Hodgkin Lymphomas: An Update

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1 Hodgkin Lymphomas: An Update Roberto N. Miranda, M.D. Professor UT MD Anderson Cancer Center November 10 th, 2018

2 Disclosures Scientific Advisory Board, Allergan Inc, 2018

3 Hodgkin Lymphomas Classical Hodgkin Lymphoma (CHL): 90% Nodular sclerosis Mixed cellularity Lymphocyte rich Lymphocyte depleted Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL): 10% A & B: Typical C F: Variants

4 Outline CHL Clinical, histopathology, immunophenotype Therapy Pathogenesis Cell of origin Cell biology and molecular targets Loss of B-cell antigens Proliferative advantage Microenvironment HL and immunodeficiency

5 CHL: Definition Nodal disease Neoplastic cells are a minority in the infiltrate (< 10%) Majority of the cells in infiltrate are reactive Small lymphocytes, eosinophils, neutrophils, histiocytes, plasma cells, and fibroblasts WHO 2008 Revised WHO 2017

6 CHL: Neoplastic Cells Mononuclear: Hodgkin cell Multilobated: Reed-Sternberg cell Rare neoplastic cells: %

7 Immunophenotype CD30+ PAX5+ CD15+ CD45-

8 Other Useful Markers EBER+ MUM1+ CD79- OCT2-

9 Background Cells CD4

10 Subtypes Nodular sclerosis (NS) 66% Mixed cellularity (MC) 27% Lymphocyte-rich (LR) 6% Lymphocyte-depleted (LD) 1% Differences: Clinical features Histopathology EBV association

11 Nodular Sclerosis HL Median age, 28 years No male predominance Stage II disease in most patients Mediastinal involvement in 80% B-symptoms in 40%

12 Nodular Sclerosis HL

13 Nodular Sclerosis HL: Syncytial Variant CD30

14 Syncytial Variant Compared with typical NSHL Lower complete response rate to ABVD 74% vs 87% Higher Progression free survival 17 months vs not reached Sethi T et al. Ther Adv Hematol 2017; 8: 13

15 Mixed Cellularity HL Median age, 37 years Male predominance Stage III or IV B-symptoms more frequent than in NS Mediastinal LNs uncommon EBV+ ~70%

16 Mixed Cellularity HL EBER LMP1

17 Lymphocyte-rich HL Nodular >> Diffuse

18 Lymphocyte-Rich HL Nodular pattern CD20 CD30

19 Lymphocyte-Depleted HL Advanced age B-symptoms (80%) Stage III or IV disease Extensive subdiaphragmatic disease Abdominal LNs Most aggressive form of HL Very rare

20 Lymphocyte Depleted HL Diffuse fibrosis: Fibroblastic proliferation Reticular: Abundant HRS cells

21 HL: Therapy Chemotherapy (ABVD or BEACOPP) + Radiation: Standard of care in USA 90% 5-y OS 60% 5-y FFS Chemotherapy alone for early stage HL Nat Oncol 2008; 5:543

22 CHL: Prognosis Current therapy has made HL curable in the majority of cases Histologic subtype is currently less relevant for prognosis Combined pathologic, laboratory, clinical stage appear more important than histologic subtype, and determine mode of therapy

23 Secondary MDS/AML in German GHSG Trials N= 11, (0.72% developed MDS/AML) Early stages: 6 < 4 cycles Intermediate stage: 18 Advanced stage: 62 > 4 cycles Eichenauer, Blood 2010

24 Stanford V CHL Therapy Lower cumulative doses of chemotherapy (adriamycin or bleomycin) to reduce risks of Acute leukemia, MDS Cardiopulmonary toxicity Lessen volume and dose of Radiation to reduce risks of Second cancers Cardiovascular toxicity

25 CHL Therapy Challenges for the future Risk assessment to decrease secondary toxicity Hope in targeted therapy

26 Targeted Therapy: Vedotin Brentuximab (Anti-CD30) Auristatin is bound to anti-cd30 Potent anti-tubulin (vincristine like) arrests G2-M phase and triggers apoptosis FDA-approved for relapsed and refractory CHL Studies underway for other CD30+ lymphomas of B- or T-cell lineage Exp Op Inv Drugs 2011; 20: 141 Berger et al. Crit Rev Oncol/Hem 2017 Viviani et al. Tumori 2017; 103: 101

27 Pathogenesis of HL Nature of the malignant cell B-cell, very abnormal, pre-apoptotic Many reactive cells HRS cells secrete cytokines that attract inflammatory cells: IL-4, IL-5, TNF-α, GM-CSF

28 Cell Biology of HRS Cells

29 Clonality Studies in CHL Single cell PCR analysis J Exp Med 1996; 184: 1495

30 Single Cell Analysis in CHL Antigen receptor-genes HRS cells show clonal Ig gene rearrangements Somatic mutations of V H immunoglobulin genes The rearranged Ig genes harbor a high load of somatic mutations

31 HRS Cells are GC B-Cells HRS Cell Somatic Mutations Yes Ongoing Mutations No Ig mrna No mrna crippling mutations 25% OCT-2 & BOB.1 No Functional Rearrangement No HRS Cell: Pre-apoptotic GC cell

32 HRS are GC B-cells Somatic Hypermutation Favorable PC or Memory B-Cell Naïve B-cell GC Unfavorable Apoptotic Cell HRS Cell

33 What is the cause of B-cell Downregulation in CHL? CD20 (-) Pax-5 dim (+) Leukemia 2008; 22: 1587 Nat Immunol 2006; 7:207

34 Downregulation of B-cell genes CD19, CD20 and CD79a Aberrant expression of Id2 and ABF1 Inactivate E2A (Early B factor) Notch-1 antagonizes B-cell transcription factors E2A and EBF (early B-cell factor) Leukemia 2008; 22: 1587 Nat Immunol 2006; 7:207

35 B-cell Downregulation in HL Id2 E2A ABF1 E2A B-CELL GENES PU.1 PAX5 NOTCH1 E2A OCT-2 EBF BOB.1 NOTCH1 Ann Rev Pathol Mech Dis 2009; 4: 151

36 Does Reconstitution of BOB.1 and No OCT-2 lead to Ig production? This finding suggests the presence of other mechanisms such as: Epigenetic changes: Inactive chromatin Inhibition of transcription Blood 2004; 104: 3326

37 Methylation: Epigenetic Silencing Loss of function as a mechanism of carcinogenesis, but without changing DNA sequence Results from aberrant methylation of promoters of genes in regions rich with CpG (Cytidine Guanidine dinucleotide)

38 Epigenetics in HL Downregulation of B-cell transcription factors BCMA LCK SYK TCL1 Downregulation of B-cell genes CD19 CD79a Ig Leukemia 2008; 22: 835

39 Hypomethylation in CHL In refractory CHL Heavily treated Partial response to azacytidine (Hypomethylating agent) Falchi et al. J Hematol Oncol 2016; 30: 132

40 Blood 2012; 119: 4017 Am J Hematol 2012; 87: 277 Exp Op Inv Drugs 2011; 20: 141 Targeted Therapy in HL Histone deacetylases inhibitors Panobinostat: 86% response rate in ASCT failures

41 Consequences of Apoptosis and B-Cell Downregulation Cell death However HRS cells survive Antiapoptosis Extrinsic Pathway Intrinsic Pathway Proliferation signals NFkB Canonical pathway Alternative pathway Hum Pathol 2007; 38:103

42 Proliferative advantage in CHL: Activation of NFκB pathway NFkB pathway may be a transforming master in CHL NFkB is a family of transcription factors involved in activation and survival of immune cells Abnormally activated in HL Other factors: JAK/STATs and AP1

43 Targeted Therapy in HL NFkB Pathway Arsenic-containing compounds Target IKK and downregulate NFkB pathway Bortezomib: May be useful in combination Blood 2012; 119: 4017 Am J Hematol 2012; 87: 277 Exp Op Inv Drugs 2011; 20: 141

44 The Microenvironment in HL

45 Role of the Microenvironment in HL Reactive cellular infiltrate Favors neoplastic proliferation Cytokines, chemokines and members of the TNF receptor family Foster a favorable environment around HRS cells Inhibit CD8 function J Clin Oncol 2005; 23: 6379

46 PD1, PDL-1 and the Immune Checkpoint Inhibitors in CHL PD1 is normally expressed in effector T cells, but inhibited through PDL-1/2 by APC cells HRS cells express PDL-1/CD274, PDL-2/CD273 JAK2 (JAK/STAT) Tumor cells overexpress PDL-1 to evade immune response Viviani et al. Tumori 2017; 103: 101 Ok & Young; J Hem Oncol 2017; 10: 103

47 Immune Checkpoint Inhibitors in HL PDL-1 or PDL-2 increase due to gains and amplification of 9p24.1 EBV can induce PDL-1 expression Immune checkpoint inhibitors nivolumab and pembrolizumab restore immune response Block interaction of PD1 with PDL-1 FDA approved in 2016 for refractory HL Green et al. Clin Cancer Res 2012; 18: 1611 Ok & Young; J Hem Oncol 2017; 10: 103 Jelinek T et al. Immunology 2017; 1

48 Role of EBV LMP-1 EBV encoded RNA (EBER) (Most sensitive test)

49 CHL: EBV 70% in MC and LD CHL 20% in NS CHL EBV infected HRS Are monoclonal: Infection occurred before clonal expansion LMP1: Activation (~CD40) LMP2A: Rescue from apoptosis (~BCR) J Clin Pathol 2007; 60: 1342

50 Targeted Therapy for EBV EBV LMP2A-specific cytotoxic lymphocytes Useful in relapsed EBV+ cases Microenvironment Immunomodulators: Thalidomide, lenalidomide Exp Op Inv Drugs 2011; 20: 141

51 Cellular Changes and Possible Mechanisms Feature B-cell Neoplasm HRS Cell CD45 (-) Absent Ig B-cell Downregulation Antiapoptosis Increased proliferation Activation: CD40 Mechanism Monoclonal IGH GR GC cell rescued from apoptosis Inactivation of b2m Absent OCT2, BOB.1, PU.1 NOTCH1, ID2 c-flip, XIAP, LMP2A NFkB LMP1

52 Evolving Concept HL and Immunodeficiency

53 HL and Immunodeficiency CHL is variable Immunocompetent: NS > MC Immunosuppressed: MC > NS HIV: If CD4+: 0.2 x 10 9 /L: HL <0.05 x 10 9 /L: BL or DLBCL HL may regress in: Patients with autoimmune diseases receiving MTX, anti-tnf Post-transplant LPD Decrease with reduction of immunosuppression

54 Case Discussion Adult patient with a history of rheumatoid arthritis Therapy with methotrexate and etanercept (anti-tnfα) Lymphadenopathy with B-symptoms

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56 CD30 CD15 EBER CD45

57 WHO Entity: Other iatrogenic immunodeficiencyassociated LPD Immunosuppression other than in transplant MTX Immunomodulators: Anti-TNFα Polymorphic to full-blown NHL or HL 40% extranodal: GI, skin, liver, spleen

58 Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL)

59 NLPHL Sites: Cervical, axillary, inguinal nodes Mostly males in 4 th and 5 th decades Rare in mediastinum, spleen and BM Most patients present in stage I or II 5 20 % present with stage III or IV Natural history: Slow development Frequent relapses, but rarely fatal WHO, 2008

60 NLPHL Nodular or nodular and diffuse pattern Large cells: LP or popcorn cells Contained within large nodular meshworks of dendritic cells LP cell is a B cell, CD20 in 100% of cases Reactive background: mainly B lymphocytes CD15 (-) / CD30 (-)

61 Histopathology Nodules are larger than follicles of follicular lymphoma or follicular hyperplasia

62 Histopathology LP cells surrounded by small lymphocytes

63 CD20 CD20 Nodules are composed mainly of B cells LP cells are CD20+

64 CD57 CD21 Rossettes Meshwork

65 OCT-2 and BOB.1 OCT-2 is a transcription factor that induces Ig synthesis by activating the promoter of the Ig genes in conjunction with BOB.1 (+) 100 % in NLPHL Stronger in LP cells > surrounding small B- cells (+) 20 % in CHL Blood 2001; 97: 496 Eur J Haematol 2000; 30:

66 NLPHL: Variant Patterns 137 biopsies Used H&E, CD3, CD20 and CD21 6 immunoarchitectural patterns A. Nodular B-cell rich B. Serpiginous C. Nodular with prominent extranodular LP cells D. Nodular T-cell rich E. Diffuse with increased T-cells: THRBCL-like F. Diffuse with B-cell rich pattern Fan et al, Am J Surg Pathol 2003: 27: 1346

67 A. Typical Nodular Pattern

68 A. Typical Nodular B-cell Rich Popcorn cells B-cell nodules Interfollicular T-cells CD21 Meshwork 67 % of all cases

69 A. Typical Nodular B-cell Rich CD20

70 B. Serpiginous : Interconnected Nodular CD20 6 % of all cases

71 C. Nodular with prominent extranodular L&H cells CD20 7 % of all cases

72 D. Nodular T-Cell Rich CD3 12 % of all cases

73 E. Diffuse T-Cell Rich (THRBCL-like) CD20 12 % of all cases More common in patients with recurrent disease (p<.003)

74 E. Diffuse T-Cell Rich-like vs THRBCL The detection of one nodule typical of NLPHL in an otherwise diffuse THRBCL excludes the diagnosis of THRBCL Reactive lymphocytes are CD8 (+), TIA-1 (+) in TCRBCL vs CD4 (+), CD57 (+) in NLPHL WHO 2008, 2016 Blood 2000; 96:

75 F. Diffuse B-Cell Rich mottled pattern 1 % of all cases CD21 meshworks are detected

76 NLPHL: Prognosis Stage I and II: > 90 % survival at 10 years Not established if immediate therapy is required for stage I disease in children Stage III or IV: Unfavorable prognosis Progression to DLBCL: 3 5 % Good prognosis if localized

77 Prognosis of NLPHL: Typical vs Variants German Hodgkin Study Group, 423 pts Typical NLPHL: Patterns A and B (n= 308) Variants: Patterns C, D, E and F (n= 105) Adverse prognosis in variants > Advanced disease: 29.5% vs 14.6% > Relapse rate: 18.1% vs 6% Hartmann S et al. Blood 2013; 122: 4246

78 LRHL vs NLPHL Overall Survival Failure-free Survival

79 Summary HLs are heterogeneous B-cell neoplasms HRS cell: Pre-apoptotic cell Does not produce Ig and lacks many B cell genes Rescued with anti-apoptotic mechanisms Important role of targeted therapy NLPHL cell: Ag selected B-cell Produces Ig and has a full set of B cell functioning genes Predictive value of variants

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