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Mantelcell lymfom Från indolent till aggressive sjukdom Del 1 Birgitta Sander patologi och biologi Del 2 Anna Laurell klinik och terapi.

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En presentation över ämnet: "Mantelcell lymfom Från indolent till aggressive sjukdom Del 1 Birgitta Sander patologi och biologi Del 2 Anna Laurell klinik och terapi."— Presentationens avskrift:

1 Mantelcell lymfom Från indolent till aggressive sjukdom Del 1 Birgitta Sander patologi och biologi Del 2 Anna Laurell klinik och terapi

2 MCL indolent till aggressive sjukdom IndolentVery Aggressive

3 Swedish Lymphoma Registry MCL 5% 70-80/år Sverige

4 Överlevnaden ökar i Sverige year OS 37% year OS 37% year OS 47% year OS 47% Abrahamsson et al 2011, Leuk Lymphoma

5 Indolent versus behandlingskrävande Population-based study Sweden-Denmark pts with MCL –Watch and wait (2.1 %) –Local radiotherapy (3.4 %) –<65 chemotherapy (33%) –>65 chemotherapy (60%) Abrahamsson et al 2013

6 Symptoms Lymphadenopathy Gastrointestinal symptoms – diarrhea, distention Cytopenia B-symptoms

7 MCL Presentation 5% Stadium I, en körtelstation Majoriteten generaliserad lgll sjukdom Allmänsymptom (B) 50% Benmärgsengaemang 70-80% (blod) Extranodala manifestationer – Waldeyer, orbita, CNS primärt mkt ovanligt

8 MCL Special KLL liknande leukemisk med splenomegali Lymfomatoid polyposis – anemi/vikt Pleuraengagemang

9 UTREDNING Standard lymfomutredning (ej CNS) Ofta extranodal lokal :pleuravätska, orbita, Waldeyer, mag-tarm Titta särskilt på tonsiller, mjälte Tänk på GI engagemang (lymfomatoid polypos) = anemi (PET positiv)

10 MCL: Fördubbling av överlevnaden Median OS increased from 2.7 to 4.8 yrs Herrmann A, et al. J Clin Oncol. 2009;27: Survival Time (Yrs) Survival Probability GLSG ( ) KLG ( ) P < Patients at Risk, n GLSG KLG

11 Riskstratifiering Proliferation (Ki67) viktigaste enskilda riskfaktorn MIPI Mantelcell International Prognostiskt Index Ålder, performance, LD, leukocyter, stadium, Ki67 Beräknas på nätet (googla MIPI)

12 Mantle Cell International Prognostic Index 455 patients with advanced- stage MCL treated with –CHOP (56%) –R-CHOP (31%) –MCP (11%) –Other (2%) 17% received ASCT in remission LR = low risk, < 5.7 IR = intermediate risk, > 5.7 < 6.2 HR = high risk, > 6.2 or more Hoster E, et al. Blood. 2008;111: Survival After Diagnosis by MIPI Mos Since Registration Probability of OS LR, median not reached IR, median: 51 HR, median:

13 Riskstratifiering MIPI Lågrisk OS 5 år 60% Intermediärrisk OS 51mån Högrisk OS 29 mån Ännu bättre idag med rituximab Ännu inget vi direkt använder för terapival

14 Q innan behandlingsbeslut 1. Indolent – behövs behandling –Nej - expektans 2. Lokaliserad sjukdom? –Ja – strålbehandling Alla andra kemoimmunterapi 3. Möjlig för HDCT?

15 Indolent versus behandlingskrävande Population-based study Sweden-Denmark pts with MCL –Watch and wait (2.1 %) –Local radiotherapy (3.4 %) –<65 chemotherapy (33%) –>65 chemotherapy (60%) Abrahamsson et al 2013

16 Watch and wait Patients without need for treatment during first 2 years Abrahamsson et al 2013

17 Strålbehandling Stage I-(II) Dose: 2/30 Gy Abrahamsson et al 2013

18 B E A M/C RE- STAGE Maxi C H O P STEM-CELL HARVEST REINFUSION Maxi C H O P Maxi C H O P Maxi C H O P Week: Week: RRRR AraCAraC AraCAraC AraCAraC Maxi C H O P Maxi C H O P Maxi C H O P B E A M/C RE- STAGE STEM-CELL HARVEST REINFUSION INDUCTION INDUCTION MCL-1 TRIAL MCL-2 TRIAL AraC: 4 Infusions: 60 years 2g/m 2 Pre-empt R in PCR+

19 MCL2 - Event-free and overall survival 63% 15% 75% 46% Geisler et al Blood 2008

20 PR, CR Cyclo 120mg/kg + TBI 12 Gy PBSCT PR, CR (2+1) x R-CHOP/R- DHAP alternating stem cell mobilization after course 6 PBSCT TBI 10 Gy Ara-C 4 x1.5 g/m 2 Melphalan 140 mg/m 2 4 x R-CHOP 2 x R-CHOP DexaBEAM (stem cell mobilization) DexaBEAM (stem cell mobilization) MCL Younger Protocol Design

21 Time to treatment failure PP European MCL Network, V p= (one sided sequential test) Hazard Ratio 0.68

22 MCL-2, MCL-3, Europeiska Rituximab+AraC alternerande med R- CHOP i induktion Överlägset R-CHOP enbart i induktion Zevalin i högdoskonditioneringen (MCL-3) MISSLYCKANDE HYPOTES: Inga lediga CD20 epitoper efter tung förbehandling med rituximab

23 MCL5: Only MIPI high risk <65 years

24 MCL-5 MCL-5 (högrisk) bara R-AraC induktion Högprolifererande MISSLYCKANDE 3 av 5 svarade otillräckligt HYPOTES: DCK aktiverar AraC – DCKbrist = resistens mot nucleosidanaloger (Klanova, Mol Cancer 2014)

25 MCL yngre (<70) NU Vi har inte lyckats starta egen studie Nordiska protokollet tills vidare standard Alternerande R-CHOP-R-AraC+BEAM Underhåll : nej efter högdos Väntar på deltagande i Europeiska TRIANGEL vår 2016? Testar ibrutinib, samt värdet av högdos versus underhåll

26 EU MCL Younger - TRIANGLE R-CHOP/DHAP +/- Ibrutinib CR+MRD-negative Remaining patients ASCT vs. Ibrutinib ASCT Maintenance: R vs. R + Ibrutinib Patients <65, all MIPI Start: spring 2015

27 European MCL network studies patients >60 years 4 x R-CHOP PR, CR IFN-α maintenance ( 3 x 3 M IU/week) or Peg-IFN (1mg/kg week) 4 x R-CHOP PR, CR 3 x R-FC Rituximab maintenance (all 2 months) 3 x R-FC

28 MCL Elderly: overall survival by induction regimen After R-CHOP After R-FC p=0.055 for interaction of induction and maintenance

29 Update October 5, 2010, European MCL Network, V2.1, MCL Elderly: RD R vs. IFN PP Hazard Ratio 0.56 p= (sequential test)

30 StiL: First-line Bendamustine + Rituximab in Patients With FL, Indolent, and MCL Rummel MJ, et al. Lancet Apr 6;381(9873): Lancet. Bendamustine + Rituximab B 90 mg/m 2 on Days 1, 2 + R 375 mg/m 2 on Day 1 Max 6 cycles, q4w (n = 260) R-CHOP Max 6 cycles, q3w (n = 253) Stage III or IV CD20+ lymphoma (N = 549)

31 StiL: PFS (Primary Endpoint) B-R superior to R-CHOP for PFS in overall population (54.9 vs 34.8 mos; P =.00012) In subanalysis, B-R superior to R-CHOP in MCL (P =.0146) Mantle cell P =.0146 B-R R-CHOP Proportion Surviving Without Progression Mos Rummel MJ, et al. Lancet Apr 6;381(9873): Lancet.

32 MCL-6 PHILEMON A phase II non-randomised, open-label multicenter trial, in relapsed/refactory MCL Primary endpoints Overall response rate (ORR)

33 MCL-6 PHILEMON Treatment plan: Up to twelve cycles, cycle duration 28 days Lenalidomide: p o days 1-21 in cycle Ibrutinib: 560 mg daily p o days 1-28, cycle 1-12 Rituximab 375 mg/m2 Day1, cycle 1-12 Responders: RI until progression 5 centra i Sverige, 15 totalt i studien

34 Second-line Therapy Options consideration of allogeneic transplantation Optional regimens or RT or clinical trial Regimens Bendamustine ± R Bortezomib ± R Cladribine + R Fludarabine-based regimens: FC ± R; FCMR; FMR Lenalidomide ± R PCR (pentostatin, cyclophosphamide, rituximab) Ibrutinib

35 European MCL network relapsed MCL R-HAD+/- bortezomib) Patients:n=250, relapsed MCL after/not appropriate for autologous PBSCT Therapy:Dexamethasone40 mg day 1-4 Rituximab 375 mg/m 2 day 1 Ara-C 2 x 1–2 g/m 2 day 2 +/- Bortezomib 1,5 mg/m 2 day 1, 4 Study aim:- Response rate - Progression-free/overall survival - Toxicity/feasability

36 New agents in MCL MechanismORRCRToxicity TemsirolimusmTOR inhibitor 22% (12/54)2%Lung, trcpenia LenalidomideCereblon inhibitor 53% (8/15)20%Hematological Carcinogenic? AgentProteasome inhibitor 33% (47/141)6%Neurotoxicity Idelalisib PI3K  inhibitor 62% (10/16)-ALAT/ASAT elevation IbrutinibBTK inhibitor68% (75/111)21%GI, Bleeding? Venetoclax BCL2 inhibitor100% (7/7)-Neutropenia

37 MCL studier Primärbehandling Recidivbehandling MCL5 (MARIT) MCL4 (LENA-BERIT) RAY (Janssen) TRIANGLE SHINE (Janssen) MCL6 (PHILEMON) ENRICH

38 Sequential treatment algorithm in patients with MCL: first-line treatment for younger, fit versus older and/or frail patients, consolidation or maintenance, and treatment for relapsed/refractory disease. Irit Avivi, and Andre Goy Clin Cancer Res 2015;21: ©2015 by American Association for Cancer Research

39 MCL framtiden ljus! B-cellsreceptorsignallering och BCL-2 hämmare nya fantastiska droger Säkert kommer IMIDs på bred front och PD1- PD1ligand hämmare Vi behandlar redan nu med regimer som helt saknar cytostatika Framtiden är redan här!

40 Att läsa Nationella riktlinjer för MCL 2013 Mantle cell lymphoma: 2015 update on diagnosis, risk- strtification and clinical managment, Vose, AJH Educational Material Impact of novel therapies on current practise, Avivi; Clin Cancer Res 2015 EBMT/EMCL consensus of auto/allo in MCL, Robinson et alLeukemia 2015


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