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High Risk Lymphoma

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Upfront autologous stem cell transplant vs. novel agents for High-Risk Lymphoma
Shashikant Apte, MD

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High Risk Lymphoma

  1. 1. Upfront Auto PBSCT v/s Novel Therapies ,High Grade NHL-Bangkok, 31st August 2014 Dr. S. J. Apte, MD FRCPA Consultant Haematologist, Sahyadri Speciality Hospital, Pune
  2. 2. UPFRONT AUTOTRANSPLANTATION IN AGGRESSIVE LYMPHOMA Not in 2014
  3. 3. Lessons from History- • Rituximab was the first major breakthrough in the treatment of NHL and not the Auto SCT
  4. 4. Transplants 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 Transplant Activity Worldwide 1968-2012 Autologous Allogeneic '68 '70 '72 '74 '76 '78 '80 '82 '84 '86 '88 '90 '92 '94 '96 '98 '00 '02 '04 '06 '08 '10 '12
  5. 5. Indications for Hematopoietic Stem Cell Transplants in the U.S. Number of Transplants 5,500 5,000 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0 Multiple Myeloma Allogeneic (Total N=7,012) Autologous (Total N=9,778) NHL AML HD ALL MDS/MPD Aplastic Anemia CML Other Leuk Non- Malig Disease Other Cancer
  6. 6. HOW TO DEFINE AGGRESSIVE LYMPHOMA?
  7. 7. Survival by Gene Expression Profiling: DLBCL Yrs OS Diffuse Large B-Cell Lymphoma DLBCL Subgroup 5-Yr OS, % Primary Mediastinal 64 Germinal Center B cell 59 like (GCB) Activated B cell (ABC) 30 1.0 0.8 0.6 0.4 0.2 0 0 2 4 6 8 10 Rosenwald A, et al. J Exp Med. 2003;198:851-862.
  8. 8. Prognosis By Interim PET Scanning - Mixed results seen in 4 studies - 2 studies confirm predictive value, 2 studies did not 100 80 60 40 20 0 Progression Free Survival n= 98 PET negative (n=73) PET positive (n=12) P=0.02 0 20 40 60 80 100 Time (months) Safar et al, J Clin Oncol 2012;30:184 1.0 0.8 0.6 0.4 0.2 0 Progression Free Survival PET Positive n= 112 0 1 3 5 6 7 Time (years) P=0.146 PET Negative 2 4 Moskowicz et al. J Clin Oncol 2010;11: 1896
  9. 9. Revised International Prognostic Index • Age >60 • Perf Status • Stage 3-4 • LDH •Extranodal 5 Overall Survival According to Yrs P < .001 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 1 2 3 4 Sehn LH, et al. Blood. 2007;109:1857 Legend Revised IPI Risk Group IPI Factors, n Very good 0 Good 1, 2 Poor 3, 4, 5
  10. 10. Standard International Prognostic Index Remains a Valid Predictor of Outcome for Patients With Aggressive CD20+ B-Cell Lymphoma in the Rituximab Era J Clin Oncol 28:2373-2380.; 2010
  11. 11. SO, THIS DEBATE IS ALL ABOUT A SMALL PERCENTAGE OF PATIENTS WHO ARE NON RESPONSIVE TO CHEMO IN ‘R’ ERA.
  12. 12. High Risk Diffuse Large Cell Lymphoma Autologous HSCT in First CR/PR
  13. 13. Standard Chemotherapy With or Without High-Dose Chemotherapy for Aggressive Non-Hodgkin’s Lymphoma: Randomized Phase III EORTC Study Hanneke C. Kluin-Nelemans, Vittorina Zagonel, Anastasia Anastasopoulou, Dominique Bron, Klaas J. Roozendaal, Ed M. Noordijk, Helen Musson, Ivana Teodorovic, Brigitte Maes, Antonino Carbone, Patrice Carde, Jose´ Thomas Background: The long-term outcome for patients with ag-gressive non-Hodgkin’s lymphoma (NHL) is poor. Conse-quently, the European Organization for Research and Treat-ment of Cancer Lymphoma Group designed a prospective randomized trial to investigate whether high-dose chemo-therapy plus autologous bone marrow transplantation (ABMT) after standard combination chemotherapy im-proves long-term survival. Methods: Patients aged 15–65 years with aggressive NHL received three cycles of CHVmP/BV polychemotherapy (i.e., a combination of cyclophosphamide, doxorubicin, teniposide, and prednisone, with bleomycin and vincristine added at mid-cycle). After these three cycles, pa-tients with a complete or partial remission and at that time no lymphoma involvement in the bone marrow were ran-domly assigned to the ABMT arm (a further three cycles of CHVmP/BV followed by BEAC [i.e., a combination of car-mustine, etoposide, cytarabine, and cyclophosphamide] che-motherapy and ABMT) or to the control arm (five more cycles of CHVmP/BV). All statistical tests are two-sided. Results: From December 1990 through October 1998, 311 patients (median age = 44 years) were registered and re-ceived the first three cycles of CHVmP/BV, and 194 patients were randomly assigned to the treatment arms. Approxi-mately 70% (140 patients) of these patients were of low or low–intermediate International Prognostic Index (IPI) risk. After a median follow-up of 53 months, an intention-to-treat analysis showed a time to disease progression and overall survival at 5 years of 61% (95% confidence interval [CI] = 51% to 72%) and 68% (95% CI = 57% to 79%), respec-tively, for the ABMT arm and 56% (95% CI = 45% to 67%) and 77% (95% CI = 67% to 86%), respectively, for the control arm. Differences between arms were not statistically significant. A subset analysis on IPI risk groups, although com-pared 80%, but did not improve the disease-free survival with the results with CHOP: In a large comparing three intensive chemotherapy regimens CHOP, no difference was found among the four Treat-ment In 1975, the European Organization for Research polychemo-therapy of Cancer (EORTC) designed CHVmP, regimen derived from CHOP, consisting re-peated cyclophosphamide, doxorubicin, teniposide, and second-generation every 3 weeks, for patients with NHL. EORTC trial for patients with stage who were aged up to 70 years, with intermediate- malignancy [Working Formulation (7)], CHVmP compared with CHVmP to which bleomycin were added at mid-cycle (CHVmP/BV). The scheme resulted in a higher rate of CR (74% versus a better overall survival at 5 years (53% versus years (34% versus 22%) (9). The next EORTC regi-men study that compared CHVmP/BV with the third-ProMACE-MOPP (i.e., a combination methotrexate, doxorubicin, cyclophosphamide, followed by mechlorethamine, vincristine, procarbazine, prednisone) found identical survival between the with far less toxicity for patients in the CHVmP/au-tologous In the mid-1980s, high-dose chemotherapy stem cell rescue became a mature therapy Obvi-ously, had activity for relapsing and refractory NHL con-ventional dose escalation appeared to cure some patients chemotherapy-resistant disease. In covering more than 1200 patients, Goldstone abla-tive Armitage (16) documented that this form of bone therapy resulted in long-term disease-free than half J of Natl the Cancer patients Inst who 2001;received 93:22–30 a transplant How-ever, minimal disease early in the course of their lymphoma. selection might have played a major role in
  14. 14. chemotherapy regimen, and found no difference in CR if all patients were taken into account. Updated results showed that ABMT might have been favorable for IPI intermediate–high-risk and high-risk patients (34). However, the next GELA trial (i.e., LNH93–3) (30) designed high-dose chemotherapy after phase) was prematurely many early relapses. Fig. 3. Kaplan–Meier curves for patients treated according to randomization. Data from all randomly assigned patients are given on the basis of the intention-to-treat analysis. Up-per panel: overall survival. Lower panel: time to disease progression. ABMT autologous bone marrow transplan-tation; O observed events; N number of patients. All statistical tests are two-sided. 4. Kaplan–Meier curves for patients treated according Journal of the National Cancer Institute, Vol. 93, No. 1, January 3, 2001 Fig. to randomization arm, grouped according to the age-adjusted International Prognostic Index (IPI) risk factors. Data from all randomly assigned patients are given on the basis of the intention-to-treat analysis. ABMT autolo-gous bone marrow transplantation; O observed events; N number of patients; L, low IPI risk; I intermediate IPI risk; H high IPI risk. J Natl Cancer Inst 2001;93:22–30 NO ADVANTAGE OF HDT IN CR 1 / PR 1
  15. 15. J Clin Oncol 21:1255-1262.; 2003 NO ADVANTAGE OF HDT IN CR 1 / PR 1
  16. 16. Final analysis of the UKLG LY02 t rial comparing 6–8 cycles of CHOP with 3 cycles of CHOP followed by a BEAM autograf t in pat ients <65 years with poor prognosis histologically aggressive NHL High dose therapy and autologous haemopoietic stem cell transplantation is the standard treatment for younger patients with chemosensitive relapsed or resistant histologically aggres-sive non-Hodgkin Lymphoma (NHL). (Philip et al, 1987, 1995; Gribben et al, 1989; Mills et al, 1995). A similar NO ADVANTAGE OF HDT IN CR 1 / PR 1 (Haioun et al, 1997, 2000). Despite this positive result, this strategy hasnot been widely adopted. Thisispartly becausethe limitation of high dose therapy to those who have already achieved a CR, excludes a significant number of patients who, although demonstrating chemosensitivity, only achieve a David C. Linch,1 Lynny Yung,1 Paul Smith,1 Ken Maclennan,2 Andrew Jack,2 Barry Hancock,3 David Cunningham,4 Peter Hoskin,5Wendi Qian,1 Harald Holte,6 Anne-Marie Boesen,6 Andrew Grigg,7 Peter Browett7 and Marek Trneny8 1NCRI UK Lymphoma Group, CRUK and UCL Cancer TrialsCentreUCL, London, 2Department of Pathology, HMDS, Leeds, 3University of Sheffield, Sheffield, 4TheRoyal Marsden Hospital, London, 5Department of Oncology, Mount Vernon Hospital, Middlesex UK, 6Nordic Lymphoma Group, 7Department of Clinical Haematology & BMT Service, TheRoyal Melbourne Hospital, Australia, and 8Department of Haematology, Charles University in Prague, Czech Republic Received 3 August 2009; accepted for publication 13 November 2009 Correspondence: Professor David C. Linch, Department of Haematology, Cancer Institute, University College London, 72, Huntley Street, London WC1E6BT, UK. E-mail: d.linch@ucl.ac.uk Summary This trial involved 457 patients and sought to assess the value of early intensification with autologous transplantation in patients with poor prognosis histologically aggressive non-Hodgkin lymphoma (NHL) showing a response to initial CHOP (cyclosphosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Randomization was made at the time of diagnosiswith 223 assigned to continuing CHOP and 234 to 3 cycles of CHOP followed by a BEAM (carmustine, etoposide, cytarabine, melphalan) autograft. Analysis was on an intention to treat basis. After the initi al three cycles of CHOP 19% of the whole group were in complete response (CR) and 53% in partial remission (PR). At the end of treatment 86% of patients in the CHOP arm had responded with 58% in CR. In the high-dose therapy arm the overall response rate was 83% with 64% in CR (difference between arms not significant). The progression-free survival (PFS) and overall survival at 5 yearsfor thecontinuingCHOParm were38% and 50% respectively, and for the autograft arm were 44% and 50% (differences not significant). Of the patients who attained CR and subsequently relapsed, there were no long-term survivors in the autograft recipients compared to 46% of the continuing CHOP recipients (P= 0Æ0008). In conclusion, no survival benefit was demonstrated for an early autograft in first response. Keywords: non-Hodgkin Lymphoma, high grade NHL, poor prognosis, autologous transplantation. British Journal of Haematology, 149, 237–243, 2010
  17. 17. WILL THIS HOLD GOOD IN RITUXIMAB ERA IS THE QUESTION?????
  18. 18. Lancet Oncol 2011; 12: 1013–22
  19. 19. Lancet 2011; 378: 1858–67
  20. 20. High Risk Diffuse Large B Cell NHL: Frontline Autologous HCT Phase II Trials containing rituximab Group n aaIPI >2 Therapy CR Rate PFS /EFS OS Follow up Tarella 2007 112 100 Mod R-HDS 80 73 76 4 yrs Vitolo 2009 97 100 R-mega CEOP x BEAM/HCT 82 73 80 4 yrs Dilhudy 2010 42 100 R CEEP BEAM HCT 55 55 74 5 yrs Fitoussi 2011 209 100 R-ACVBP + BEAM/HCT 60 76 78 4 yrs
  21. 21. Only patients with two or three risk factors (Ann Arbor stage III or IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group [ECOG] performance status 2 or 3) of the age-adjusted IPI were eligible Lancet Oncol 2012; 13: 1250–59
  22. 22. Lancet Oncol 2012; 13: 1250–59
  23. 23. Lancet Oncol 2012; 13: 1250–59
  24. 24. Lancet Oncol 2012; 13: 1250–59 NO ADVANTAGE OF HDT IN CR 1 / PR 1
  25. 25. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: Preliminary results of the GOELAMS 075 prospective multicenter randomized trial. Results: 340 pts included 01/2005 to 06/2010, 286 pts evaluable at time of abstract, 143 in each arm. Characteristics of the pts in the 2 arms are super imposable. Overall 56% bulk, 72% >2 AA stage and 58% aa IPI>1. The Rdz tx was completed in 67% in the R-CHOP arm and 53% in the R-HDT arm. The interm evaluation showed the same rate of response with CT scan (CR + CRu: 65% and 62% following 4 x R-CHOP14 and first 3 courses of R-HDT). PET remained more often pos after the first 3 courses of R-HDT (41% vs 28%; p=0.03). Of the 98 pts with pos interm PET, 84 had a salvage of which 62 underwent auto PBSCT. On ITT the ORR (CR + Cru) was 82% and 76% in the R-CHOP and R-HDT arms respectively (p=0.8). With a med FU of 25 m, the 3y OS is 83%. No difference according to the tx arm in any of the aaIPI strata. The 3y PFS and DFS are 76% and 83%, no difference according to the tx arm. The 3 y OS and DFS for pts in R-CHOP arm and in R-HDT arm acc to interm PET are shown in the table. Conclusions: R-CHOP14 is as efficient, less toxic, and spares resources as compared to this R-HDT program. Salvage based on interm PET is not harmful and provides excellent results. PET neg PET pos R-CHOP 3y OS/DFS 88% / 80% 84% / 82% R-HDT 3y OS/DFS 80% /92% 86% / 89% J Clin Oncol 29: 2011 (suppl; abstr 8003)
  26. 26. Ann Oncol 2011;22(Suppl 4):072.
  27. 27. Randomized phase III U.S./Canadian intergroup trial (SWOG S9704) comparing CHOP ±R for eight cycles to CHOP ±R for six cycles followed by autotransplant for patients with high-intermediate (H-Int) or high IPI grade diffuse aggressive non-Hodgkin lymphoma (NHL). Results: Of 370 induction eligible pts 253 were randomized to standard (128) or transplant (125) therapies; 35% had High IPI Conclusions: For advanced stage H-Int and High IPI diffuse aggressive NHL, early autotransplant improves PFS for responders, including those induced with CHOP-R, with a stronger outcome seen for those with High IPI grade. J Clin Oncol 29: 2011 (suppl; abstr 8001)
  28. 28. High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non- Hodgkin Lymphoma (NHL) in adults (Review) Greb A, BohliusJ, Schiefer D, Schwarzer G, SchulzH, Engert A
  29. 29. Analysis 1.1. Comparison 1 Overall Survival, Outcome 1 Overall Survival - all studies. Review: High-dose chemotherapy with autologousstemcell transplantation in the first line treatment of aggressive Non-Hodgkin Lymphoma (NHL) in adults Comparison: 1 Overall Survival Outcome: 1 Overall Survival - all studies Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio (SE) IV,Fixed,95%CI IV,Fixed,95%CI De Souza -0.0807 (0.3672) 3.2 % 0.92 [ 0.45, 1.89 ] Gianni -0.6527 (0.385) 2.9 % 0.52 [ 0.24, 1.11 ] Gisselbrecht 0.3683 (0.1487) 19.5 % 1.45 [ 1.08, 1.93 ] Haioun -0.0387 (0.1529) 18.5 % 0.96 [ 0.71, 1.30 ] Intragumtornchai -0.448 (0.3852) 2.9 % 0.64 [ 0.30, 1.36 ] Kaiser 0.0761 (0.1834) 12.9 % 1.08 [ 0.75, 1.55 ] Kluin-Nelemans 0.2031 (0.2697) 5.9 % 1.23 [ 0.72, 2.08 ] Martelli -0.3773 (0.4473) 2.2 % 0.69 [ 0.29, 1.65 ] Martelli 2003 0.0087 (0.2748) 5.7 % 1.01 [ 0.59, 1.73 ] Milpied -0.4402 (0.2481) 7.0 % 0.64 [ 0.40, 1.05 ] Rodriguez 2003 0.2921 (0.3482) 3.6 % 1.34 [ 0.68, 2.65 ] Santini -0.2141 (0.2697) 5.9 % 0.81 [ 0.48, 1.37 ] Verdonck 0.3368 (0.329) 4.0 % 1.40 [ 0.73, 2.67 ] Vitolo 0.3412 (0.2749) 5.7 % 1.41 [ 0.82, 2.41 ] Total (95% CI ) 100.0 % 1.05 [ 0.92, 1.19 ] Heterogeneity:Chi2 = 18.55, df = 13 (P= 0.14); I2 =30% Test for overall effect: Z = 0.67 (P= 0.50) Test for subgroup differences:Not applicable 0.1 0.2 0.5 1 2 5 10 FavoursHDCT Favours control
  30. 30. Main results Fifteen RCTsincluding 3079 patientswereeligiblefor thismeta-analysis. Overall treatment-related mortality was6.0% in theHDT group and not significantly different compared to conventional chemotherapy (OR1.33 [95%CI 0.91 to 1.93], P= 0.14). 13 studies including 2018 patients showed significantly higher CR rates in the group receiving HDT (OR 1.32, [95% CI 1.09 to 1.59], P = 0.004). However,HDT did not havean effect on OS,when compared to conventional chemotherapy. ThepooledHRwas1.04 ([95% CI 0.91 to 1.18], P= 0.58). Therewasno statistical heterogeneity among thetrials. Sensitivity analysesunderlined therobustnessof theseresults. Subgroup analysisof prognostic groupsaccordingto IPI did not showany survival differencebetween HDT and controls in 12 trials(low and low-intermediate risk IPI: HR 1.41[95% CI 0.95 to 2.10], P= 0.09; high-intermediate and high risk IPI: HR 0.97 [95% CI 0.83 to 1.13], P = 0.71. Event-freesurvival (EFS) also showed no significant difference between HDT and CT (HR 0.93, [95%CI 0.81 to 1.07], P=0.31). Other possiblerisk factorssuch astheproportion of patient with diffuselargecell lymphoma, protocol adherence, HDT strategy, response status beforeHDT, conditioning regimens and methodological issueswere analysed in sensitivity analyses. However, therewasno evidencefor an association between thesefactorsand theresultsof our analyses. Authors’ conclusions . Despite higher CR rates, there is no benefit for high-dose chemotherapy with stem cell transplantation as a first line treatment in patientswith aggressiveNHL. DESPITE HIGH CR RATES, THERE IS NO BENEFIT FOR HIGH DOSE CHEMOTHERAPY WITH SCT AS A FIRST LINE TREATMENT IN PATIENTS WITH AGGRESSIVE NHL. P L A I N L A N G U A G E S U M M A R Y High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non-Hodgkin
  31. 31. Interpretation and Conclusions. Overall, the analysis of published evidence reveals very heterogeneous results and no overall survival benefit. Therefore, HDT/ASCT can-not be recommended as standard first line treatment for patients with aggressive NHL. However, the exploratory analyses presented here may help to design new trials for this treatment modality. Haematologica 2003; 88:1304-1315
  32. 32. SO, CURRENT EVIDENCES DO NOT SUPPORT HIGH DOSE THERAPY IN PATIENTS WITH AGGRESSIVE LYMPHOMA AS THERE IS NO SURVIVAL ADVANTAGE. WE NEED TO WAIT FOR SOME MORE TIME (!!) TILL THIS CAN BE CONSIDERED AS A STANDARD RECOMMENDATION. TILL THEN NO ASCT AT CR1 FOR AGGRESSIVE NHL IN CR1!!!!!!!
  33. 33. So Novel approaches may be the way • Antibody • Kinase Inhibitors • Immune Modulation • Other Targets
  34. 34. Newer Antibodies Drug • Ofatumumab [60] Anti-CD20 mAb R/R DLBCL II No ORR: 11%; CR: 4%; mDR: 6.9 months; mPFS: 2.5 months • GA101 [67] Anti-CD20 mAb R/R DLBCL and MCL II Yes EOTR: All: 28%; DLBCL: 29%; MCL: 27% • Veltuzumab [56] Anti-CD20 mAb R/R NHL I/II No ORR: DLBCL: 43%; MZL: 83%, including CR/CRu: 33% ORR: FL: 44%, including CR/CRu: 27% • Epratuzumab [69] Anti-CD22 mAb R/R NHL (with rituximab) II No ORR: 47%; DLBCL: CR: 33% • Epratuzumab [70] Anti-CD22 mAb Previously untreated DLBCL (with R-CHOP) II No ORR: 95%; CR/CRu: 73%; 1-year EFS rate: 80%; 1-year PFS rate: 82%; 1-year OS rate: 88% • Milatuzumab [57] Anti-CD74 mAb R/R NHL (with veltuzumab) I/II Dose-finding PR: 1/3 in Cohort 1 (8 mg/kg); 2/3 in Cohort 2 (16 mg/kg) • Dacetuzumab [77] Anti-CD40 mAb R/R DLBCL (with rituximab and gemcitabine)Ib Dose-findingORR: 54% • Lucatumumab [74] Anti-CD40 mAb R/R HL or NHL Ia/II Dose-finding RR: R refractory: 40%; ORR: DLBCL: 11% (phase Ia); ORR: DLBCL: 15% (phase II) • Blinatumomab (MT103) [83]Single-chain bispecific anti-CD19 and CD3 mAb construct R/R NHL I Dose-finding FL: 11/21 responses; MCL: 3/21 responses
  35. 35. Newer Antibodies • Drug Eligibility (and design) RandomizedResults • I-131 tositumomab Previously untreated DLBCL (with R-CHOP) No 1-year PFS rate: 75%; 1-year OS rate: 83% • Inotuzumab ozogamicin CD22 targeted cytotoxic immunoconjugate R/R CD22+ and CD20+ NHL (with R) I No ORR: 80%; 1-year PFS rate: 89% • Inotuzumab ozogamicin CD22 targeted cytotoxic immunoconjugate R/R CD22+ and CD20+ DLBCL prior to HDT-ASCT (with R) No ORR: 21% • 90Y-epratuzumab tetraxetan [92] Radiolabeled humanized anti-CD22 mAb R/R NHL I/II Dose-finding ORR: 62%; CR/CRu: 48%; mPFS: 9.5 months • 90Y-epratuzumab tetraxetan [97] Radiolabeled humanized anti-CD22 mAb Consolidation after first-line R-CHOP in DLBCL II No Improved remission status 6 weeks after RIT: 30.7% • Brentuximab vedotin (SGN-35) [104] Antitubulin monomethyl auristatin E (MMAE) anti-CD30 mAb conjugate R/R lymphoma I ORR: 46%; CR: 29%
  36. 36. Current Trials with novel Approaches • • Enzastaurin DLBCL –CR1 after R-CHOP NCT00332202 PRELUDE Ongoing; not recruitingNA • • Inotuzumab ozogamicin + R versus investigator's choice of gemcitabine + R or B + RR/R aggressive NHL NCT01232556 Recruiting NA • Single-agent pixantrone dimaleate versus investigator’s choice therapy [49] Third-line treatment of R/R aggressive NHL NCT00088530 EXTEND (PIX301) Completed; final results presented at ASH 10 Pixantrone superior to other single-agent therapies • Pixantrone + R versus gemcitabine + R R/R DLBCL patients not eligible for SCT NCT01321541 PIX-R (PIX306) Recruiting NA
  37. 37. Kinase Inhibitors in Aggressive NHL • Dinaciclib [183] CDK1, 2, 5, 9 inhibitor R/R in low-grade lymphoma and DLBCL I No PR: DLBCL: 1/7; SD: FL: 2/7; MCL: 1/1 • Fostamatinib [198] Syk inhibitor R/R B-cell NHL and CLL I/II No ORR: DLBCL: 22%; FL: 10% SLL/CLL: 55% in SLL/CLL: MCL: 11%; overall mPFS: 4.2 months • Dasatinib [202] RTK inhibitor of BCR-ABL, SRC, c-Kit, PDGF and ephrin receptor kinases R/R NHL I/II No ORR: 32%; 2-year PFS: 13%; 2-year OS: 50% • Enzastaurin [201] Protein kinase beta inhibitor R/R DLBCL II No FFP: 22% • PCI-32765 [204] Bruton’s tyrosine kinase inhibitor R/R B-cell NHL I Dose-finding ORR: 43% • SB1518 [208] JAK2 inhibitor R/R lymphoma I Dose-finding PR: 3/26 (2 in MCL) • Sorafenib [221] TKI inhibitor of RAF/MEK/ERK/c-kit/Flt3, VEGFRs, PDGFRs, RET R/R NHL II No ORR: 10%; CR: 5% • Sorafenib [222] TKI inhibitor of RAF/MEK/ERK/c-kit/Flt3, VEGFRs, PDGFRs, RET R/R lymphoma (with Akt inhibitor perifosine) II No ORR: 23% (all PR; all in HL) • Sorafenib [223] TKI inhibitor of RAF/MEK/ERK/c-kit/Flt3, VEGFRs, PDGFRs, RET R/R MM or lymphoma (with mTOR inhibitor everolimus) I/II Dose-finding ORR: 33%
  38. 38. Targeted Therapies • Drug MOA (target)Eligibility Phase Randomized Results • Bortezomib [127] Proteasome inhibitor Previously untreated DLBCL (with R-CHOP) I/II Dose-finding CR/CRu: 92% • Bortezomib [128] Proteasome inhibitor R/R DLBCL (with chemotherapy) II No ABC versus GCB: ORR: 83% versus 13%; mOS: 10.8 versus 3.4 months • Everolimus [151] mTOR inhibitor R/R NHL II No ORR: 30%; mDR: 5.7 months • Everolimus [152] mTOR inhibitor R/R NHL I 2 dose cohorts2 responses in DLBCL and 2 responses in FL, in 13 patients • Temsirolimus [154] mTOR inhibitor R/R NHL (with rituximab) II No ORR: 59%; CR: 19%; PR: 40% • Vorinostat [167]Deacetylase inhibitor R/R lymphoma (with R-ICE) I No 19/27 responses • Vorinostat [168]Deacetylase inhibitor R/R lymphoma (with DOXIL) I Dose-finding 4/14 disease control • Oblimersen sodium [183] Bcl-2 antisense oligonucleotide R/R B-cell NHL (with R) II No ORR: 42%; ORR in FL: 60% • PF-3512676 [209] TLR9-antagonist R/R NHL (with R) I Dose-finding ORR: 24%; ORR in extended treatment cohort: 50% • Bevacizumab [221] Anti-VEGF mAb Previously untreated DLBCL (with R-CHOP) II No 1-year PFS rate: 77%; 2-year PFS rate: 69%; 1-year OS rate: 86%; 2-year OS rate: 79% • Aflibercept [220] VEGF fusion protein Previously untreated B-cell lymphoma (with R-CHOP) I Dose-finding ORR: 100%; CR: 80%
  39. 39. Immunomodulatory Agents • Drug Eligibility Phase Randomized Results • Lenalidomide aggressive NHL II No ORR: 35%; CR/CRu: 12%; mDR: 6.2 months; mPFS: 4.0 months • Lenalidomide aggressive NHL II No ORR: 35%; CR/CRu: 13%; mPFS: 3.5 month5.6 month • Lenalidomide Previously untreated DLBCL (with R-CHOP21) I/II Dose-finding CR: 15/21; PR: 1/21
  40. 40. Summary • In ‘ R “ Era novel approaches may be the way to go. • Newer trials will mature and may HELP us or Confuse us. • Data may not be extrapolated across the IPIs or subtypes
  41. 41. ACKNOWLEDGEMENT • Patients and Family members • My teachers from CMC Vellore & Westmead Hospital , Sydney. • Nursing and Medical Teams, SSH • Blood Bank & Pathology teams , SSH • Administrative staff and SSH • Megh Apte & Dr. Netra Apte,Parents

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