Hochmaligne Lymphome/ZNS Lymphome Gerald Illerhaus

Transkript

1 Höhepunkte des Amerikanischen Hämatologie-Kongresses 2016 Stuttgart, Hochmaligne Lymphome/ZNS Lymphome Gerald Illerhaus Klinikum Stuttgart Klinik für Hämatologie, Onkologie und Palliativmedizin Stuttgart Cancer Center - Tumorzentrum Eva-Mayr-Stihl

2 Inhalt DLBCL Mantelzell-Lymphom Hodgkin-Lymphom ZNS-NHL

3 Inhalt DLBCL Mantelzell-Lymphom Hodgkin-Lymphom ZNS-NHL

4 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo et al.) Obinutuzumab (GA101; G) Glycoengineered type II anti-cd20 mab Greater direct cell death induction and ADCC/ADCP activity than R GOYA (NCT ) compared the efficacy and safety of G-CHOP with R- CHOP in pts with previously untreated DLBCL Typ II anti-cd20 mak 1 Direkter Zelltod verstärkt 2 Glykomodifizierte Fc-Region 2 Antikörperabhängige zelluläre Zytotoxizität (ADCC) verstärkt 2

5 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo et al.) Previously untreated DLBCL Age 18 years IPI 2 or IPI 1 not due to age alone or IPI 0 with bulky disease (one lesion 7.5cm) Adequate hematologic function 1 bi-dimensionally measurable lesion ECOG PS 2 Target enrolment: 1400 Randomized 1:1 G-CHOP arm G 1000mg C1 D1/8/15 and C2 8 D1 CHOP 6 or 8 cycles every 21 days R-CHOP arm R 375mg/m 2 C1 8 D1 CHOP 6 or 8 cycles every 21 days

6 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo et al.) R-CHOP, n=712 CT-based G-CHOP, n=706 R-CHOP, n=665 CT + PET-based G-CHOP, n=669 ORR 80.3% 81.7% 77.9% 77.4% CR 33.8% 35.1% 59.5% 56.7% PR 46.5% 46.6% 18.3% 20.8% SD 2.0% 1.6% 0.3% 1.2% PD 9.6% 7.4% 6.5% 5.1% Not evaluable 2.0% 2.5% 9.6% 9.6% Missing 6.2% 6.8% 5.7% 6.7% INV-assessed and IRC-assessed response rates at EOT were similar

7 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo)

8 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo) Probability Kaplan-Meier plot of investigator-assessed PFS by treatment arm 0 0 No. of patients at risk R-CHOP 712 G-CHOP R-CHOP (n=712) G-CHOP (n=706) Time (months) Pts with event, n (%) R-CHOP, n= (30.2) G-CHOP, n= (28.5) 1-yr PFS, % yr PFS, % yr PFS, % HR (95% CI), p-value* 0.92 (0.76, 1.11), p= Median follow-up: 29 months

9 DLBCL - Erstlinie GOYA: Obinutuzumab vs Rituximab + CHOP (Umberto Vitolo) Fazit: G-CHOP ist nicht besser als R-CHOP in Bezug auf PFS Safety-Profil ohne Überraschungen, aber: die meisten Grad 3-5 AE s und SAE s im G-CHOP-Arm R-CHOP bleibt der Standard!

10 DLBCL Erstlinie CALGB/Alliance 50303: R-CHOP vs. DA-EPOCH-R (Wyndham H.Wilson et al.) Cunningham et al. Lancet. 2013;381: Wilson et al. Haematologica. 2012;97:

11 DLBCL Erstlinie CALGB/Alliance 50303: R-CHOP vs. DA-EPOCH-R (Wyndham H.Wilson et al.) Phase III, n= 2 x 265 Patients Primary objectives: Compare EFS of R-CHOP vs. DA-EPOCH-R in untreated DLBCL Secondary Compare RR, OS and toxicity of R-CHOP vs. DA-EPOCH-R

12 DLBCL Erstlinie CALGB/Alliance 50303: R-CHOP vs. DA-EPOCH-R (Wyndham H.Wilson et al.) R-CHOP x 6 (mg/m2) DA-EPOCH-R x 6 DL1 (mg/m2) Rituximab Cyclophosphamide * Doxorubicin (over 96 hr)* Etoposide 200 (over 96 hr)* Inclusion criteria: Stage 2-4, (Stage I PMBCL) Age 18 Vincristine 1.4 (2 mg cap) 1.6 (over 96 hr, no cap) Prednisone 40 D BID D1-5 GCSF PRN X * Escalated based on nadir ANC, platelets each cycle CNS prophylaxis (IT MTX x 4 doses, D1 of C3-6) required if 2 extranodal sites AND elevated LDH or bone marrow or testicular involvement with large cell lymphoma

13 DLBCL Erstlinie CALGB/Alliance 50303: R-CHOP vs. DA-EPOCH-R (Wyndham H.Wilson et al.) R-CHOP DA-EPOCH-R Enrolled (N=524) Withdrew before treatment 4 7 Ineligible / elig. pending 9/16 9/14 Characteristic R-CHOP (%) DA-EPOCH R P-value (%) Median Age 58 (18-86) 57 (19-84) (range) ECOG 0-1 vs vs vs Stage 1 - PMBCL Efficacy Analysis (n= 465) IPI

14 DLBCL Erstlinie CALGB/Alliance 50303: Grade 3-5 Toxicity Event R-CHOP DA-EPOCH-R P-value Treatment related deaths* 2% 2% ALL Gr % 96.5% <0.001 Hematologic 73.1% 97.7% <0.001 Non-Hematologic 41.3% 70.9% <0.001 ANC 68% 96% <0.001 Platelets 11% 65% <0.001 Febrile neutropenia 17% 35% <0.001 Infection 11% 14% Mucositis 2% 6% Neuropathy - sensory 2% 14% <0.001 Neuropathy - motor 1% 8% <0.001

15 DLBCL Erstlinie CALGB/Alliance 50303: Response R-CHOP DA-EPOCH-R P-value ORR 89.3% 88.8% CR/CRu 62.3% 61.1% PR 27% 27.2% SD 2.6% 3.5% PD 1.7% <1% Missing 6.4% 6.9%

16 DLBCL Erstlinie CALGB/Alliance 50303: EFS Overall Survival Probability event free Arm R-CHOP DA-EPOCH-R R-CHOP DA-EPOCH-R N Years from Study Entry Events yr (95% CI).81 ( ).79 ( ) Median f/u 5.0 years HR=1.14( ) p-value= yr (95% CI).69 ( ).66 ( ) Survival Probability R-CHOP DA-EPOCH-R Arm R-CHOP DA-EPOCH-R N Years from Study Entry Events yr (95% CI).85 ( ).85 ( ) HR=1.18( ) p-value= yr (95% CI).80 ( ).76 ( )

17 DLBCL Erstlinie CALGB/Alliance 50303: 5-yr EFS by IPI and age % of Pts ALL R-CHOP DA-EPOCH-R P-value Age % 73% 70% > % 65% 61% IPI < % 90% 72% % 72% 68% % 50% 61% % 40% 60%

18 DLBCL Erstlinie CALGB/Alliance 50303: Kein Unterschied im 3-yr EFS / 3-yr OS Deutlich erhöhte Gr-3-4 Toxizität (Hämatotox, F/N, Neuropathie) Keine Subgruppe profitiert von DA-EPOCH-R

19 DLBCL Lenalidomid Erhaltung REMARC Study from LYSA (C. Thieblemont et al) international, multicenter, doubleblind, randomized, placebocontrolled, phase III trial To assess the benefit of lenalidomide maintenance after response to R- CHOP in patients aged 60 to 80 with untreated DLBCL, FL3b, or transformed lymphoma

20 DLBCL Lenalidomid Erhaltung REMARC Study from LYSA (C. Thieblemont et al) Primary Endpoint PFS Secondary Endpoints Safety PR to CR conversion rate Overall survival Efficacy according to the response to R-CHOP

21 DLBCL Lenalidomid Erhaltung REMARC: PFS

22 DLBCL Lenalidomid Erhaltung REMARC: OS Grade 3/4 TEAEs

23 DLBCL Lenalidomid Erhaltung REMARC-Studie Fazit: PFS kann durch Lenalidomid-Erhaltung verbessert werden nicht aber das OS (median follow-up:52 Monate) R-CHOP ohne Erhaltung zunächst weiter Standard

24 Inhalt DLBCL Mantelzell-Lymphom Hodgkin-Lymphom ZNS-NHL

25 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.) W1 W4 W7 W10 OBSERVATION R-DHAP R-DHAP R-DHAP R-DHAP R-BEAM If < VGPR R-CHOP If > VGPR RITUXIMAB MAINTENANCE every 2 months during 3 years

26 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.) Inclusion criteria: MCL patients with a least one tumor site for assessment (not isolated BM or spleen involvement) years Primary objective: 4-years EFS Secondary objectives: PFS and OS, response rates (CR, PR, SD, PD)

27 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.) TOTAL N=299 (%) Age, median (range), yrs 57 (27-65) Male sex-no (%) 236 (79) Ann Arbor Stage-no.(%) II 18 (6) III 31 (10.5) IV 249 (83.5) B symptoms-no.(%) 89 (29.8) PS ECOG-no.(%) <2 282 (94.3) BM involvement-no.(%) 192 (64.5) LDH elevation-no.(%) 115 (38.5) MIPI score-no.(%) low risk 159 (53) intermediate risk 82 (27.5) high risk 58 (19.5) TOTAL N=299 % of Ki-67 positive cells >30% 76 (35.2) missing 83 bio-mipi low risk 51 (23.6) intermediate risk 104 (48.1) high risk 61 (28.2) Variant MCL-no.(%) Local blastoid 35 (11.7) pleomorphic 7 (3.5) Central review blastoid 12 (5.8) pleomorphic 27 (13)

28 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.)

29 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.)

30 MCL Erhaltung nach Hochdosis LyMa Trial: Rituximab Erhaltung nach HDT/ASCT (Steven Le Gouill et al.) Fazit: Rituximab als Erhaltungstherapie nach HDT/ASCT führt zu einer signifikanten Verbesserung von: EFS: 78.9% vs 61.4% at 4 years (HR=0.457; ; p= ) PFS: 82.2% vs 64.6 % at 4 years (HR=0.4; ; p= ) OS : 88.7% vs 81.4 % at 4 years (HR=0.502; ; p= ) Neuer Standard!!!

31 Inhalt DLBCL Mantelzell-Lymphom Hodgkin-Lymphom ZNS-NHL

32 Hodgkin-Lymphom - Rezidivtherapie Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.) Brentuximab vedotin disrupts the microtubule network and triggers an immune response through the induction of endoplasmic reticulum stress a Nivolumab targets the programmed death-1 (PD-1) immune checkpoint pathway and restores antitumor immune responses Tumor cell IFNγ Antigen IFNγR T-cell MHC receptor PD-L1PD-1 PD-L2 PD-1 PI3K NFκB Other T cell Shp-2 Shp-2 T-cell receptor Antigen MHC CD28 B7 PD-1 PD-L1 PD-1 PD-L2 Nivolumab blocks the PD-1 receptor Dendritic cell

33 Hodgkin-Lymphom Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.) Objectives Evaluate safety and tolerability of brentuximab vedotin (BV) in combination with nivolumab (Nivo) Population Adults aged 18 years with R/R Hodgkin lymphoma after failure of frontline therapy (no allo/auto TX)

34 Hodgkin-Lymphom Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.) N=55 After completion of the Cycle 4 response assessment, patients were eligible to undergo ASCT

35 Hodgkin-Lymphom Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.)

36 Hodgkin-Lymphom Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.) SPD change from baseline a CR (18/29) = 62% 95% CI: 42.3, 79.3 SPD: sum of products of diameters

37 Hodgkin-Lymphom Brentuximab + Nivolumab in r/r HL (Alex F. Herrera et al.) Fazit: Die Kombination von Nivolumab und Brentuximab ist machbar und effektiv Kein Antagonismus zwischen BV und Nivo Unklar ob besser als DHAP / ICE

38 Hodgkin-Lymphom Nivolumab alleine in r/r HL - CheckMate 205 Update (12Mo FU) (John Timmermann et al.)

39 Hodgkin-Lymphom CheckMate 205 Update (12Mo FU) (John Timmermann et al.)

40 Hodgkin-Lymphom CheckMate 205 Update (12Mo FU) (John Timmermann et al.) Best reduction from baseline in target lesion (%) Best Change in Target Lesions Cohort B: Nivolumab After BV Post-ASCT ** * *********************************** ***************** Patients

41 Hodgkin-Lymphom CheckMate 205 Update (12Mo FU) (John Timmermann et al.) PFS by Response Cohort B: Nivolumab After BV Post-ASCT Probability of PFS CR PR SD PD No. of patients at risk Months CR PR SD PD

42 Hodgkin-Lymphom - Rezidive Nivolumab alleine in r/r HL - CheckMate 205 Update Fazit: Hohe Ansprechraten (68%) bei BV vorbehandelten und bei BV naiven Patienten Dauerhafte Ansprechraten, CR deutliche besser als PR, SD, und PD Sehr effektive Therapieoption bei Rezidiv oder Progress nach HD/ASCT

43 Hodgkin-Lymphom - Rezidive Pembrolizumab - Phase 2 KEYNOTE-087 Study (Moskowitz et al.)

44 Hodgkin-Lymphom - Rezidive Pembrolizumab - Phase 2 KEYNOTE-087 Study (Moskowitz et al.)

45 Hodgkin-Lymphom - Rezidive Pembrolizumab - Phase 2 KEYNOTE-087 Study (Moskowitz et al.) T: Pyrexie (11%) Diarrhoe (6,5%) Fatique (6,7%) Rash (6,2%) Kofschmerzen (6,2%), Nausea (5,7%) Median number of treatment cycles: 13 (range,1-21) Treatment is ongoing in 120 (57%) patients Median follow-up: 10.1 ( ) months Median (range) time to response: 2.8 ( ) months Response duration 6 months: 75.6%

46 Hodgkin-Lymphom - Rezidive Pembrolizumab - Phase 2 KEYNOTE-087 Study (Moskowitz et al.) Cohort 1 Cohort 2 Cohort 3 + Treatment Ongoing Complete Response Partial Response Progressive Disease Last Dose Death Months

47 Hodgkin-Lymphom - Rezidive Pembrolizumab - Phase 2 KEYNOTE-087 Study (Moskowitz et al.) Fazit: Hohe Ansprechraten 66-68% in allen Kohorten Sehr effektive Therapieoption bei r/r HL

48 Inhalt DLBCL Mantelzell-Lymphom Hodgkin-Lymphom ZNS-NHL

49 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.)

50 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) Ferreri AJM, Illerhaus et al ASH 2016

51 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.)

52 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) WBRT ASCT Grade Neutropenia 3 ( 5%) 1 (2%) 3 (5%) 0 (0%) 2 ( 3%) 0 ( 0%) 41 (71%) 0 (0%) Thrombocytopenia 0 ( 0%) 1 (2%) 1 (2%) 0 (0%) 0 ( 0%) 3 ( 5%) 42 (72%) 0 (0%) Anaemia 7 (13%) 2 (4%) 0 (0%) 0 (0%) 21 (36%) 17 (29%) 2 ( 3%) 0 (0%) FN/infections 0 ( 0%) 1 (2%) 0 (0%) 0 (0%) 1 ( 2%) 12 (21%) 3 ( 5%) 2 (3%) Hepatotoxicity 3 ( 5%) 1 (2%) 0 (0%) 0 (0%) 15 (26%) 3 ( 5%) 1 ( 2%) 0 (0%) Nephrotoxicity 2 ( 4%) 0 (0%) 0 (0%) 0 (0%) 6 (10%) 0 ( 0%) 0 ( 0%) 0 (0%) Cardiotoxicity 0 ( 0%) 0 (0%) 0 (0%) 0 (0%) 5 ( 9%) 1 ( 2%) 0 ( 0%) 0 (0%) Coagulopathy/DVT 2 ( 4%) 0 (0%) 3 (5%) 0 (0%) 6 (10%) 1 ( 2%) 0 ( 0%) 0 (0%) Gastrointestinal 8 (15%) 0 (0%) 0 (0%) 0 (0%) 24 (41%) 11 (19%) 0 ( 0%) 0 (0%) Mucositis 2 ( 4%) 0 (0%) 0 (0%) 0 (0%) 15 (26%) 12 (21%) 3 ( 5%) 0 (0%) Erythema 7 (13%) 0 (0%) 0 (0%) 0 (0%) 0 ( 0%) 0 ( 0%) 0 ( 0%) 0 (0%) Acute neurotoxicity 7 (13%) 3 (5%) 0 (0%) 0 (0%) 4 ( 7%) 0 ( 0%) 0 ( 0%) 0 (0%)

53 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) WBRT (n= 55) ASCT (n= 58) Total Tumor relapse Deaths (toxicity; unrelated) Refused NPS tests Incomplete NPS assessments Assessed patients

54 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) After induction 32 CR (54%) Arm D (WBRT) CR (95%) After induction 31 CR (53%) Arm E (ASCT) CR (93%)

55 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) MEDIAN FOLLOW-UP: 40 MONTHS (24-76) EVENTS: 45 WBRT(%) ASCT (%) Relapse 16 (27%) 18 (31%) PD during consolidation 2 ( 3%) 2 ( 3%) Toxic death 0 ( 0%) 2 ( 3%) Death off-therapy (NED) 2 ( 3%) 3 ( 5%)

56 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) EFFICACY: PFS B 1,0 0,8 Probability, PFS 0,6 0,4 0,2 WBRT p= 0.62 ASCT 0, Months

57 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) EFFICACY: OS PP

58 PCNSL Erstlinie IELSG-32-Studie Update 1. Randomisierung: (Ferreri, Illerhaus et al.) 1,0 A EFFICACY: OS Arm A Arm B B 1,0 Arm C MEDIAN FOLLOW-UP: 0,8 40 MONTHS (24-76) 0,8 Arm A Arm B Arm C Probability, PFS 0,6 0,4 Probability, OS 0,6 0,4 0,2 0,2 0, , Months Months A vs. B= 0 06, HR= 0 68, 95%CI= A vs. B= 0 14, HR= 0 73, 95%CI= A vs. C= , HR= 0 66, 95%CI= A vs. C= , HR= 0 65, 95%CI= B vs. C= 0 049, HR= 0 63, 95%CI= B vs. C= 0 02, HR= 0 57, 95%CI=

59 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.)

60 PCNSL Erstlinie IELSG-32-Studie - 2- Randomisierung: (Ferreri, Illerhaus et al.) Fazit: MATRix ist die effektivste Induktionstherapie WBRT und ASCT als Konsolidierung sind beide gut durchführbar und effektiv Langzeit-Neurotoxozität durch WBRT muss in die Therapieentscheidung mit einbezogen werden.

61 PCNSL Neue Substanzen - Ibrutinib Ibrutinib Exclusion: Prior allogenic stem cell transplant Grommes et al. ASH 2016

62 PCNSL Neue Substanzen - Ibrutinib Ibrutinib Median age 69 years (range, 21-85) 13 PCNSL, 7 SCNSL; 13 parenchymal brain lesions, 3 isolated CSF involvement, and four both Median number of prior therapies: 2 (range, 1-8) (MTX chemotherapy (100%) Median ECOG score: 1 (range, 0-2) 75% had failed prior MTX-based salvage therapy FDA limited dose escalation above 840mg for concerns of liver toxicity Grommes et al. ASH 2016

63 PCNSL Neue Substanzen - Ibrutinib Ibrutinib Grommes et al. ASH 2016

64 PCNSL Neue Substanzen - Ibrutinib Ibrutinib

65 PCNSL Neue Substanzen - Ibrutinib Ibrutinib (Grommes et al.) Fazit: Ibrutinib bis 840mg wird gut toleriert (keine DLT) Adaequate Liquorkonzentrationen 75% Ansprechrate, PFS: 5.42 Monate Ibrutinib Monotherapie als Therapieoption bei R/R PCNSL, SCNSL Ibrutinib + MTX wird derzeit in einer prospektiven Studie geprüft

66 PCNSL Neue Substanzen - Nivolumab Nivolumab Preclinical & clinical studies have shown that lymphoid malignancies with 9p24.1/PD-L1/PD-L2 alterations are genetically predisposed to rely on PD-1 mediated immune evasion

67 PCNSL Neue Substanzen - Nivolumab Nivolumab lymphoid malignancies with 9p24.1/PD- L1/PD-L2 alterations (copy gain) are genetically predisposed to rely on PD-1 mediated immune evasion Comparison of DLBCL vs. PCNSL/PTL Copy Number Alterations : Monti and Chapuy et al, Cancer Cell, 2012; 22: Chapuy and Roemer et al Blood 2016; 127:

68 PCNSL Neue Substanzen - Nivolumab Nivolumab N= 5 pts (2 women, 3 men) Recurrent PCNSL 3 Refractory PCNSL 1 Recurrent PTL (SCNSL) 1 Median Age= 64 yrs (range, yrs) Median KPS= 70% (range, %) Nayak et al. ASH 2016

69 PCNSL Neue Substanzen - Nivolumab Nivolumab Patients Disease Refractory Relapsed Relapsed Relapsed Relapsed PTL PCNSL PCNSL PCNSL PCNSL in brain Presenting symptoms, KPS % Radiographic response Neurologic response, KPS % Progression-free survival (mo) Visual field defect, cognitive change; 70 Mild cognitive change; 80 Nausea, vomiting, ataxia; 40 Asymptomatic; 80 CR CR PR CR CR Complete resolution; 90 Complete resolution; 80 Resolution; 70 Stable (asym); Aphasia, impaired LOC; 40 Resolution; 80 Nayak et al. ASH 2016

70 PCNSL Neue Substanzen - Nivolumab Nivolumab Patients Disease Refractory PCNSL Relapsed PCNSL Relapsed PCNSL Relapsed PCNSL Relapsed PTL in brain Presenting symptoms, KPS % Visual field defect, cognitive change; 70 Mild cognitive change; 80 Nausea, vomiting, ataxia; 40 Asymptomatic; 80 Aphasia, impaired LOC; 40 Radiographic response CR CR PR CR CR Neurologic response, KPS % Complete resolution; 90 Complete resolution; 80 Resolution; 70 Stable (asym); 80 Resolution; 80 Progression-free survival (mo) Nayak et al. ASH 2016

71 PCNSL Neue Substanzen - Nivolumab Nivolumab Fazit Nivolumab ist hochaktiv bei R/R PCNSL and PTL Multizentrische Phase 2 single-arm Studie mit Nivolumab bei R/R PCNSL und PTL Patienten (CA ) läuft ab Zentren in Deutschland (Stuttgart, Heidelberg)

72 PCNSL Rezidive HDT/ASCT: (Kasenda, Illerhaus et al.)

73 PCNSL Rezidive HDT/ASCT: (Kasenda, Illerhaus et al.) May 2007 July 2012, 39 patients from 12 German centres Characteristics Measurement Median age (range) 57 (37 65) Female, N (%) 20 (51.3) Median KPS (range) 90 (60 100) Ocular involvement 2 (5.1) Serum LDH increased, N (%) 8 (20.5) Remission status at inclusion Relapse, N (%) 28 (71.8) Progression, N (%) 8 (28.2) Prior treatment lines One prior line, N (%) 33 (84.6) Two prior lines, N (%) 5 (12.8) More than 2 prior lines, N (%) 1 (2.6) Prior radiotherapy, N (%) 4 (10.3) Prior HCT ASCT, N (%) 2 (5.1)

74 PCNSL Rezidive HDT/ASCT: (Kasenda, Illerhaus et al.) 4 (10.3%) treatment related deaths 3 sepsis (1 during induction) 1 CNS toxicity after HCT-ASCT Toxicities (Gr>=3) During induction (N=39) During HCT ASCT (N=32) Platelets 31 (79.5) 31 (96.9) White cell count 28 (71.8) 32 (100) Haemoglobin 14 (35.9) 21 (65.6) Infections 5 (12.8) 21 (65.6) Fever 5 (12.8) 16 (50.0) GPT/ALT 1 (2.6) 3 (9.4) Bilirubin 0 (0) 1 (3.1) Arrhythmias 1 (2.6) 3 (9.4) Mucositis 0 (0) 13 (40.6) Emesis 0 (0) 3 (9.4) Nausea 1 (2.6) 7 (21.9)

75 PCNSL Rezidive HDT/ASCT: (Kasenda, Illerhaus et al.) Remissions status Remission before HCT ASCT N(%) 30 days after HCT ASCT N (%) CR 4 (10.3%) 22 (56.4%) primary endpoint PR 18 (46.2%) 6 (15.4%) SD 5 (7.7%) 1 (2.6%) PD 9 (23.1%) 1 (2.6%) Not done 3 (7.7%) 9 (17.8%) * 6 patients in PR received WBRT after HCT ASCT *Seven patients did not undergo HCT ASCT and two patients died due to treatment associated complications before the final scan

76 PCNSL Rezidive HDT/ASCT: 1 and 2 year PFS 51.3% and 46.0%, median PFS 12.4 months 1 and 2 year OS 61.5% and 56.4%, median OS not reached All 39 registered patients Median follow-up for all patients 45.2 months

77 PCNSL Rezidive HDT/ASCT: (Kasenda, Illerhaus et al.) Fazit: HDT/ASCT nach kurzer Induktion ist sicher und effektiv bei r/r PCNSL HDT/ASCT als Standard bei transplant-tauglichen Patienten

78 Take-Home Messages DLBCL: R-CHOP steht wie ein Fels in der Brandung Hodgkin-Lymphom: Die Daten zur Immuntherapie in der r/r-situation konsolidieren sich Mantelzell-Lymphom: R-Erhaltung als neuer Standard nach HDT / ASCT ZNS-NHL Hochdosis als Standard-Konsolidierung in der 1st line und Rezidiv nach konv. Therapie Ibrutinib und Nivolumab wirken!

79 Vielen Dank!