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

MCL indolent till aggressive sjukdom CR, complete response; MCL, mantle cell lymphoma; OS, overall survival. Indolent Very Aggressive

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

Överlevnaden ökar i Sverige 2006 -2010 5 year OS 47% 2000-2005 5 year OS 37% Abrahamsson et al 2011, Leuk Lymphoma

Indolent versus behandlingskrävande Population-based study Sweden-Denmark 2000-2010 1389 pts with MCL Watch and wait (2.1 %) Local radiotherapy (3.4 %) <65 chemotherapy (33%) >65 chemotherapy (60%) Abrahamsson et al 2013

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

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

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

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)

MCL: Fördubbling av överlevnaden Median OS increased from 2.7 to 4.8 yrs 1.0 GLSG (1996-2004) 0.8 KLG (1975-1986) 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 202 134 171 105 145 74 117 43 82 30 47 12 20 3 3 2 0 1 Herrmann A, et al. J Clin Oncol. 2009;27:511-518.

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

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;111:558-565.

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

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

Indolent versus behandlingskrävande Population-based study Sweden-Denmark 2000-2010 1389 pts with MCL Watch and wait (2.1 %) Local radiotherapy (3.4 %) <65 chemotherapy (33%) >65 chemotherapy (60%) Abrahamsson et al 2013

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

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

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: 1 4 7 10 13 14 MCL-2 TRIAL 2000-2006 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: 1 4 7 10 13 16 19 20 AraC: 4 Infusions: < 60 years 3g/m2, > 60 years 2g/m2

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

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

Time to treatment failure PP Hazard Ratio 0.68 p=0.0382 (one sided sequential test) European MCL Network, V0.3 26.11.2010 21

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

MCL5: Only MIPI high risk <65 years

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)

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

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

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)

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

MCL Elderly: RD R vs. IFN PP Hazard Ratio 0.56 p=0.0118 (sequential test) Update October 5, 2010, European MCL Network, V2.1, 29.10.2010

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. 2013 Apr 6;381(9873):1203-10.

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 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. 2013 Apr 6;381(9873):1203-10.

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

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

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

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 375 mg/m2 day 1 Ara-C 2 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

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

MCL studier Primärbehandling TRIANGLE MCL5 (MARIT) MCL4 (LENA-BERIT) SHINE (Janssen) ENRICH Recidivbehandling RAY (Janssen) MCL6 (PHILEMON) 2012 2013 2014 2015 2016

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;21:3853-3861 ©2015 by American Association for Cancer Research

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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