Managing the Controversies in the Treatment of Mantle Cell Lymphoma

Michael Wang, MD�Puddin Clarke Endowed Professor�Director, Mantle Cell Lymphoma Program of Excellence�Section Chief, Rare Lymphomas�Co-PI, B-cell Lymphoma Moonshot Project�Department of Lymphoma and Myeloma�MD Anderson Cancer Center

Disclosures

Consultancy: Acerta Pharma, AstraZeneca, Bristol Myers Squibb, Boxer Capital, Galapagos NV, Genmab, InnoCare, Janssen, Kite Pharma, Lilly, Merck, PER, Pfizer, Oncternal

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Research: Abbvie, Acerta Pharma, AstraZeneca, Bantam Pharma, BeiGene, BioInvent, Celgene, Genmab, Genentech, Innocare, Janssen, Juno Therapeutics, Kite Pharma, Lilly, Loxo Oncology, Molecular Templates, Nurix Therapeutics, Oncternal, Pharmacyclics, Velosbio, Vincerx

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Honoraria: AstraZeneca, BeiGene, Binaytara Foundation, Bristol Myers Squibb, CAHON, Editorial Medica AWWE SA, East Virtinia Medical School, Instituto Scientifico Romagnolo, Janssen, Kite Pharma, Mayo Clinic, MJH Life Sciences, Merck, MSC National Research Institute of Oncolgy, Pfizer, Physicians Education Resources (PER), Plexus Communications, PromCon S.R.E., Research to Practice, Studio ER Congressi, South African Clinical Hematology Society, Medscape/WebMD, VJHemonc

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Approaching a MCL patient new to me

• Age, <65, >=65; 65+/-5=60-70
• Urgent or Non-urgent, immediate Rxs (steroids+/-R, chemo =/-XRT, XRT alone, apheresis, HD, nephrostomy tubes)
• Clinical, PS, comorbidity (especially cardiac hx, renal function, BM function, etc)
• Organ system involvement:- Ln/mass, splenomegaly, GI tract, bone marrow, CNS involvement(high-risk), orbit, sinus, adrenal
• Labs, lymphocytosis, creatinine, LFTs, CBC-diff, PB flow
• Pathology, CLL/MCL?, pleomorphic/blastoid?, Ki67: ,30%-50%-100%, Ki67 > morphology, Complex karyotype
• Staging, Cheson criteria, Lugano Criteria, BM, GI scopes, CR confirmation at MDACC (PET-CT, BM and GI biopsies)
• Treatment Hx response and duration to each prior Rx, POD 24? BTKi hx? CAR T hx?, transplant Hx, Toxicities?
• Genetics, TP53, Sox11, c-Myc, (others like NSD2, NOTCH1/2, KMD-2, etc)
• Patient personal hx, insurance, home location, family support, collaborations (team set up), etiology
• At MDACC MCL Program of Excellence, front-door genetic panel and MRD, RNA-seq for R/R MCL

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Controversies at Frontline Therapy for Pts =>65

• Trials, R-Pirtobrutinib, R-Pirtobrutinib-Venetoclax, Acalabrutinib-Venetoclax-R (Traverse trial)

• Off trials, A-R, R2, Rarely: BR-R or RCHOP-R, BR-Acalabrutinib (ECHO)
• High Risk, Ki67>50%, TP53, Pleomorphic/blastoid, use clinical trials if available
• Consider AVR (acalabrutinib-venetoclax-R)
• Consider ZVO (zanubrutinib-venetoclax-O)
• Consider AR2 (acalabrutinib-revlimid-R)
• Frontline therapy, most important therapy, many patients have only one opportunity!
• natural history of MCL, response hx to therapies, toxicities to therapies, patients’ biological resources, patients financial/social resources
• There is art in maintenance after any frontline Rx, it is a mandatory consideration!
• Be aware of COVID risks

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Acalabrutinib plus bendamustine and rituximab in untreated mantle cell lymphoma (MCL): Results from the phase 3, double-blind, placebo-controlled ECHO trial

Michael Wang¹, Jiri Mayer², David Belada³, Yuqin Song⁴, Wojciech Jurczak⁵, Jonas Paludo⁶, Michael P. Chu⁷, Iryna Kryachok⁸, Laura Fogliatto⁹, Chan Cheah¹⁰, Marta Morawska^11,12, Juan-Manuel Sancho¹³, Yufu Li¹⁴, Caterina Patti¹⁵, Cecily Forsyth¹⁶, Jingyang Zhang¹⁷, Robin Lesley¹⁷, Safaa Ramadan¹⁸, Simon Rule¹⁸, Martin Dreyling¹⁹

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¹MD Anderson Cancer Center, University of Texas, Houston, TX, USA; ²University Hospital Brno, Brno, Czech Republic; �³4th Department of Internal Medicine – Haematology, Charles University, Hospital and Faculty of Medicine, Hradec Králové, Czech Republic; �⁴Peking University Cancer Hospital & Institute, Beijing, China; ⁵Malopolskie Centrum Medyczne S.C, Krakow, Poland; �⁶Mayo Clinic, Rochester, MN, USA; ⁷Cross Cancer Institute, University of Alberta, Edmonton, Canada; ⁸National Cancer Institute, Kyiv, Ukraine; �⁹Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil; ¹⁰Sir Charles Gairdner Hospital, Nedlands, Australia; ¹¹Experimental Hematooncology Department, Medical University of Lublin, Lublin, Poland; ¹²Hematology Department, St. John's Cancer Center, Lublin, Poland; �¹³ICO-IJC-Hospital Germans Trias i Pujol, Badalona, Spain; ¹⁴Henan Cancer Hospital, Zheng Zhou, China; �¹⁵A.O.O.R. Villa Sofia Cervello, Palermo, Italy; ¹⁶Central Coast Haematology, North Gosford, Australia; �¹⁷AstraZeneca, South San Francisco, CA, USA; ¹⁸AstraZeneca, Cambridge, UK; ¹⁹Klinikum der Universitaet Munchen, Muenchen, Germany

Presented at the European Hematology Association (EHA) Annual Meeting; June 13–16, 2024; Madrid, Spain

Study Design

Crossover to acalabrutinib after PD was permitted

ECHO: multicenter, double-blind, placebo-controlled, Ph 3 trial

^aBendamustine 90 mg/m² on days 1 and 2. ^bRituximab 375 mg/m² on day 1.

BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; MCL, mantle cell lymphoma; sMIPI, simplified Mantle Cell Lymphoma International Prognostic Index; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; PR, partial response.

Enrollment: Apr 2017–Mar 2023

Sites: 195 globally

1 cycle = 28 days

Acalabrutinib 100 mg BID, PO until PD or toxicity 

Placebo BID, PO until PD or toxicity 

Best Overall Response and Complete Response Rates

• An additional 13% of patients achieved CR with acalabrutinib + BR

91.0%

88.0%

BR, bendamustine + rituximab; CI, confidence interval; CR, complete response; ORR, overall response rate; PR, partial response.

PFS (primary endpoint) Was Significantly Improved With Acalabrutinib + BR

^aAt a median follow-up of 45 months.

ABR, acalabrutinib + bendamustine + rituximab; BR, bendamustine + rituximab; BTKi, Bruton tyrosine kinase inhibitor; CI, confidence interval; HR, hazard ratio; NE, not estimable; PBR, placebo + bendamustine + rituximab; PD, progressive disease; PFS, progression-free survival.

• Significant improvement in median PFS by ~17 mo
• 27% reduction in risk of PD or death^a

69% received BTKi as subsequent treatment

Progression-Free Survival, %

Number at risk

Acala + BR

Placebo + BR

Acalabrutinib + BR

Placebo + BR

Overall Survival Including Crossover

Overall Survival, %

Number at risk

Acala + BR

Placebo + BR

Acalabrutinib + BR

Placebo + BR

Median follow-up of 45 months.

ABR, acalabrutinib + bendamustine + rituximab; BR, bendamustine + rituximab; CI, confidence interval; HR, hazard ratio; NE, not estimable; OS, overall survival; PBR, placebo + bendamustine + rituximab.

Controversies at Firstline Therapy for Pts =<65

Trials, R-Pirtobrutinib, R-Pirtobrutinib-Venetoclax, Acalabrutinib-Venetoclax-R (AVR

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Off trials, AVR, A-R2, Boven (ZVO), Nordic, R-HCVAD/MTX-Ara C, Triangle

• High Risk, Ki67>50%, TP53, Pleomorphic/blastoid,
• Consider AVR (acalabrutinib-venetoclax-R) or ZVR (zanubrutinib-venetoclax-R)
• Consider ZVO (zanubrutinib-venetoclax-O)
• Consider AR2 (acalabrutinib-revlimid-R)
• Frontline therapy, most important therapy, many patients have only one opportunity!
• There is art in maintenance after any frontline Rx, it is a mandatory consideration!
• Future:
• genetics, frontline bi/tri-abs, scFv T cell engagers, CAR T/NK/NKTs, targets
• MRD (mutation-based)

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TRIANGLE: �autologous Transplantation after a �Rituximab/Ibrutinib/Ara-c containing iNduction �in Generalized mantle cell Lymphoma – �a randomized European mcl network trial

M Dreyling, J Doorduijn, E Giné, M Jerkeman, J Walewski, M Hutchings, U Mey, J Riise, M Trneny, V Vergote, M Celli, O Shpilberg, �M Gomes da Silva, S Leppa, L Jiang, C Pott, W Klapper, D Gözel, C Schmidt, M Unterhalt, M Ladetto*, E Hoster

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LMU University Hospital Munich, Germany; Erasmus MC Cancer Institute, University Medical Center Rotterdam, Netherlands; Hospital Clinic of Barcelona, Spain; Skane University Hospital and Lund University, Lund, Sweden; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland; Rigshospitalet, Copenhagen University Hospital, Denmark; Kantonsspital Graubuenden, Chur, Switzerland; Oslo University Hospital, Oslo, Norway; Charles University and General University Hospital, Prague, Czech Republic; University Hospitals Leuven, Belgium; Ospedale degli Infermi di Rimini, Italy; Assuta Ramat Hahayal Medical Center, Tel Aviv, Israel; Instituto Português de Oncologia, Lisboa, Portugal; Helsinki University Hospital Comprehensive Cancer Center, Finland; �IBE, LMU University Munich, Germany; University of Schleswig-Holstein, Kiel, Germany; Az Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Presented at ASCO 2022 Annual Meeting; June 3-7, 2022; Chicago, IL, USA.

TRIANGLE: Trial Design

• MCL patients
• previously untreated
• stage II-IV
• younger than 66 years
• suitable for HA and ASCT
• ECOG 0-2

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• Primary outcome: FFS�
• Secondary outcomes:
• Response rates
• PFS, RD
• OS
• Safety

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• R maintenance was added following national guidelines �in all 3 trial arms
• Rituximab maintenance (without or with Ibrutinib) was started in �168 (58 %)/165 (57 %)/158 (54 %) of A/A+I/I randomized patients.

TRIANGLE: FFS Superiority of A+I vs. I ?

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• Test A+I vs. I ongoing, �no decision yet

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A+I arm: IR-CHOP/R-DHAP+ASCT+I; I arm: IR-CHOP/R-DHAP+I. I: ibrutinib

TRIANGLE: Overall survival

• 3-year OS:
• A: 86% (MCL Younger exp.: 84%)
• A+I: 91%
• I: 92%
• Too early to evaluate �statistical significance

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A arm: R-CHOP/R-DHAP+ASCT; A+I arm: IR-CHOP/R-DHAP+ASCT+I; I arm: IR-CHOP/R-DHAP+I. I: ibrutinib

ACE-LY-106: Acalabrutinib plus Venetoclax and Rituximab in Patients with Treatment-Naïve MCL

Phase 1b multicenter, open-label trial

CR, complete response; ECOG PS, Eastern

Cooperative Oncology Group performance status; PD, progressive disease; PR, partial response; SD, stable disease.

Wang ML, et al. Blood 2021;138(Suppl_1):2416.

• Previously untreated MCL
• ECOG PS ≤2
• No history of CNS lymphoma or leptomeningeal disease
• No significant cardiovascular disease
• Primary endpoint = safety

Acalabrutinib-Venetoclax-Rituximab: Survival

Trial Therapy for Relapsed/refractory MCL at MDACC

• Targeted agents/combinations
• BTK degraders, BCL-2i
• Acalabrutinib-Venetoclax, Pirtobrutinib-Venetoclax, pirtobrutinib VS covalent BTKi
• Ab and Bispecific Ab
• Epicuritamab, glofitamab, tafasitamab-lenalidomide-venetoclax
• polatuzumab-Mosunotuzumab, tafatuzumab-lenalidomide
• Tri-specific antibodies, CD19-CD79b-CD3
• Odronextamab
• Cellular therapies
• CD70 Car NK cells
• CD20-CD19 dual CAR T cells

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Off-Trial Therapy for Relapsed/refractory MCL

• Targeted agents/combinations
• BTKis, covalent (acalabrutib, zanubrutinib); non-covalent (pirtobrutinib)
• R2, bortezomib, venetoclax, DR2Ve (Dex-R—Revlimd-Velcade)+/-XRT, R2-Venetoclax
• Brexucabtagene Autoleucil (tecartus) and Lisocabtagene Maraleucil (Liso-cel)
• Preparation for Car T therapy, PS, family conference
• Bridging therapy to control pre-infusion tumor load, use of XRT
• CRS, NE and Infections
• Chemotherapy
• BR, RCHOP, CTX based therapy, Ara-C based therapy, DHAP, MINE, RICE, Gem-Ox, HCVAD/Ara C, R-BAC, ESHAP (IdSHAP), and other therapies
• Use of R-Hyper CTX-Dex +/- XRT
• Allogeneic stem cell transplant
• XRT is important, many forget, low-dose XRT is novel, synergy should always be considered
• Be aware of COVID risks

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FDA Approved Therapies for MCL

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma

Unique Presentations in MCL

• CNS MCL, almost all in relapsed setting, orbital MCL is part of CNS MCL, Leptomeningeal MCL
• BTKis, R-acalabrutinib, R2, XRT, MTX-based therapies, pirtobrutinib?
• Extreme lymphocytosis
• Screen for PE, consider lymphocytosis, MCL versus CLL (CD20 density, slow rituximab, chemo with delayed rituximab), apheresis
• Cutaneous MCL
• Almost always aggressive when multiple lesions, resistant to all therapies including to Car T cells, combined modality and multi-agent maintenance
• MCL in testicles, adrenal glands, thyroids, tear ducts, lungs
• Spontaneous regressions of MCL
• MCL flares with immunotherapies
• MCL emergencies
• pain, headache, spleen rapture, renal failure, blocked tubes, effusions/ascites

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Special Considerations in MCL

• Watch and wait
• Secondary malignancies in MCL, under-estimated, under-reported, chemo vs chemo-free, multiple malignancies
• Strategy, plan for the whole life
• Geographic limitations and considerations
• Collaboration with patients and families
• Be available, my experience with cell phones and emails

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Challenges in MCL

• Faster translation of basic research data to clinical outcomes
• Enrolment is down due to improved therapies and competing trials, set up network
• Mentoring the next generation
• Evolving FDA policies on indication approvals
• Inadequate Collaborations
• Slow transition from Relapsed to frontline and combinations
• Emerging toxicities due immunotherapies
• Too dependent on other diseases for progress such as DLCL, FC, CLL/SLL
• Non-uniform MRD methods
• Non-targetable genetic lesions
• Basic and Translational research is inadequate

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Thank you!