CHRONISCHE LYMPHATISCHE LEUKÄMIE (CLL)

Transkript

1 CHRONISCHE LYMPHATISCHE LEUKÄMIE (CLL) NIO KONGRESS 2018 Hannover 20. Januar 2018 Barbara Eichhorst

2 OFFENLEGUNG POTENTIELLER INTERESSENSKONFLIKTE 1. Anstellungsverhältnis oder Führungsposition - 2. Beratungstätigkeit Janssen, Gilead, Roche, Abbvie, Mundipharma, GSK 3. Aktienbesitz - 4. Honorare Roche, Mundipharma, GSK, Gilead, Janssen, Abbvie, Celgene 5. Finanzierung wissenschaftlicher Untersuchungen Roche, Jannse, Abbvie, Gilead, Celgene, Mundipharma 6. Gutachtertätigkeit - 7. Andere finanzielle Beziehungen -

3 THERAPIEOPTIONEN BEI DER CLL FCR BR/BOfa CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTX

4 THERAPIEOPTIONEN BEI DER CLL Erstlinientherapie FCR BR/BOfa CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTX

5 CHEMOIMMUNTHERAPIE: KEINE OPTION BEI NACHWEIS EINER DEL(17P) ODER TP53 MUTATION FCR CLB, CLBR, CLBOBI N Pts alive, % Median OS +12q NR 13q NR 11q NR Not* NR 17p Stilgenbauer S. et al., Blood 2014 Herling C et al., Blood 2016

6 CHEMOIMMUNOTHERAPIE-OPTIONEN IN DER ERSTLINIENTHERAPIE DER CLL OHNE TP53 DEL/MUT Fludarabin/Cyclophosphamid (FC) Rituximab Bendamustin Ofatumumab Chlorambucil Obinutuzumab

7 SEHR LANGES PFS BEI MUTIERTEM IGHV STATUS MIT FCR MDA Studie und CLL8 Studie: FCR bei fitten Patienten Median PFS FCR IGHV mutated Not reached FC IGHV mutated 42 months FCR IGHV unmutated 42 months FC IGHV unmutated 29 months Thompson PA, et al. Blood 2016; 127: Fischer K, et al. Blood 2016; 127:.

8 GUTE PROGNOSE NACH FCR THERAPIE FÜR FITTE PATIENTEN CLL8: Überleben bei IGHV mutated/unmutated Patienten Median observation time 5.9 years Median PFS FCR IGHV mutated Not reached FC IGHV mutated Not reached FCR IGHV unmutated 86 months FC IGHV unmutated 75 months Fischer K et al. Blood 2016

9 ZWISCHENLÖSUNG? BENDAMUSTINE +CD20 AK Stilgenbauer et al. ASH 2015 Flinn et al. Am J Hematol 2016 Eichhorst et al. Lancet Oncol 2016 Michallet et al. IWCLL 2015 Regimen B + Obinit., B+ Ofat. BR BR N pts 84 unfit Median age 69 (all) 62 (34-86) 62 (34-81) 72 (41-86) Fitnes CIRS > 6 or CreaCl Ineligble for F- based therapy CIRS 6 & normal creatinine clearance Ineligble for F-based therapy ORR 76% 96% 96% 91% CRR 34% 43% 35% 24% PFS Not reached at 11 mo Not reached at 29 mo 57% at 3 years 40 mo

10 ABER: VOR ALLEM PATIENTEN < 65 JAHRE PROFITIEREN VON FCR CLL10 Studie: FCR vs BR bei fitten Patienten < 65 Jahre Patients 65 years: P < FCR 53.6 months BR 38.5 months Patients > 65 years: P = FCR not reached BR 48.5 months Eichhorst B et al. Lancet Oncology 2016

11 MRD NEGATIVITÄT UND PROGNOSTISCHE BEDEUTUNG FÜR DAS PFS: FCR VS BR MRD- FCR 137 NR 1 MRD- BR MRD+ FCR MRD+ BR GCLLSG CLL10 updated analysis 2016 unpublished

12 WENIGER TOXIZITÄT VON BR GEGENÜBER FCR BEI PATIENTEN 65 JAHRE CLL10 Studie: FCR vs BR Adverse event FCR (% of pt) BR (% of pt) p value All Infections <0.001 All infections in patients 65years All infections in patients > 65years <0.001 SPM 49 (18%) 35 (12%) Solid tumor 28 (10%) 25 (8%) Skin tumor 9 (4%) 8 (3%) all 12 (4%) 2 (1%) AML/MDS > 65 ys only 6 (7%) 1 (1%) RT 5 (2%) 8 (3%) GCLLSG CLL10 updated analysis 2016 unpublished

13 WENIGER FITTE PATIENTEN: CLB+ CD20 AK Zwei Phase III Studien beide im Vergleich gegenüber CLB alleine CLL11 COMPLEMENT G-Clb (n=336) R-Clb (n=321) O-Clb(n=217) Age 74 (39-88) 73 (40 90) 69 (35 92) ORR 78% 65% 82% CRR 21% 7% 14% MRD neg. 8%* 1% 8%** PFS med. (mo) * BM negativity only; ** BM and PB negativity Goede V, et al. NEJM 2014/ Hillmen P. et al, Lancet 2015

14 TTNT GCLB VERSUS RCLB Mediane Beobachtungszeit 40 Monate Goede et al., Blood 2015, 126:1733 (ASH)

15 THERAPIEOPTIONEN BEI DER CLL Erstlinientherapie FCR BR/BOfa CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTX

16 UPDATE RESONATE-2 STUDIE Ibrutinib vs Chlorambucil in der Erstlinientherapie > 65 J Median FU = 28.6 Monate Patients (N=269) Treatment-naïve CLL/SLL with active disease Age 65 years For patients years, comorbidity that may preclude FCR del17p excluded R A N D O M I Z E 1:1 ibrutinib 420 mg once daily until progression progression (n=136) chlorambucil 0.5 mg/kg (to maximum 0.8 mg/kg) days 1 and 15 of 28-day cycle up to 12 cycles (n=133) CLL progression or 1115 study closure PCYC-1116 Extension Study* In clb arm, n=55 crossed over to ibrutinib following PD P Barr et al., Abstract 234

17 BTK-INHIBITOR IBRUTINIB IN DER ERSTLINIENTHERAPIE ÄLTERER PATIENTEN Resonate 2: PFS Ibrutinib versus Chlorambucil Burger J et al. N Engl J Med 2015;

18 BTK-INHIBITOR IBRUTINIB IN DER ERSTLINIENTHERAPIE ÄLTERER PATIENTEN Resonate 2: PFS nach IGHV-Status P Barr et al., ASH 2016 Abstract 234

19 BTK-INHIBITOR IBURINTIB IN DER ERSTLINIENTHERAPIE ÄLTERER PATIENTEN Resonate 2: Gesamtüberleben Ibrutinib versus Chlorambucil mit Crossover n=136 n=133 P-Wert = P Barr et al., ASH 2016 Abstract 234

20 ERSTLINIENTHERAPIE VON PATIENTEN MIT TP53 MUT/DEL Ibruitnib in 35 untreated patients Idelalisib + R in 9 untreated patients Faaroqui et al., Lancet Oncol 2015 O Brien et al., Blood 2015

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22 Therapieempfehlungender DCLLSG Erstlinientherapie Binet Stadium A/B ohne Symptome C, A/B mit Symptomen Fitness Genetische TP53- Veränderungen Erstlinientherapie irrelevant irrelevant keine go go slow go nein ja ja nein FCR (BR 65 Jahre) Ibrutinib, Bei Kontraindikationen bzgl. Ibrutinib: Venetoclax, Idelalisib + R, (allo-hctx) Chlorambucil + CD20-Antikörper (Obinutuzumab, Ofatumumab, Rituximab) oder Ibrutinib * Bei Patienten ohne del(17p)/tp53-mutationen nur nach Versagen von Chemoimmuntherapie und BCR- Inhibitor

23 THERAPIEOPTIONEN BEI DER CLL Rezidivtherapie FCR BR CLB + Ofa/Rit AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTX

24 5-JAHRES UPDATE PCYC-1102/1103 Phase II Studie zu Ibrutinib-Monotherapie Phase 2 (PCYC-1102) N=132 Extension Study (PCYC-1103) Patients with CLL/SLL treated with oral, once-daily ibrutinib (420 or 840 mg/day) Treatment Naïve (TN) 65 years n=31 Relapsed/Refractory * (R/R) n=101 SD Long-Term Follow-Up S O Brien et al., Abstract 234

25 EFFEKTIVITÄT: PFS UND OS Median PFS 5-year PFS TN (n=31) NR 92% R/R (n=101) 52 mo 43% Median OS 5-year OS TN (n=31) NR 92% R/R (n=101) NR 57% S O Brien et al., Abstract 234

26 IDELALISIB + R VS PLACEBO + R STUDYDESIGN Primary Study 116 Extension Study 117 Double-Blind Initial Therapy Double-Blind Continuous Therapy Blinded Dose Open-Label Screen Arm A N=110 Arm B N=110 Rituximab (6 mo) Idelalisib (150 mg BID) Placebo (BID) Rituximab (6 mo) Disease Progression Idelalisib (300 mg BID) Idelalisib (150 mg BID) Randomization/ Stratification Blinded, Independent Review Interim Analyses and Unblinding Independent Review Median Follow-up, months IDELA + R PBO + R 1 st Interim Analysis 4 4 DMC halted trial (Furman NEJM 2014) 2 nd Interim Analysis 6 5 Blind ended (Coutre ASCO 2014) Arm A continues Arm B crosses over Update PFS, OS by subgroup analysis

27 Furman et al., NEJM 2014 R+IDELA VERSUS R+PLACEBO PFS und OS

28 THERAPIEOPTIONEN BEI DER CLL Rezidivtherapie FCR BR CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTx

29 BR + IBRUTINIB VS BR + PLACEBO: PFS & OS Chanan-Khanet al. Lancet Oncol 2016

30 BR PLUS IDELALISIB VERSUS PLACEBO: PFS & OS Median observation time 12 mo Median observation time 21 mo IDELA + BR BR + Placebo Median PFS (mo) HR (95% CI) 0.33 (0.24, 0.45) p-value < IDELA+BR PBO+BR Median OS, mo NR 40.6 Hazard Ratio, 95% CI 0.67 (0.47, 0.96)* P-value 0.04 (stratified) Median follow-up, mo (range) 21 (0.1, 43.3) P ro b a b ility o f P F S ID E L A + B R B R + P la c e b o T im e (m o n th s ) Zelenetz A et al. Lancet Oncol 2017/ Zelentz et al. ASH 2016

31 THERAPIEOPTIONEN BEI DER CLL Rezidivtherapie FCR BR CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibitor Venetoclax +/- R Allogene SCTx

32 SCHLECHTE PROGNOSE NACH KINASEINHIBITORVERSAGEN 178 Patienten nach Abbruch der Therapie mit Kinaseinhibitoren A Mato et al., Blood 2016

33 PHASE II STUDIE ZUM EINSATZ VON VENETOCLAX NACH THERAPIE MIT EINEM KINASEINHIBITOR Arm A = Ibrutinib als letzte Therapie; Arm B = Idelalisib als letzte Therapie Arm A n=43 Arm B n=21 Age, median (range), years 66 (48 80) 68 (56 85) Unmutated IGVH,* n/n (%) 25/29 (86) 11/13 (85) del(17)(p13.1),* n/n (%) 21/43 (49) 2/21 (10) Prior therapies, median (range) 4 (1 12) 3 (1 11) Prior ibrutinib, n (%) Months on ibrutinib, median (range) Refractory, n (%) 43 (100) 17 (1 56) 39 (91) 5 (24) 6 (2 11) 2 (10) Prior idelalisib, n (%) Months on idelalisib, median (range) Refractory, n (%) 4 (9) 10 (2 31) 2 (5) 21 (100) 8 (1 27) 14 (67) 2 received only frontline ibrutinib; 2 received only frontline idelalisib. J Jones et al., ASH 2016 Abstract 637

34 EFFEKTIVITÄT VON VENETOCLAX Mediane Beobachtungszeit = 11,8 Monate P a tie n ts w ith R e s p o n s e (% ) D u ra tio n o f R e s p o n s e A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) A ll p a tie n ts M o n th s s in c e firs t d o s e N o. a t r is k P r o g re s s io n -fre e s u rv iv a l (% ) P ro g re s s io n -F re e S u rv iv a l A rm A (R /R ib ru tin ib ) A rm B (R /R id e la lis ib ) A ll p a tie n ts M o n th s s in c e firs t d o s e J Jones et al., Abstract 637

35 MURANO: STUDIENDESIGN Relapsed/refractory CLL (N=389) 18 years of age Prior 1 3 lines of therapy, including 1 chemo-containing regimen Prior bendamustine only if DoR 24 months Stratified by: Del(17p) by local labs Responsiveness to prior therapy* Geographic region R 1:1 VEN 5-week rampup C1D1 Venetoclax 400 mg orally once daily to PD, cessation for toxicity, or max. 2 years from Cycle1 Day1 Rituximab 375 mg/m 2 Day 1, Cycle 1; 500 mg/m 2 Day 1 Cycles 2 6 Bendamustine 70 mg/m 2 Days 1 and 2 Cycles Rituximab Seymour J at al.,ash 2017 LBA 02

36 MURANO: PATIENTENCHARACTERISTIKA Status Venetoclax + Rituximab (N=194) Bendamustine + Rituximab (N=195) Age, median (range), years 64.5 (28 83) 66.0 (22 85) Lymphocyte count ( 10 9 /L), median (range) 43.1 ( ) 54.7 ( ) Del(17p)*, n/n (%) 46/173 (27) 46/169 (27) Unmutated IGHV*, n/n (%) 123/180 (68) 123/180 (68) Mutated TP53*, n/n (%) 48/192 (25) 51/184 (28) Number of prior therapies, n (%) (57) 117 (60) 2 57 (29) 43 (22) 3 22 (11) 34 (17) >3 4 (2) 1 (1) Prior therapies, n (%) Alkylating agent 182 (93) 185 (95) Purine analog 157 (81) 158 (81) Anti-CD20 antibody 153 (78) 148 (76) B-cell receptor pathway inhibitors 5 (3) 3 (2) Seymour J at al.,ash 2017 LBA 02

37 MURANO: VR VS BR PFS Treatment Pts with events, n (%) 1-yr PFS % 2-yr PFS % VenR (n=194) 32 (16.5) BR (n=195) 114 (58.5) Median (range) duration of follow-up, 23.8 ( ) months: Venetoclax + rituximab, 24.8 months; bendamustine + rituximab, 22.1 months Seymour J at al.,ash 2017 LBA 02

38 MURANO: VR VS BR OS Treatment Pts with events (%) 1-year OS (%) 2-year OS (%) VenR (n=194) 15 (7.7) BR (n=195) 27 (13.8) Seymour J at al., LBA 02

39 MURANO: AES AEs, n (%) Venetoclax + Rituximab (N=194) Bendamustine + Rituximab (N=188) Neutropenia 112 (58) 73 (39) Anemia 21 (11) 26 (14) Thrombocytopenia 11 (6) 19 (10) Febrile Neutropenia 7 (4) 18 (10) Pneumonia 10 (5) 15 (8) Infusion-Related Reaction 3 (2) 10 (5) Tumor Lysis Syndrome 6 (3) 2 (1) Hypotension 0 5 (3) Hyperglycemia 4 (2) 0 Hypogammaglobulinemia 4 (2) 0 Seymour J at al., LBA 02

40 AUSWAHL DER REZIDIVTHERAPIE: NW-PROFIL Ibrutinib Idelalisib Venetoclax Untersuchung EKG CMV GFR Cave Antikoagulantien OP CMV PJP Prophylaxe Große Lymphomlast Relative KI Alter + Blutungen + Antikoag. VH flimmern CMV Infektion Transaminitis Colitis Niereninsuffizienz Mangelnde Kompliance

41 THERAPIEOPTIONEN BEI DER CLL FCR BR CLB + CD20 AK AK alleine Ibrutinib Idelalisib + R BR + Kinaseinhibior Venetoclax +/- R Allogene SCTX

42 TP53 REMAINS A PREDICTIVE & PROGNOSTIC FACTOR IN CLL 132 CLL patients 1st line and R/R receiving ibrutinib 56 R/R CLL patients receiving venetoclax Byrd J et al., Blood 2015 Roberts A et al., NEJM 2015

43 ALLOGENE HSCTX BEI HÖCHSTRISIKO CLL 10-Jahres OS aus der CLL3x Studie Percent PFS Percent PFS y PFS 34% (23, 44)(+/- 5%) Months from HCT HR 0.83 ( ); p 0.54 TP53les yes (24) TP53les no (49) Months from HCT Percent Survival Percent Survival y OS 51% (40%-62%) Months from HCT HR 1.09 ( ); p 0.80 TP53les yes (24) TP53les no (49) Months from HCT Krämer et al. Blood 2017

44 Resistance to BTKi and/or BCL2i? No TP53 abn? No Yes Yes No HR, Continue PI HR II Complex karyotype, multiple lines HR I Alternate PI Alternate PI HCT ineligible - Frail or - no donor and - no CART available High/low HCT risk - Comorbidity permitted - Well-matched or partially-matched donor or CART available Low HCT risk - Younger age and - No comorbidity and - Well-matched donor or CART available High HCT risk - Older age or - Comorbidity or - No well-matched donor or CART available Continue PI HCT HCT Continue PI Progression Relapse Progression Experimental therapy PI used for bridging DLI or CART HR II

45 Therapieempfehlungender DCLLSG Rezidiv Rezidiv Fitness Genetische TP53- Veränderungen Rezidivtherapie Früh (< 2 Jahre) Spät (> 2 Jahre) irrelevant irrelevant ja nein Ibrutinib, Idelalisib + R, Venetoclax +/- R, Alemtuzumab, BR/BO, Ofatumumab mono, HD-Rituximab, Lenalidomid (+R), Bei fitten Patienten konsolidierende allo-hctx diskutieren. Wiederholung der Erstlinientherapie, Venetoclax + R * Bei Patienten ohne del(17p)/tp53-mutationen nur nach Versagen von Chemoimmuntherapie und BCR- Inhibitor

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