Mantle Cell Lymphoma

MANTLE CELL LYMPHOMA

Dr Tobias Weiglein, MD, MHBA & Prof Dr Martin Dreyling, MD Ludwigs-Maximilians University Munich, Medical Department for Hemathology and Oncology, Campus Groβhadern, Munich, Germany LEARNING OBJECTIVES

1. To understand the biology of MCL

2. To understand the diagnostic and prognostic factors in MCL

3. To choose the most appropriate first line treatment for different subsets of patients

4. To know about molecular targeted substances and therapy concepts at relapse and refractory disease MANTLE CELL LYMPHOMA

Epidemiology and characteristics

 Accounts for approximately 6% of all NHL cases

 Median age 60-70 years

 Male predominance (men > women 3:1)

 Very frequent extranodal disease manifestation

 Since its worldwide recognition in 1994, it has been known to have a dismal prognosis (“the worst lymphoma to have”), with a median overall survival (OS) rate of 3 years only PROGNOSIS OF MANTLE CELL LYMPHOMA PROGNOSIS OF MCL

Overall survival of MCL compared to other B-NHL entities

Survival of B-cell lymphoma subtypes in the series of the Oncology Institute of Southern Switzerland,1980-2006. Republished with permission of American Society of Hematology, from Blood, Ghielmini M, et al., Blood, 114, 8, 2009, permission conveyed through Copyright Clearance Center, Inc. MANTLE CELL LYMPHOMA HISTOLOGY

A classical; B small cell; C pleomorphic; D: blastoid; E: classical & pleomorphic; F: classical/pleomorphic

Tiemann M, et al., Br J Haematol 2005;131(1):29–38. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. © 2005 Blackwell Publishing Ltd. MANTLE CELL LYMPHOMA BIOLOGY

RB signal pathway in MCL I RB M G1

cdk4/ G2 cyclin D1

S RB P MANTLE CELL LYMPHOMA: A SPECTRUM OF DISEASE

“Indolent” MCL (15%) “Classical” MCL (80%) “Transformed” (5%)

Dreyling M, ASCO Educational 2014. Courtesy of Prof Martin Dreyling MANTLE CELL LYMPHOMA: TWO KINDS OF DISEASE?

Dreyling M, ESMO CR 2017. Courtesy of Prof Martin Dreyling PROGNOSIS OF MCL

 In 1980 -1990s overall median survival (OS) was dismal with 2-4 years at time of diagnosis

 Prognosis depending on clinical variables

 Age

 Stage

 Performance Score

 LDH

 And biological features

 Proliferation Index (Ki67)

 growth pattern (blastoid vs. classical)

Risk factor proliferation: MCL 35

MIPI and MIPI-c MIPI MIPI MIPI low intermediate high

MIPI: Age ECOG Performance status Ki67 Ki67 Ki67 Ki67 Ki67 Ki67 <30% ≥30% <30% ≥30% <30% ≥30% LDH level WBC count

MIPI-c: MIPI-c MIPI-c MIPI-c MIPI-c MIPI + Ki-67 index low low-intermediate high-intermediate high The more refined combined MIPI (MIPI-c) classifies MCL patients into four prognostic groups dependent on MIPI group and Ki-67 index According to MIPI-c, patients are assigned to the low, low-intermediate, high-intermediate, or high risk group

Dreyling M, et al., Haematologica 2016;101(2):104–114. Obtained from the Haematologica Journal website http://www.haematologica.org; Hoster, J Clin Oncol 2016;34(12):1386-94. PROGNOSIS OF MCL

Combined MIPI (MIPI-c)

Patients >65 years Patients <65 years

Hoster E, J Clin Oncol, 34(12), 2016:1386-94. Reprinted with permission. © 2016 American Society of Clinical Oncology. All rights reserved. MANTLE CELL LYMPHOMA TREATMENT MANTLE CELL LYMPHOMA TREATMENT Optimal treatment for MCL?

Induction Consolidation

Maintenance

+/- Immuno-chemotherapy ! SCT

=> lymphoma remission => MRD elimination MANTLE CELL LYMPHOMA TREATMENT Young, fit patients

Young Fit Patient (<65) Old Fit Patient (>65) Old Unfit Patient (>65) Organ Function Organ Function Organ Function Comorbidity Comorbidity Comorbidity Performance Status Performance Status Performance Status

Intensive Therapy: Less Intensive Therapy: Mild Supportive Therapy: Long Term Survival Remission and Better Survival Symptom Control , Survival First Line Therapy*

*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible Dose-intensified Conventional Mild Therapy Immunochemotherapy Immunochemotherapy e.g. R-Chlorambucil R-CHOP / R- DHAP followed by e.g. R-CHOP, B-R B-R Autologous SCT VR -CAP R-CVP + R- Maintenance + Rituximab Maintenance Best Supportive Care? MANTLE CELL LYMPHOMA TREATMENT Role of anti-CD-20 antibody rituximab

 Adding rituximab to CHOP clearly improves PFS an ORR, (ORR 94% vs. 75%, CR 34% vs. 7%)

 Improvement of ORR and PFS with addition of rituximab to polychemotherapy have been confirmed in successive trials

 R-Chemo standard of care in first and successive treatment lines

1. Hoster E, et al., Blood 2008;112(11):3049. Presented at ASH Annual Meeting 2008. Courtesy of Prof Martin Dreyling; 2. Buske C, et al., 2009 Leukemia 2009;23:153–161. MANTLE CELL LYMPHOMA TREATMENT Why CHOP?

From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of older patients with mantle-cell lymphoma, 367,520–31. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. MANTLE CELL LYMPHOMA TREATMENT Autologous SCT and IFN survival rates

Remission duration Overall survival

Treat- Hazard ment Ratio 95% CI p R 0.60 0.42 0.86 0.0056 ASCT 0.50 0.35 0.70 0.0001

Treat- Hazard ment Ratio 95% CI p

R 0.70 0.44 1.12 0.14

ASCT 0.63 0.41 0.97 0.0379

Dreyling M, et al., Blood 2005;105:2677–2684; Hoster E, et al. Blood 2009;114(22):880. Presented at ASH Annual Meeting 2008 Courtesy of Prof Martin Dreyling. MANTLE CELL LYMPHOMA TREATMENT Young fit patients <65 years

3 x R-CHOP PR, CR! 3 x R-CHOP 3 x R-DHAP alternating 3 x R-CHOP (stem cell mobilisation after course 4) PR, CR! DexaBEAM (stem cell mobilisation) TBI 10 Gy Ara-C 4 x 1.5 g/m2 Cyclo 120 mg/kg Melphalan 140 mg/m2 + TBI 12 Gy PBSCT PBSCT

Hermine O, et al., Lancet 2016;388(10044):565–75. MANTLE CELL LYMPHOMA TREATMENT Time to treatment failure in “MCL younger” trial

From The Lancet, 388(10044), Hermine O, et al. ( Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network, 388:565–75. Copyright © 2016 with permission from Elsevier. MANTLE CELL LYMPHOMA TREATMENT MRD at end of induction: Effect of ASCT

R-CHOP R-DHAP 100 ns * p = 0.03

* p = 0.08 * p = 0.007

75 * * 85%

83% 79% 70%

50 % MRD negative MRD % 70% 60% 25 58% 37%

0 PB BM PB BM

Hermine O, et al., Lancet. 2016;388(10044):565–75. MANTLE CELL LYMPHOMA TREATMENT Post ASCT rituximab maintenance: “LyMa” trial

W1 W4 W7 W10 Observation

R-DHAP R-DHAP R-DHAP R-DHAP R-BEAM Rituximab maintenance every 2 months during 3 years If < VGPR If > VGPR

R-CHOP

R-DHAP: Rituximab 375 mg/m2; aracytine 2 g/m2 x2 IV 3 hours injection 12 hours interval; dexamethasone 40 mg d1- 4; Cisplatin 100 mg/m2 d1 (or oxaliplatin or carboplatin) R-BEAM: Rituximab 500 mg/m2 d-8; BCNU 300 mg/m2 d-7; Etoposide 400 mg/m2/d d-6 to -3; aracytine 400 mg/m2/d d-6 to d-3; melphalan 140 mg/m2 d-2

Le Gouill S, et al. N Engl J Med. 2017;377(13):1250-1260 MANTLE CELL LYMPHOMA TREATMENT Post ASCT rituximab maintenance: “LyMa” trial

From N Engl J Med, Le Gouill S, et al. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma, 377, 1250–60. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. MANTLE CELL LYMPHOMA TREATMENT First line treatment young patients: Conclusion

Watch and wait strategy in indolent, low tumour burden patients possible Rituximab – chemo is standard of care in any induction therapy Induction-regimes containing high-dose cytarabin seem to further improve PFS, OS and MRD negativity. ORR is 80-90% with 40-50% CR High-dose chemotherapy, followed by autologous stem cell transplantation prolongs PFS and OS and is the current standard of care for younger patients, generally providing high responses and long survival rates, but is hampered by acute and long-term toxicity R-hyper-CVAD or R-HD-MTX-Ara-C regimen, followed by a consolidation with BEAM and ASCT is an alternative dose intensified (and toxic) approach and are debated, especially between European and American clinical groups Rituximab maintenance every 2 months for 3 years after ASTC improves OS MANTLE CELL LYMPHOMA TREATMENT Older patients / Unfit patients

Intensive Therapy: Less Intensive Therapy: Mild Supportive Therapy: Long Term Survival Remission and Better Survival Symptom Control , Survival First Line Therapy*

*Watch and Wait Strategy in Indolent, Low Tumour Burden Patients Possible Dose-intensified Conventional Mild Therapy Immunochemotherapy Immunochemotherapy e.g. R-Chlorambucil R-CHOP / R- DHAP followed by e.g. R-CHOP, B-R B-R Autologous SCT VR -CAP R-CVP + R- Maintenance + Rituximab Maintenance Best Supportive Care? IMMUNO-CHEMOTHERAPY IN ELDERLY >65 YEARS Progression-free survival

• Bendamustine in combination with rituximab can be applied with comparable ORR and OS rates as R-CHOP, but with lesser side effects

Reprinted from The Lancet, 381(9873), Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial, 1203–10. Copyright 2013, with permission from Elsevier. MANTLE CELL LYMPHOMA TREATMENT MCL elderly survival rates (R-CHOP)

Remission duration Overall survival

• Rituximab as maintenance therapy every two months following R-CHOP chemotherapy significantly improves PFS

From N Engl J Med, Kluin-Nelemans HC, et al. Treatment of Older Patients with Mantle-Cell Lymphoma, 367:520–31. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. BORTEZOMIB IN MCL

VR-CAP vs. R-CHOP

 No maintenance Therapy after induction!

 59% improvement with VR-CAP vs. R-CHOP (hypothesised: 40% improvement)

 Median PFS by investigator was 16.1 vs. 30.7 months with R-CHOP vs. VR-CAP

From N Engl J Med, Robak T, et al. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma, 372:944–53. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. FIRST LINE ELDERLY PATIENTS

Conclusion

In elderly patients with compromised organ function and performance score, conventional immuno-chemotherapy is the first choice with ORR of ~90% Fludarabin-containing regimens are inferior to R-CHOP in terms of OS Rituximab as maintenance therapy every two months following R-CHOP chemotherapy significantly improves PFS Bendamustin in combination with Rituximab can be applied with comparable ORR and OS rates as R-CHOP, but with lesser side effects Bortezomib in combination with R-CAP (VR-CAP) shows better PFS compared to R-CHOP with more (haemoto-) toxicity and may be a good option for aggressive (e.g. blastoid) MCL in elderly patients not eligible for ASCT In very frail patients Rituximab mono or Rituximab and oral Chlorambucil is an effective and well tolerated regime, especially in low risk or rather indolent cases MANTLE CELL LYMPHOMA TREATMENT

First Relapse / Refractory Disease

Immunochemotherapy Immunochemotherapy Immunochemotherapy e.g. B-R e.g. B-R, R-CHOP, R-BAC e.g. B-R (dose reduced) R-BAC Targeted Approaches Targeted Approaches Best Targeted Approaches Repeat First Line? Supportive Care? Repeat First Line? Consider: R- Maintenance Consider: Allogeneic SCT Radioimmunotherapy

Higher Relapse

Targeted Approaches: Ibrutinib, Lenalidomide, Temsirolimus, Bortezomib (preferable in combination with chemotherapy) Alternatively: repeat previous therapy (long remissions)

R, Rituximab, B-R, Bendamustine-Rituximab, R-CHOP, Rituximab/ Cyclophosphamide/ Doxorubicin/ Vincristine/Prednisone, VR-CAP, Bortezomib/Rituximab/Cyclophosphamide/Doxorubicin/Prednisone R-DHAP, Dexamethason/high-dose Cytarabine/Cisplatin, R-CVP- Rituximab/Cyclophosphamide/Prednison R-BAC, Rituximab/Bendamustine/Cytarabine, SCT- Stem-Cell Transplantation TARGETED SUBSTANCES AT RELAPSE

Temsirolimus is registered in EU and has shown superiority over other agents in heavily pre-treated patients with ORR of 23%, and PFS of 4.8 months

1.0 Lenalidomide IC 0.9 (n = 170) (n = 84) 0.8 Median PFS, mo (95% CI) 8.7 (5.5-12.1) 5.2 (3.6-6.9) 0.7 HR (95% CI) 0.61 (0.44-0.84); P = 0.004 Lenalidomide 0.6 8.7 mo 0.5 0.4

Survival probability Survival 0.3 Control 0.2 5.2 mo Lenalidomide 0.1 IC 0.0 0 5 10 15 20 25 30 35 40 45 50 55 Progression-free survival, months Number of patients at risk Lenalidomide 170 86 63 36 27 20 16 12 7 1 1 0 IC 84 31 15 7 5 4 4 2 0

Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival with lenalidomide compared to investigator's choice of monotherapy

Reprinted from The Lancet Oncol, 17(3), Trněný M, et al. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial, 319–31, Copyright 2016, with permission from Elsevier. TARGETED SUBSTANCES AT RELAPSE Ibrutinib TARGETED SUBSTANCES AT RELAPSE Ibrutinib Temsirolimus Median PFS (months) 14.6 6.2 100 Hazard ratio (HR) 0.43 90 95% confidence interval (CI) 0.32-0.58 80 Log-rank p value < 0.0001

70 ITT population 60 Median follow-up: 20 months

50 40 Ibrutinib

30 % alive without without progression alive % 20

10 Temsirolimus 0 0 3 6 9 12 15 18 21 24 27 30 Patients at risk Months Ibrutinib 139 114 101 83 77 45 34 8 5 0 0 Temsirolimus 141 93 69 45 33 19 11 3 1 0 0

At a 2-year landmark, the PFS rate was 41% for ibrutinib versus 7% for temsirolimus Investigator-assessed HR for ibrutinib versus temsirolimus was 0.43 (95% CI, 0.32-0.58)

Reprinted from The Lancet, 387(10020), Dreyling M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study, 770–8, Copyright 2015, with permission from Elsevier. TARGETED SUBSTANCES AT RELAPSE Adverse events ibrutinib

*AEs were updated with an estimated median follow-up of 26.7 months Republished with permission of American Society of Hematology, from Blood, Wang ML, et al. 126(6), 2015, permission conveyed through Copyright Clearance Center, Inc. OUTLOOK: TAILORED MEDICINE

First line MCL suggested therapeutic algorithm

TP53, SOX11 negative NOTCH1, Mutational screening without adverse other mutations MIPI-c risk

High High Low Low intermediate intermediate HD AraC + HD AraC + HD AraC Conventional treatment anthracyclin biological agent (low tumour load: + biological agent MRD+ MRD- watch and wait)

Post-treatment risk ASCT evaluation: MRD

MRD+ MRD- Consolidation/ Observation maintenance

Dreyling M, et al. Haematologica 2016;101(2):104–14. Obtained from the Haematologica Journal website http://www.haematologica.org THERAPY AT RELAPSE

Conclusion I

Immuno-chemotherapy is standard of care at relapse and is chosen depending on patient fitness and age, comorbidities, earlier therapy and duration of response

The mTOR-inhibitor temsirolimus can achieve better ORR, PFS and OS compared to mono-chemotherapy at relapsed or refractory disease

In relapsed or refractory disease ibrutinib increases ORR from 40% to 72% and PFS (hazard ratio 0,43; median 8,4 months) compared to temsirolimus. OS is not affected by ibrutinib (due to crossover)

Lenalidomide also increases ORR and PFS compared to physicians choice in relapsed and refractory disease THERAPY AT RELAPSE

Conclusion II

Bortezomib also shows promising activity in MCL as monotherapy or in combination, yet no Phase III data is available in refractory or relapsed disease, e.g. a combination of bortezomib and bendamustin + rituximab (BERT) shows high activity in a Phase II study

Rituximab maintenance therapy after salvage immunochemotherapy leads to improved PFS and can be discussed

If HD-Ctx and ASCT has not been performed as first line therapy, eligible patients should be offered a HD-Ctx and ASCT after lymphoma remission in relapse

Young fit patients relapsing after HD-Ctx and ASCT should be offered an allogenic transplantation if a donor is available OUTLOOK: BCL-2 INHIBITION

Venetoclax

75% OR 38% 18% (21%) (CR 11%) (12%)

Davids MS, et al. J Clin Oncol, 35(8), 2017:826–33. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved. OUTLOOK: CHEMOTHERAPY FREE COMBINATIONS? First line: Rituximab-lenalidomide

Progression-free survival

From N Engl J Med, Ruan J, et al. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma, 373:1835–44. Copyright © 2015 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. OUTLOOK: COMBINATION THERAPY European MCL Network Study generation 2017

< 65 years > 60 years > 65 years MCL younger: MCL elderly R2: MCL elderly I: R-CHOP/DHAP =>ASCT R-CHOP vs. R-CHOP/Ara-C BR +/- Ibrutinib R-CHOP/DHAP+I =>ASCT => I => Rituximab M => Rituximab M R-CHOP/DHAP + I => I +/-Lenalidomide +/- Ibrutinib

1. Relapse

R-HAD +/- Bortezomib

2. Relapse (or not qualifying for R-HAD)

BeRT Ibrutinib vs. temsirolimus BR-temsirolimus THANK YOU!