Mantelcell lymfom Från indolent till aggressive sjukdom

En presentation över ämnet: "Mantelcell lymfom Från indolent till aggressive sjukdom"— 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
CR, complete response; MCL, mantle cell lymphoma; OS, overall survival. Indolent Very Aggressive

3 Swedish Lymphoma Registry
MCL 5%% Mest visade diagrammet från SLR – tre vanliga typer, resten ovanliga sjd. 70-80/år Sverige 3

4 Överlevnaden ökar i Sverige
5 year OS 47% 5 year OS 37% Abrahamsson et al 2011, Leuk Lymphoma

5 Indolent versus behandlingskrävande
Population-based study Sweden-Denmark 1389 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 1.0 GLSG ( ) 0.8 KLG ( ) 0.6 Survival Probability 0.4 0.2 GLSG, German Low Grade Lymphoma Study Group; KLG, Kiel Lymphoma Study Group; MCL, mantle cell lymphoma; OS, overall survival. P < .0001 1 2 3 4 5 6 7 8 9 10 Survival Time (Yrs) Patients at Risk, n GLSG KLG 145 74 117 43 82 30 47 12 20 3 3 2 0 1 Herrmann A, et al. J Clin Oncol. 2009;27:

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 Survival After Diagnosis by MIPI 1.0 0.8 0.6 Probability of OS 0.4 LR, median not reached 0.2 IR, median: 51 HR, median: 29 12 24 36 48 60 72 84 96 ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MCL, mantle cell lymphoma; MCP, melphalan, chlorambucil, prednisone; MIPI, mantle cell lymphoma international prognostic index; OS, overall survival; R, rituximab. Mos Since Registration Hoster E, et al. Blood. 2008;111:

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 1389 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 MCL-1 TRIAL 1996-2000 MCL-2 TRIAL 2000-2006 B E A M/C B E A M/C R R RR
INDUCTION RE- STAGE STEM-CELL HARVEST REINFUSION B E A M/C Maxi C H O P Maxi C H O P Maxi C H O P Maxi C H O P Week: MCL-2 TRIAL INDUCTION RE- STAGE STEM-CELL HARVEST REINFUSION R R RR B E A M/C Disappointed by the results of MCL1, we designed a second protocol, using the same inclusion criteria. Including 2 additional agents, 3 courses of cytarabine and 4 doses of rituximab. One rituximab dose was given immediately before stem cell harvest as in vivo purging. We also followed MRD by PCR during and after chemotherapy, giving pre-emptive rituximab x4 if PCR+. This trial went on for 6 years, included 160 pts. Pre-empt R in PCR+ Maxi C H O P A r a C Maxi C H O P A r a C Maxi C H O P A r a C Week: AraC: 4 Infusions: < 60 years 3g/m2, > 60 years 2g/m2

19 MCL2 - Event-free and overall survival
63% 15% 75% The improvemnet in response translated into a marked improvement in survival. By intention to treat, we see an event-free survival plateau at 63% at 5 years in protocol 2, vs 15% in protocol 1. The overall survival is 75% vs 46%, both differences highly statistically significant. 46% Geisler et al Blood 2008

20 mobilization after course 6
MCL Younger Protocol Design (2+1) x R-CHOP/R-DHAP alternating 4 x R-CHOP 2 x R-CHOP PR, CR stem cell mobilization after course 6 PR, CR DexaBEAM (stem cell mobilization) TBI 10 Gy Ara-C 4 x1.5 g/m2 Melphalan 140 mg/m2 Cyclo 120mg/kg + TBI 12 Gy PBSCT PBSCT 20

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

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

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

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

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

30 StiL: First-line Bendamustine + Rituximab in Patients With FL, Indolent, and MCL
B 90 mg/m2 on Days 1, 2 + R 375 mg/m2 on Day 1 Max 6 cycles, q4w (n = 260) Stage III or IV CD20+ lymphoma (N = 549) R-CHOP Max 6 cycles, q3w (n = 253) B, bendamustine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; FL, follicular lymphoma; MCL, mantle cell lymphoma; R, rituximab. Rummel MJ, et al. Lancet Apr 6;381(9873):

31 StiL: PFS (Primary Endpoint)
B-R superior to R-CHOP for PFS in overall population (54.9 vs 34.8 mos; P = ) In subanalysis, B-R superior to R-CHOP in MCL (P = .0146) Mantle cell 1.0 0.8 P = .0146 R-CHOP 0.6 Proportion Surviving Without Progression B-R 0.4 B-R, bendamustine, rituximab; MCL, mantle cell lymphoma; PFS, progression-free survival; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone. 0.2 12 24 35 48 60 72 Mos Rummel MJ, et al. Lancet Apr 6;381(9873):

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 2-12. 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
Regimens Bendamustine ± R Bortezomib ± R Cladribine + R Fludarabine-based regimens: FC ± R; FCMR; FMR Lenalidomide ± R PCR (pentostatin, cyclophosphamide, rituximab) Ibrutinib FC, fludarabine, cyclophosphamide; FCMR, fludarabine, cyclophosphamide, mitoxantrone, rituximab; FMR, fludarabine, mitoxantrone, rituximab; NCCN, National Comprehensive Cancer Network; PCR, pentostatin, cyclophosphamide, rituximab; PEPC, prednisone, etoposide, procarbazine, cyclophosphamide; R, rituximab; RT, radiotherapy. consideration of allogeneic transplantation Optional regimens or RT or clinical trial

35 relapsed MCL R-HAD+/- bortezomib)
European MCL network relapsed MCL R-HAD+/- bortezomib) Patients: n=250, relapsed MCL after/not appropriate for autologous PBSCT Therapy: Dexamethasone 40 mg day 1-4 Rituximab mg/m2 day 1 Ara-C x 1–2 g/m2 day 2 +/- Bortezomib 1,5 mg/m2 day 1, 4 Study aim: - Response rate - Progression-free/overall survival - Toxicity/feasability

36 New agents in MCL Venetoclax Mechanism ORR CR Toxicity Temsirolimus
mTOR inhibitor 22% (12/54) 2% Lung, trcpenia Lenalidomide Cereblon 53% (8/15) 20% Hematological Carcinogenic? Agent Proteasome 33% (47/141) 6% Neurotoxicity Idelalisib PI3Kd 62% (10/16) - ALAT/ASAT elevation Ibrutinib BTK inhibitor 68% (75/111) 21% GI, Bleeding? Venetoclax BCL2 inhibitor 100% (7/7) Neutropenia

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

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. 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. First-line treatment is commonly selected on the basis of patient's age and condition, gauging a patient's tolerability to aggressive versus less aggressive induction immunochemotherapy. Patients eligible for HDT are typically considered for cytarabine-containing induction regimen, such as R-CHOP/R-DHAP followed by ASCT or R-hyper-CVAD if tolerated. Older, transplant-ineligible or unfit patients mainly receive BR, R-CHOP, or R-CHOP-bortezomib induction followed by rituximab maintenance. Non-myeloablative allogeneic transplant is a potential approach for special cases of fit patients who failed several lines of therapy; its use reflects a physician preference rather than significant clinical evidence. FDA-approved therapies for relapsed/refractory MCL include bortezomib, lenalidomide, and ibrutinib, whereas temsirolimus is approved in the EU. CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; EU, European Union; HD, high dose; PD, progressive disease; R, rituximab; R-CHOP, rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone; R-DHAP, rituximab, dexamethasone, cytarabine, cisplatin; SCT, stem cell transplantation. 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