Abc, gcb and doule hit diffuse large b
Download as PPTX, PDF8 likes2,058 views
- Diffuse large B-cell lymphoma (DLBCL) can be classified into molecular subtypes including germinal center B-cell-like (GCB) and activated B-cell-like (ABC) subtypes, as well as double hit lymphomas that have a poor prognosis. - New targeted agents in combination with R-CHOP have shown promising results for DLBCL subtypes, with proteasome inhibitors and immunomodulatory agents showing more activity in ABC DLBCL and BCL6 inhibitors, HDAC inhibitors, and etoposide showing potential in GCB DLBCL. - For double hit and MYC-positive lymphomas, intensive chemotherapy such as dose-adjusted
Abc, gcb and doule hit diffuse large b
- 1. тАЬABC, GCB and Double-Hit diffuse large B cell lymphoma: Does subtype make a difference in Therapy Selection?тАЭ Journal Club Moderator: Dr. Suresh Babu MC Presenter: Dr. Gita R Bhat
- 2. Authors: Grzegorz S. Nowakowski, Myron S. Czuczman ASCO 2015, Educational Book
- 3. Overview тАв Personalized therapy for treatment of patients with cancer is rapidly approaching and is an achievable goal in the near future. тАв DLBCL is the most common NHL тАв 40% patients have refractory disease or disease that will relapse after initial response тАв 2 major biologically distinct molecular subtypes of DLBCL: GCB and ABC тАв Double hit lymphomas (approx 5%-10%) of patients and double expressor lymphomas are aggressive and associated with poor prognosis. тАв Early clinical trials evaluating combination of novel targeted agents in combination with R-CHOP have shown encouraging results. тАв Hence, molecular classification: Prognostication + personalization of therapy for DLBCL.
- 4. тАв Addition of rituximab (R) to CHOP in patients with DLBCL: dramatic improvements in PFS and OS. тАв Inspite of this, 40% relapse or have refractory disease. тАв Various strategies to improve outcomes: intensification of chemotherapy, use of maintenance therapy, novel agents.
- 5. тАв Alternate regimens for front-line R-CHOP : тАв Dose тАУdense R-CHOP 14: Phase III trial showed no additional clinical benefit тАв Dose-adjusted R-EPOCH тАв R-CEOP 90 тАв Phase III trial: 1080 patients тАУ No additional clinical benefit was observed in patients treated wih R-CHOP14 vs. R-CHOP21.
- 6. тАв Addition of novel agents (X) to R-CHOP: тАв XR-CHOP тАв тАЬDLBCL has molecular heterogeneityтАЭ тАв тАЬX тАУ targets specific oncogenic pathwaysтАЭ
- 8. тАв Classification of DLBCL based on the cell of origin (COO): тАв GCB (CD10, BCL6) тАв Non-GCB ABC (poor outcome) Primary mediastinal B-cell types тАв Associated with differences in clinical outcome
- 9. GCB DLBCL ABC DLBCL Markers of germinal centre differentiation (CD10 and BCL6) - - NF-╬║B pathway is constitutively active High expression of NF-╬║B genes BCL2 + BCL2+ (> 4 fold higher than in GCB DLBCL) Arises from germinal centre B cell Post-germinal centre B cell, blocked during plasmacytic differentiation Outcome of GCB DLBCL and ABC DLBCL treated with RCHOP
- 10. Primary mediastinal B cell lymphoma Arises from Thymic B cell Predominantly in young women Shares many features with CHL-NS OCT-2 and BOB-1 (B cell transcription factors) are positive, Immunoglobulin production is defective
- 11. Agents predominantly active in Non-GCB (ABC) DLBCL тАв Pathways that are constitutively activated in ABC DLBCL: тАв B-cell receptor (BCR) pathway тАв Pathways downstream of BCR pathway тАв Constitutive activation of NF-kB genes тАв Proteasome inhibitors тАв Immunomodulatory agents тАв B-cell receptor signaling pathway inhibitors
- 12. B-cell receptor pathways тАв Plays an important role in proliferation and survival in B-NHL тАв Targets: тАв Spleen tyrosine kinase (SyK): Survival тАв Bruton tyrosine kinase (BTK): BCR signaling and maturation
- 13. Proteasome inhibitors тАв Inhibit transcription factor NFkB тАв Downstream pathway of BCR pathway тАв Bortezomib combined with DA-EPOCH: тАв ORR: GCB DLBCL (13%) vs. ABC DLBCL (83%) тАв Median OS: GCB (10.8 months) vs. ABC ( 3.4 months)
- 14. IMiDs тАв Structural and functional analogues of thalidomide тАв Regulate production of T-helper cells тАв Inhibit cytokine production тАв Inhibit production of TNFa тАв Induce G0/G1 cell cycle arrest тАв Inhibit angiogenesis through suppression of VEGF and FGF тАв Decrease NFkB activity
- 15. тАв Single agent Lenalidomide in relapsed refractory/refractory NHL including DLBCL тАв Phase II study, n= 217 patients тАв DLBCL subpopulation: median PFS (2.7 months) and Response duration (4.6 months)
- 16. B-cell receptor signaling pathway inhibitors - IBRUTINIB тАв Bruton tyrosine kinase inhibitor тАв Forms covalent bond with cysteine -481 in BTK тАв High BTK specificity тАв Daily oral dosing produces 24-hour BTK inhibition тАв Blocks NF-kB activation in ABC DLBCL тАв Phase II study: ORR 22%, CR 5%, PFS: 1.6 months (relapsed/ refractory DLBCL)
- 17. тАв SYK inhibitor: FOSTAMATANIB тАв Phase II study, 23 patients тАв Median PFS 2.7 months тАв ORR: 22%
- 18. Agents with potential activity in GCB DLBCL тАв GCB DLBCL has better outcomes than ABC subtype тАв 20% of patients with GCB DLBCL relapse after R-CHOP or R-CHOP like chemotherapy тАв Associated with poor outcomes
- 19. тАв BCL6: highly expressed in GCB subtype тАв Key transcription factor тАв Translocations/ mutations enhance the inhibitory effect of BCL6 on apoptotic stress response тАв This leads to tumor proliferation and treatment failure
- 20. Therapeutic implications A) Small molecule inhibitor of BCL-6: тАв 79-6 complex тАв Binds to the co-repressor binding groove of the BCL6 domain and kills BCL-6 positive lines B) HDAC inhibitors to overcome the effects of BCL6 repression on p53
- 21. тАв C) Etoposide: Topoisomerase II inhibition тАУ ubiquitin mediated protein degradation and transcriptional inhibition --- downregulates BCL6 тАв DSHNHL study: better EFS in those who received CHOEP vs. CHOP alone тАв GCB DLBCL has higher incidence in younger patients, hence they benefit more from the addition of Etoposide.
- 22. тАв D) DA-EPOCH-R тАв Inhibition of Topo II is optimised by continuous delivery of drugs over 96 hours тАв This ensures steady state concentration тАв 5 years of follow-up: EFS (95% to 100%) тАв E) EZH2: EZH2 inhibitors тАв Gain of function mutations in EZH2 result in increased H3K27 methylation
- 23. BCL2 inhibitors тАв Members of BCL-2 family (BCL-2, BCL-XL, BCL-w, MCL- 1, BFL1/A-1, and BCL-B): тАв Suppress apoptosis through interaction with, and inactivation of, pro-apoptotic proteins such as BH3 тАв BCL2 inhibitors are active in ABC and GCB DLBCL тАв In GCB: BCL2 is overexpressed as a result of translocation тАв In ABC: BCL2 is overexpressed at the protein level тАв ABT-737 and ABT-263: target BCL-2, BCL-Xl and BCL-w тАв ABT-199: potently and selectively inhibits BCL2
- 24. Front-line treatment: XR-CHOP тАв Bor-RCHOP тАв R2-CHOP тАв IR-CHOP
- 25. Bor-RCHOP тАв Untreated DLBCL or mantle cell lymphoma тАв Ongoing Phase III RCT: CHOP vs. Bor-RCHOP in DLBCL ORR тАУ 100% CR or Cru: 86% 2-year PFS: 64% 2-year OS: 70%
- 26. R2-CHOP тАв R2-CHOP: тАв Lenalidomide-RCHOP тАв Improves the poor prognosis usually reported in non-GCB DLBCL тАв Grade 3 and 4 AEs: Neutropenia (31%), leucopenia (28%), thrombocytopenia (13%)
- 27. тАв Phase II trial: newly diagnosed DLBCL тАв Treated with R2-CHOP vs R-CHOP тАв Addition of Lenalidomide can improve the poor prognosis in non-GCB population 2-year OS GCB DLBCL Non-GCB DLBCL R2-CHOP 75% 83% R-CHOP 78% 46%
- 28. тАв IR-CHOP: тАв Phase I randomized trial, 33 patients тАв Newly diagnosed DLBCL (22 patients) , Mantle cell lymphoma, Follicular lymphoma тАв ORR 100% (CR 64% and PR 36%) тАв Most common AEs: Neutropenia, nausea, thrombocytopenia, vomiting, anemia
- 29. тАв IR-CHOP: тАв BrutonтАЩs tyrosine kinase inhibitor тАв Ibrutinib тАв Phase Ib: Newly diagnosed DLBCL, mantle cell lymphoma, follicular lymphoma
- 30. MYC-positive and Double-hit DLBCL тАв MYC is a transcription factor тАв Potent proto-oncogene тАв Regulates 10%-15% of human genome тАв Member of the helix-loop-helix leucine zipper family of nuclear transcription factors тАв Key to formation and maintenance of germinal centres
- 31. тАв It can be activated via 3 modes: тАЬAvalanche effectтАЭ тАв Translocation (5% - 14%) тАв Copy gain (19% to 38%) тАв Amplification (2%) тАв Mutation (32%)
- 32. Target genes of MYC Process involved Function Target genes induced Target genes repressed Cell cycle Transit through cell cycle G0 to S transition Cyclin D2, CDK4 P21, p15, GADD45 Differentiation Blocks many cellular systems LDH, ribosomal proteins, EIF4E, EI2A Growth and metabolism Increase in cell size and number N-cadherin, integrin Adhesion/migration Enables anchorage dependent growth Thrombospondin Angiogenesis Induces angiogenesis IL 16, mir 17-92 Chromosomal instability Telomere aggregation, ROS production MAD2, TOP1, BUBR1, Cyclin B1 Stem cell self renewal Potentiates induced pluripotent stem cells ? ? Transformation Drives tumorigenesis Several genes Several genes
- 33. MYC-associated pathways of regulation of proliferation and survival
- 37. Neoplasms with MYC gene rearrangements тАв Burkitt lymphoma тАв t(8;14) тАв Simple karyotype тАв Sole chromosomal abnormality тАв DLBCL (7% - 14%) тАв Unclassifiable B-cell lymphoma (35%) тАв Plasmablastic lymphoma (50%) тАв Plasma cell myeloma (15% - 50%) тАв Mantle cell lymphoma тАв Complex karyotype тАв Secondary genetic events
- 38. Why is this important?
- 39. тАв MYC rearrangement predicts an inferior outcome in DLBCL тАв These are seen in 58% - 83% of MYC-translocated DLBCL тАв OS when treated with RCHOP is тЙд 12 months ? Due to the MYC rearrangement itself Double hit DLBCL тАв Concurrent BCL2 translocation тАв Less likely BCL6 Triple hit DLBCL тАв Concurrent translocations in MYC+ BCL2 +BCL6
- 41. Concurrent MYC + BCL2 MYC 1) Cell growth 2) Cell cycle transit 3) Angiogenesis BCL2 1) Increased anti- apoptosis (drug resistance)
- 42. тАв Double-expressor lymphomas: тАв High percentage of MYC and BCL2 protein тАв By IHC staining тАв Tumor cells should express at least 40% MYC and at least 50% to 70% BCL2 positivity тАв These are primarily ABC-like тАв R-CHOP or CHOP-like chemotherapy: inferior OS and PFS
- 43. FISH vs IHC for detecting Double hit DLBCL тАв ? Effect of MYC alone (FISH or IHC) without BCL2 on outcome тАв BCL2+ MYC by IHC or FISH has worst outlook тАЬAssessment of MYC and BCL2 expression by IHC represents a robust, rapid, and inexpensive approach to risk-stratify patients with DLBCL at diagnosisтАЭ
- 44. тАв DHL patients have several poor prognostic factors: тАв Median age: 7th decade тАв Stage III/IV disease тАв IPI: High intermediate/high тАв Elevated LDH тАв High frequency of extra-nodal sites (excluding CNS)
- 45. тАв Of the several intensive chemotherapy regimens used: тАв R-EPOCH тАв (1) has curative potential in BL тАв (2) is better tolerated than most dose- intensive regimen тАв (3) appears to have similar efficacy compared to other dose-intensive therapies
- 46. Combination chemotherapy in Double-hit lymphoma
- 47. Initial therapy for Double hit lymphoma тАв Petrich AM et al. Blood 2014; 124:2354-2361 тАв Retrospective study of outcomes in 23 US centres over 12 years: тАв 311 patients with newly diagnosed DLBCL (154), BCLU (150), FL (7) тАв MYC-R and BCL2 (87%) or BCL6 (5%) by FISH/cytogenetics тАв 76% raised lDH, 33% тЙе3* ULN тАв 65% stage IV, 41% BM +ve, &% CNS +ve
- 49. Comparison of long-term, progression-free, and overall survival. Adam M. Petrich et al. Blood 2014;124:2354-2361 ┬й2014 by American Society of Hematology
- 50. Role of stem cell therapy тАв Autologous SCT in those who achieve CR: тАв Does not significantly change clinical outcomes тАв Inherent rapid tumor cell growth and inherent drug resistant DHL cells (Minimal residual disease)
- 51. тАв Allogenic SCT is unlikely to have a major effect since: тАв 1) limited data from a small number of selected patients тАв 2) the risk of relapsed disease while awaiting graft-vs-lymphoma to occur тАв 3) the need for a suitable HLA-compatible donor тАв 4) chronic GvHD
- 52. Overall survival by SCT versus observation in first complete remission. Adam M. Petrich et al. Blood 2014;124:2354-2361 ┬й2014 by American Society of Hematology
- 53. тАв Adverse factors for OS at diagnosis: тАв Leukocytosis тАв LDH >3*ULN тАв Advanced Ann Arbor stage тАв CNS involvement
- 54. тАв Hence, тАв DA-R-EPOCH induction + CNS prophylaxis is a reasonable approach тАв Further escalation of chemotherapy, especially in the salvage setting is unlikely to be of benefitтАж. Hence, novel agentsтАж
- 55. Waiting in the wingsтАж.
- 56. ABT - 199 Platelet sparing BCL2 inhibitor (BH3 mimetic) restores apoptosis Bromodomain inhibitors Down-regulation of MYC-associated transcription: Decreased cell proliferation and inhibition of MYC-driven neoplasms CAR-T cells Autologous T-cell mediated killing of CD19-positive lymphoid neoplasm Aurora kinase inhibitors (Alisertib) Aurora kinase is required for tumor maintenance of MYC- driven lymphoma mTor inhibition mTor plays an important role in tumor maintenance by MYC in B lymphocytes Second generation Proteasome inhibitor (Ixazomib) Degrade MYC and can induce lymphoma cell death PI3K inhibition In GCB-DLBCL: Loss of PTEN leads to activation of PI3K/AKT pathway ___ MYC upregulation Inhibition of mitochondrial peptide deformylase Apoptosis in MYC-over expressing hematopoietic neoplasms SIRT4 protein Suppresses tumor formation in MYC-induced B-cell lymphoma
- 57. Key points тАв ABC subset of DLBCL is biologically distinct тАв Associated with poor outcomes when treated with a standard therapy. тАв Activation of the clonic B-cell receptor pathway allows for therapeutic targeting. тАв Targeted agents in relapsed DLBCL can be combined with R-CHOP in front- line therapy of DLBCL. тАв The germinal center B-cell (GCB) subset of DLBCL is associated with better outcomes and may require different therapeutic approaches. тАв Double-hit lymphoma (DHL) is responsible for a substantial number of relapses in GCB DLBCL тАв All newly diagnosed DLBCL biopsy samples should be tested for DHL by fluorescent in situ hybridization and by immunohistochemistry for double- expressor DLBCL тАв Whenever possible, patients should be referred to participation in clinical trials тАв DHL: DA-R-EPOCH plus central nervous system prophylaxis until more effective novel targeted agents for this lymphoma subtype are developed
- 58. Thank you!
Editor's Notes
- #50: Comparison of long-term, progression-free, and overall survival. Kaplan-Meier curves comparing the long-term (A) progression-free survival (PFS) and overall survival (OS) of the entire cohort; PFS (B) and OS (C) by induction regimen; PFS (D) and OS (E) comparing R-CHOP with other intensified induction regimens (ie, DA-EPOCH, Hyper CVAD, and CODOX/M-IVAC).
- #53: Overall survival by SCT versus observation in first complete remission. Kaplan-Meier curves demonstrating overall survival (OS) by (A) use of SCT compared with observation among those in first complete remission (CR); OS by (B) those who were positive for central nervous system (CNS) involvement at the time of diagnosis compared with those who did and did not receive CNS-directed prophylaxis (PPX); and OS for (C) those with relapsed/refractory disease based on whether salvage therapy was administered (those who were not known to receive salvage therapy are included with those confirmed to have not received salvage therapy).