BHS Educational Course on Hodgkin lymphoma and aggressive lymphoma Special situations

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1 BHS Educational Course on Hodgkin lymphoma and aggressive lymphoma Special situations Daan Dierickx BHS Educational Course Seminar 12 Hof Ter Musschen, 7th March 2015

2 Special situations Primary central nervous system lymphoma (PCNSL) Posttransplant lymphoproliferative disorder (PTLD) AIDS related lymphoma (ARL)

3 Special situations Primary central nervous system lymphoma (PCNSL) Posttransplant lymphoproliferative disorder (PTLD) AIDS related lymphoma (ARL)

4 PCNSL definition and incidence Extranodal NHL limited to CNS (brain, cranial nerves, leptomeninges, CSF, intraocular structures, spinal cord) no systemic involvement (= secondary CNS lymphoma) Rare: <1% of all NHL 2-3% of all brain tumors

5 Question 1 What s the most important risk factor for development of PCNSL?

6 PCNSL risk factors Immunodeficiency states Congenital Acquired PTLD HIV EBV Immune competent patients Villano JL, et al. Br J Cancer 2011;105:

7 >95% DLBCL PCNSL presentation 20% intraocular involvement (rare: PIOL) Golden standard for diagnosis: stereotactic biopsy (ideal: without steroids) Staging: MRI brain with gadolinium (PET?+) CT whole body Bone marrow examination Slit lamp examination

8 PCNSL presentation Wang CC, et al. Br J Haematol 2014;166:311-25

9 PCNSL prognostic scores The International Extranodal Lymphoma Study Group (IELSG) prognostic index (0-5 scale) : Age > 60 yr, performance state (ECOG 2), LDH, elevated protein concentration in CSF and involvement of deep brain structures The Nottingham/Barcelona prognostic score (0-3 scale): Age >60 yr, performance state (ECOG 2), multifocal disease The Memorial Sloan Kettering Cancer Center (MSKCC) prognostic score (0-2 scale): : Age > 50 yr, performance state (ECOG 2) Ferreri AJ, et al. J Clin Oncol 2003;21: Bessell EM, et al, Int J Radiat Oncol Biol Phys 2004;59:501-8 Abrey LE, et al, J Clin Oncol 2006;24:5711-5

10 Question 2 Which therapeutic regimen is the backbone in the treatment of PCNSL?

11 PCNSL treatment Median OS: 12 months Majority (88%) of recurrences: within boost field Major problem: delayed neurotoxicity (especially > 60 years) Nelson DF, et al. Int J Radiat Oncol Biol Phys 1992;23:9-17

12 PCNSL adding chemotherapy to WBRT CHOD no survival benefit BBB HD-MTX based chemotherapy Marked survival benefit: median OS months Late neurotoxicity (up to 25%) Abrey L, et al. J Clin Oncol 2000;18: DeAngelis LM, et al. J Clin Oncol 2002;20:4643-8

13 PCNSL eliminating WBRT Multiple retrospective and prospective phase 2 trials: inferior outcomes Only 1 prospective phase 3 study: G-PCNSL-SG-1 trial Thiel E, et al. Lancet Oncol 2010;11:

14 PCNSL G-PCNSL-SG-1 trial: long term follow up Thiel E, et al. Lancet Oncol 2010;11: Korfel A, et al. Neurology 2015 Feb 25, [Epub ahead of print]

15 PCNSL G-PCNSL-SG-1 trial: long term follow up Thiel E, et al. Lancet Oncol 2010;11: Korfel A, et al. Neurology 2015 Feb 25.[Epub ahead of print]

16 PCNSL alternatives to WBRT Reduced dose radiotherapy (23.4 Gy) High dose therapy with autologous stem cell transplantation Non-myeloablative chemotherapy (etoposidecytarabine) Morris PG, et al. J Clin Oncol 2013;31: Omuro A, et al. Blood 2015 Jan 7. [Epub ahead of print] Rubenstein JL, et al. J Clin Oncol 2013;31:3061-8

17 Rituximab? PCNSL other questions Intrathecal chemotherapy?

18 PCNSL treatment Young, fit patients MTX 3,5 gr/m² day 1 Cytarabine 2 x 2 gr/m² day 2 and 3 Every 3 weeks Four cycles Followed by WBRT if no CR after 1 cycle HDT + ASTx Ferreri AJM, et al. Lancet 2009;374:

19 Elderly PCNSL EORTC protocol 1. First cycle (induction chemotherapy) IV MTX 1 g/m 2 days 1, 10, 20 PO lomustine 40 mg/m 2 day 1 PO procarbazine 60 mg/m 2 days 1 7 IV or PO methylprednisolone 120 mg/m 2 every other day from days 1 20 and 60 mg/m 2 days (IT methotrexate 15 mg and cytarabine 40 mg days 1, 5, 10, and 15) 2. If SD or PD: stop PCNSL treatment 3. If CR or PR: five more cycles every 6 weeks (maintenance chemotherapy) IV methotrexate 1 g/m 2 day 1 PO lomustine 40 mg/m 2 day 1 PO procarbazine 60 mg/m 2 days 1 7 (IT methotrexate 15 mg and cytarabine 40 mg day 1) Hoang-Xuan K, et al. J Clin Oncol 2003;21:

20 Special situations Primary central nervous system lymphoma (PCNSL) Posttransplant lymphoproliferative disorder (PTLD) AIDS related lymphoma (ARL)

21 Gruhlich AE et al. Lancet 2007;370:59-67

22 Risk factors Type of transplanted organ EBV status at time of transplantation (recipient negative/donor positive) Intensity/duration of immunosuppressive therapy Underlying disorder Infectious agents other than EBV (CMV?, HCV?) Age of donor and recipient Number and severity of rejection episodes Cytokine gene polymorphisms HLA alleles/haplotypes/mismatches/antibodies

23 Question 3 Which organ transplantation is associated with the lowest risk for development of PTLD?

24 Risk factors: 1. organ type Organ Number of transplantations (% men) Number of PTLDs % of PTLDs Organ specific incidence (%) Kidney 3566 (59%) Liver 853 (53%) Lung 568 (53%) Heart 519 (80%) HSCTx 1092 (59%) Total 6598 (60%) Dierickx D, et al. Leuk Lymphoma 2013;54:

25 Risk factors: 2. EBV status Mismatch (donor seropositive / receptor seronegative): significant increased risk (10-75x) = most important risk factor EBV naive patients: higher risk explains higher incidence in childhood EBV naive patients: Often initially presentation with EBV-associated PTLD type early lesions or polymorfic type Often early onset PTLD Remains risk factor Shahinian VB, et al. Transplantation 2003;75:851-6

26 Risk factors: 3. immunosuppressive therapy Halloran PF. New Engl J Med 2004;351:

27 Risk factors: 3. immunosuppressive therapy Association Controversial No association Tacrolimus Azathioprin ATG OKT3 Belatacept Efalizumab EBV+ Tofacitinib Cyclosporin A mtor inhibitors MMF Alemtuzumab Basiliximab/daclizumab

28 Pathogenesis 67%: EBV-associated PTLD Deficient EBV specific cellular immune response SOT: immune suppressive medication HSCTx: conditioning, T cell depletion and immune suppressive medication 33%: EBV-negative PTLD Pathogenesis less clear Therapy similar (except for EBV-targeted therapy)

29 Rezk SA, et al. Hum Pathol 2007;38: Thorley Lawson DA. Nat Rev Immunol 2001; 1:75-82 Thorley-Lawson DA. J Allergy Clin Immunol 2005;116: Pathogenesis

30 Pathogenese Hawkins JB, et al. PLoS Pathog 2013;9(10):e

31 Saha A, Robertson E S Clin Cancer Res 2011;17: Pathogenesis

32 Pathogenesis: role of EBV IMMORTALIZATION Thorley Lawson DA. Nat Rev Immunol 2001;1:75-82

33 Classification: WHO 2008 Immunodeficiency Associated Lymphoproliferative Disorders Lymphoproliferative diseases associated with primary immune disorders Lymphomas associated with HIV infection Post-transplant lymphoproliferative disorders Other iatrogenic immunodeficiency-associated lymphoproliferative disorders Swerdlow H, et al. IARC Press: Lyon 2008

34 Classification: WHO 2008 POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS Early lesions Reactive plasmacytic hyperplasia Infectious mononucleosis-like Polymorphic PTLD Monomorphic PTLD B-cell neoplasms (DLBCL; BL; PCM; plasmacytoma-like lesions, other) T-cell neoplasms (PTCL,NOS; HSTCL; other) Hodgkin lymphoma/hodgkin-like lymphoma Jaffe ES, et al. IARC Press: Lyon 2008

35 Question 4 What is the critical step in the initial treatment of PTLD?

36 Treatment Gottschalk, et al. Annu.Rev.Med 2005;56:29-44

37 Treatment Gottschalk, et al. Annu.Rev.Med 2005;56:29-44

38 Treatment Gottschalk, et al. Annu.Rev.Med 2005;56:29-44

39 Treatment: restoring T cell function 1. Reduction of immune suppression (RIS) PTLD = excess immune suppression No consensus/uniform guidelines: STOP antimetabolites Reduce CNI dose Continue or increase steroids 1-4 weeks response rates: 0 - >50% Highest response rates: Early lesions EBV positive

40 Treatment: restoring T cell function 1. Reduction of immune suppression (RIS) Treatment Overall response rate (CR) Pennsylvania RIS only 45% (37%) Baltimore Sequential therapy (RIS IFNα chemo) 6% (0%) Reshef R, et al. Am J Transplant 2011;11: Swinnen LJ, et al. Transplantation 2008;86:215-22

41 Treatment: restoring T cell function 1. Reduction of immune suppression (RIS) Organ dependent Kidney: dialysis rescue Hematopoietic stem cell: less efficious Heart: risk sudden death Aull MJ, et al. Transplantation 2004;78: Switch to mtor inhibition? Currently very controversial

42 2. Adoptive immunotherapy Treatment: restoring T cell function EBV specific CTLs Kennedy-Nasser AA, et al. Mediterr J Hematol 2009;17;1(2):e

43 1. Chemotherapy Treatment: reduction of B cell mass Retrospective analysis IPITTR: PTLD following SOT n = 193 Regimen 5yrOS (%) PTLD-specific mortality (%) CHOP ProMACE Other multidrug Monotherapy 5 48 Buell JF, et al. Transplant Proc 2005;37:956-7

44 1. Chemotherapy Treatment: reduction of B cell mass Immuno-chemotherapy (Rituximab + CHOP): standard of care in immune competent patients PTLD: higher TRM (infections) Solutions? Better supportive care G-CSF, anti-infectious agents Low dose chemotherapy Sequential therapy Only 1 prospective study in children

45 Treatment: reduction of B cell mass 2. Monoclonal anti-b cell antibodies Stamataki Z, et al. PLoS One 2011;6:e25789

46 Prospective studies: Treatment: reduction of B cell mass 2. Monoclonal anti-b cell antibodies Author Year Phase n ORR(%) Oertel 2005 II Blaes 2005 II Choquet 2006 II Gonzalez-Barca * 2007 II (CRR) In most studies: rituximab 375 mg/m²/week during 4 consecutive weeks * risk adapted extended treatment (PR): upgrading CR 34% 60.5%

47 Treatment: reduction of B cell mass 2. Monoclonal anti-b cell antibodies Rituximab or chemotherapy? No prospective randomized trials Retrospective analysis (Pennsylvania University) n = 35 (34 SOT, 1 HSCTx) 22 R, 23 chemo Rituximab: RR 68%, OS 31 months Chemotherapy: RR 72%, OS 42 months Rituximab: excellent tolerance; chemotherapie TRM 26% Treatment failure after rituximab: salvage with chemotherapy later Important: better performance status following rituximab Elstrom RL, et al. Am J Transpl 2006;6:569-79

48 Treatment: reduction of B cell mass PTLD1 trial Sequential Treatment Trappe R, et al. Lancet Oncol 2013;13:

49 Percent OS Treatment: reduction of B cell mass PTLD1 trial 100 p= CR or PR after 4 cycles of rituximab (n=35) SD or PD after 4 cycles of rituximab (n=23) Months

50 Treatment: reduction of B cell mass PTLD1 trial Risk Stratified Sequential Treatment

51 Treatment Zimmermann H, Trappe R. Hematology Am Soc Hematol Educ Program 2013;2013:95-102

52 Prophylaxis/prevention/preemptive Problems Who? High risk patients Definition? Which test? How? EBV PCR, FLC(?), scxcl13 RIS Rituximab Adoptive immunotherapy Source? Cut off? Increase? Mostly retrospective single center data

53 Prophylaxis/prevention/preemptive Rasche L, et al. Bone Marrow Transplant 2014;49:163-7

54 Prophylaxis/prevention/preemptive Choquet S, et al. Am J Transplant 2014;14:857-66

55 Special situations Primary central nervous system lymphoma (PCNSL) Posttransplant lymphoproliferative disorder (PTLD) AIDS related lymphoma (ARL)

56 Classification: WHO 2008 Immunodeficiency Associated Lymphoproliferative Disorders Lymphoproliferative diseases associated with primary immune disorders Lymphomas associated with HIV infection Post-transplant lymphoproliferative disorders Other iatrogenic immunodeficiency-associated lymphoproliferative disorders Swerdlow H, et al. IARC Press: Lyon 2008

57 Question 5 Is the incidence of ARL increasing or decreasing?

58 ARL incidence Gruhlich AE et al. Lancet 2007;370:59-67

59 ARL subtypes Carbone A, et al. Nat Rev Clin Oncol 2014;11:223-38

60 Franceschi S, et al. Br J Cancer 2010;103:416-22

61 ARL treatment and prognosis Treatment: Early initiation of cart (during chemotherapy) Lymphoma-specific treatment Supportive care New treatment strategies needed (PEL, PBL) Prognostic factors: Low CD4 count, poor PS aaipi, histological subtype

62 ARL treatment and prognosis Barta SK, et al. Ann Oncol 2015 [Epub ahead of print]

63 ARL treatment DLBCL DLBCL: R-CHOP or R-EPOCH Barta SK, et al. Ann Oncol 2015 [Epub ahead of print]

64 Montoto S, et al. J Clin Oncol 2012;30: Hentrich M, et al, J Clin Oncol 2012;30: Uldrick TS, Little RF. Blood 2015;125: ARL treatment HL Mostly advanced stage Higher CD4 counts EBV associated Subtype: NS, LD and MC HL: ABVD

65 ARL treatment BL BL: short intensive chemotherapy + rituximab Galicier L, et al. Blood 2007;110: Xicoy B, et al, Leuk Lymphoma 2014;55:2341-8

66 ARL treatment BL BL: short intensive chemotherapy + rituximab or SC-EPOCH-RR? Dunleavy K, et al, N Engl J Med 2013;369:

67 ARL treatment PCNSL: HD MTx/Ara-C +/- RT PBL and PEL: very poor prognosis PBL and PEL: new treatments needed Castillo JJ, et al, Cancer 2012;118: Schommers P, et al. Br J Haematol 2014 Nov 17.[Epub ahead of print]

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