pts received CHO(E)P ± R for 6-8 courses or  NOT for high risk pts MegaCHOEP + R Current prophylaxis (IT MTX) – not needed in “low risk” / NOT “helpful” in high risk  redefine risk factors? HD MTX?Peyrade, et al. ASH 2010. Abstract 853
  66. 66. Can we add to R-CHOP?
  67. 67. DLBCL: Add Mab (anti CD22) to R-CHOPR-CHOP-21 + Epratuzumab 360 mg/m2 on day 1 of each cycle 107 pts ER-CHOP feasible / appears to improve EFS comp to historical controls Micallef et al, Blood Oct 2011
  68. 68. DLBCL: Add Mab to R-CHOPTherapy type Drug / Rationale / designAnti CD20 GA-101 / OfatumumabRIT R-CHOP  RIT HDT RIT salvageAnti-angiogenesis?? Bevacizumab MAIN trial stopped Anti VGEF (aflibercept)Anti CD30 Brentuximab vedotin 64% CR rate in CD30+ve lymphomas
  69. 69. DLBCL – Novel Therapies New biologicals: small moleculesTherapy type Drug Comments Rationale / design Efficacy / ToxicityProteasome Strong rationale for R-CHOP-Bzinhibitors combinations R-EPOCH-BzmTOR inhibitors RAD-001 (Everolimus) ORR 30% / DOR ≈ 6ms PILLAR 2 trial: rand maintenance in CR post R-CHOPIMiDs Lenalidomide NHL-003 trial ORR 31% Median of 3 prior RX (1-10) R2-CHOP Len 265 days 1-10 / 30 pts ORR 100% / CR rate 83% ++ MAINT post R-CHOP in > 60y (REMARC)PKCβ inhibitor Enzastaurin Maintenance post R-CHOP / suggest > PFSOther HDAC inhibitors Ongoing
  70. 70. Validation of NFKB Target in ABC DLBCL Differential efficacy of Bortezomib + chemotherapy within molecular subtypes of DLBCL Rationale for ongoing trial R-CHOP +- Bortezomib in ABC-DLBCL (PYRAMID Trial)Dunleavey, Blood June 2009
  71. 71. Differences in responses to Lenalidomide monotherapy in relapsed/refractory GCB vs. Non GCB DLBCL P= % of response 0.004 P = 0.006 ORR 8.7% in GC vs. 53% in non-GCB DLBCL treated with lenalidomide-monotherapy (n=40) (p = 0.006) No differences in the median number or treatments, IPI score, histology, stage or other demographic characteristics @ time lenalidomide Rx btw the two groupsHernandez-Ilizaliturri, et al, Cancer April 2011
  72. 72. Targeting BCR Pathway in Lymphoma BCR-associated kinases are targets of new drugs in preclinical and clinical development Inhibitor Activity in DLBCL Syk (spleen 5/23 responded tyrosine ORR: 22% kinase) Fostamatinib Btk (Bruton’s ORR 29% tyrosine ? More CR in kinase) PCI- ABC 32765 PI3K inhibitor Activity in CLL, CAL-101 MCL, FL 1 Quiroga MP, et al. Blood 114(5):1029-37, 07/2009From: Nat Rev Immunol 2:945 2 Niedermeier M, et al. Blood 113(22):5549-57, 5/2009
  73. 73. DLBCL: Strategies to improve / R-CHOP 6 cycles enough! R-CHOP-14 vs 21 “More“ chemo no difference Patients stratification will Continuous infusion R-EPOCH? help develop novel ? Subset benefit from strategies in DE-(RE)FINED HDT-ASCT upfront New combinations subsets of pts R-CHOP + X NEW maintenance strategies Prediction response on PET? Patients stratification ++
  74. 74. DLBCL: Considerable Progress!BEFORE ASCT No CHOP-21 HDT / ASCT Debated? maintenanceInduction Consolidation Maintenance Relapse New MabNOW DAC R-CHOP-21 No HDT/ASCT New Lenalidomide +++ Subset of pts? agents ?? BTZ SYK BTKi

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