mantle cell lymphoma...abdominal pain/fullness, anorexia, weight loss symptoms from other organ...

Mantle Cell Lymphoma

Lymphoma Research FoundationPatient Education Forum

October 19, 2019

Kami Maddocks, MD

The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute 2

Overview

Treatment OptionsFrontlineRelapse Side Effects

Research and Clinical Trials

Questions and Answers

Disease Biology

Evaluation and Testing

Signs/symptoms

Overview of Mantle Cell Lymphoma


Lymphoma

B-lymphocytes 80-85%

Non-Hodgkin’s Lymphoma

Low Grade/Indolent Lymphoma

Mantle Cell Lymphoma

High Grade/ Aggressive Lymphoma

Hodgkin’s Disease

T-lymphocytes 13-14%

NK cells 1-2%


Blood cells• White blood cell (fights infection)

• Red blood cell (carries oxygen)

• Platelet (helps blood to clot) Plasma• The liquid part of the blood

• Mostly water

• Vitamins, minerals, proteins, hormones and other natural chemicals


• Marrow

• Lymphocytes

• Lymph nodes

• Spleen


Epidemiology

74,200 cases of NHL diagnosed in 2019 MCL represents 3-10% of NHL ~5,000 new cases/year

Median age 68 years old Male Predominance 2:1

The Ohio State University Comprehensive Cancer Center –Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

Subtypes of Mantle Cell Lymphoma

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Classical

Leukemic

Signs/Symptoms of Mantle Cell Lymphoma


Symptoms/Presentation

Lymphadenopathy - Enlarged Lymph Nodes (75%)

Enlarged spleen (50-60%) Abdominal pain/fullness, anorexia, weight loss

Symptoms from other organ involvement (25%) GI tract, orbit, pleura

B symptoms (1/3) Fevers, drenching night sweats, weight loss


Symptoms/Presentation

CBC abnormalities – abnormal blood counts Elevated white blood cell count – MCL cells in the

peripheral blood

Low blood counts: anemia (low hemoglobin), thrombocytopenia (low platelets) or low WBC Abnormal on blood check Symptoms including fatigue, shortness of breath, bleeding, infection Can be due to bone marrow involvement or enlarged spleen

Evaluation of Mantle Cell Lymphoma


Diagnosis Lymph node or other tissue biopsy Better to have more tissue than less such as an entire

lymph node

Testing on the blood Immunophenotyping or flow cytometry – specific cell

markers Chromosome Translocation – t(11;14)

Results in dysregulation of cell cycle – cyclin D1 protein Drives increased proliferation

Bone marrow biopsy


Uniform small-to-medium sized pale cytoplasm irregular nucleus


Evaluation/Testing (“Staging”) Laboratory studies including CBC with differential,

chemistry panel, lactate dehydrogenase (LDH), uric acid

Imaging Computed tomography (CT) scans Positron emission tomography (PET) scans

Bone marrow biopsy and aspirate Additional potential testing Hepatitis Echocardiogram LP


Ann Arbor Staging System

Stage I Stage II Stage III Stage IV


Sites of disease Most patients will have Stage III-IV disease Lymph nodes most common site involved More often diffuse

Spleen, Bone Marrow, Peripheral Blood Other organs - Extranodal sites

GI tract such as colon, stomach Tonsils Less common but possible: bone, lungs, liver, CSF


Prognosis Improved with new treatments available at relapse

MCL is a heterogenous disease – Not everyone’s disease behaves the same Some people have very slow growing/indolent, some more

fast growing/aggressive

New treatment strategies now and in development Different chemotherapies, new targeted therapies,

maintenance approaches, autologous stem cell transplant Likely to continue to improve with current research therapies

available


Prognostic Factors Type of cells and Growth Pattern (Morphology) Blastoid variant

Mantle Cell Prognostic Index Age, LDH, WBC, PS

Rate of cell division (ki-67) ≤ 30% vs > 30%

Complex karyotype

Mutated or dysregulated genes TP53 (17p)

Treatment Options for Mantle Cell Lymphoma

Initial Therapy


Treatment Options No Standard Therapy for MCL Harder to study treatments in large groups of

patients because not as common of lymphoma Several acceptable or “right” therapies - prolong

time in remission Treatment choices dependent on several factors Stage of Disease Symptoms and behavior Patient Age Patient’s general health conditions


Treatment Options: Stage Early stage disease – Stage I or II Not common Radiation alone Combination of chemotherapy and radiation Chemotherapy alone

Advanced stage disease – Stage III or IV Symptoms and behavior Patient Age Patient’s general health condition


Treatment Options: Advanced Stage Population of patients with MCL who can be

observed without therapy similar to other indolent/slow growing lymphomas Elderly Asymptomatic Low risk disease Slow growing disease Often are patients with disease in blood, bone

marrow, spleen but not in the lymph nodes Majority will need treatment within a year or a little

longer but some can go several years (> 5)


Treatment Options: Advanced Stage Age and General Health Condition

Younger and Healthy No age cut-off but generally ≤ 65-70 years of age Without major organ problems although not much is

absolute – bad heart disease, bad lung disease, not able to get around well

Elderly or Less Fit

Healthy but more indolent disease that needs treatment


Treatment Options Younger and healthy Aggressive Chemoimmunotherapy Regimens ± Autologous stem cell transplant ± Maintenance therapy after transplant Clinical trial

Elderly or less fit Combined Chemoimmunotherapy ± Maintenance therapy after transplant Clinical trial

Healthy but more indolent disease that needs treatment Combined Chemoimmunotherapy ± Maintenance therapy after transplant Clinical Trial


Treatment of MCL

Younger Clinical trial, as no standard of

care Advanced stage disease

R-Hyper-CVAD +/-transplantation

R-CHOP/RDHAP + transplantation

Nordic Regimen R-DHAP + transplantation R-Bendamustine + HiDAC +

transplantation R-Bendamustine +/- maintenance

rituximab

Elderly Clinical trial, as no standard of

care Advanced stage disease

R-CHOP + transplantation R-CHOP + maintenance

rituximab R-Bendamustine +/-

maintenance rituximab R-Lenalidomide R-BAC Vr-CAP R-lenalidomide


Treatment of MCL

Rituximab Cyclophosphamide Vincristine Doxorubicin Cytarabine Cisplatin, Carboplatin,

Oxolaplatin Methotrexate

Prednisone Dexamethasone Bendamustine Lenalidomide Bortezomib Ibrutinib Acalabrutinib Venetoclax


Stem Cell Transplantation

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Autologous stem cell transplantation:

• A procedure that uses the patient’s own stem cells to restore blood cell production after intensive chemotherapy

Reduced-intensity stem cell transplantation:

• Involves lower intensity conditioning therapy

Allogeneic stem cell transplantation:

•A procedure where stem cells from another person (a donor) are infused into the patient’s body

•Entails intensive chemotherapy followed by standard or reduced-intensity stem cell transplantation


Toxicities/Side effects Drop in blood cell counts

Infection, need for transfusion, shortness of breath, bleeding

Fatigue GI symptoms – nausea, vomiting, diarrhea, constipation Hair loss Skin rashes Damage to the nerves – numbness, tingling, change in

strength, balance Heart to not function/pump as well Damage to the kidneys


Long-term effects

Long-term physical effects Cardiac effects, reproduction, pain, fatigue Male and female sexual dysfunction Cognitive decline

Secondary Malignancies 2-10% of patients develop Dependent on chemotherapeutic agents and

radiation therapy

Psychosocial issues Anxiety, depression, sleep disorders Employment, finances, insurance Exercise


Newly Diagnosed Stage II-IV Mantle Cell Lymphoma

Age > 65-70 or non-transplant eligible

Age < 65-70 and transplant eligible

RHyperCVAD/Methotrexate + Cytarabine X 8 cycles*must be < 65

R-chemotherapy (Rituximab and cytarabine containing regimen)

Autologous Transplant

BR, VrCAP, B-RAC, or RCHOP followed by maintenance R

Observation in highly selected cases

Clinical Trial OR

Rituximab Maintenance

Clinical Trial OR

Observation in highly selected cases

Therapy at Relapse


Treatment Options: Relapse Responds to initial therapy but majority of

patients will relapse Several acceptable or “right” therapies that can

provide remission or very good control of disease

Dependent on several factors How long to relapse Patient age Patient’s general health condition Prior therapies received Toxicities of prior therapies


Treatment Options: Relapse Chemotherapy options Targeted therapy Ibrutinib (Imbruvica) Acalabrutinib (Calquence) Bortezomib (Velcade) ± Rituximab

Oral immune therapy Lenalidomide (Revlimid) ± Rituximab

Transplantation Autologous stem cell transplant if not given initially

and patient is a candidate Allogeneic stem cell transplant if patient is candidate

Clinical Trial


B-cell receptor signalling

Stevenson F K et al. Blood 2011;118:4313-4320


Treatment Options Ibrutinib – Bruton’s tyrosine kinase inhibitor Targets signaling pathway that allows lymphoma cells

to grow, divide, survive Oral therapy Taken every day continuously as long as it is working

Given alone or with rituximab Most common side effects: GI, infections (upper

respiratory), fatigue, edema Less common but serious: Bleeding, irregular

heart rhythms


Treatment Options Acalabrutinib – Bruton’s tyrosine kinase inhibitor Targets signaling pathway that allows lymphoma cells

to grow, divide, survive Oral therapy Taken twice day continuously as long as it is working


Treatment Options Lenalidomide – oral immunomodulatory drug Works in several ways Some killing of the cells Most is activing and changing body’s immune

cells/system to kill the tumor/lymphoma cells

Given alone or with rituximab therapy Being studied as initial therapy both with Rituximab

and as maintenance after chemotherapy Most common side effects: drop in blood counts,

rash, GI symptoms Less common but serious: blood clots, birth defects

Research Updates

Initial Therapy


What are Clinical Trials?

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• A carefully controlled research study conducted by doctors too Improve treatment optionso Increase survivalo Improve quality of life

• Designed to give patients the safest, potentially most effective therapies


Clinical Trials

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Who should participate?

• Trials are not only for people with the most advanced disease.

• Patients should not wait for standard treatment to fail before asking about trials.

• Trials can be designed to test new treatments that improve response rates or improve quality of life of patients with newly diagnosed or very limited disease as well.


Research – Initial Therapy Younger and Healthy Improve chemotherapy regimens by addition of targeted

therapies Study if transplant is necessary in all patients or if there is

a select group of patients that transplant benefits Maintenance therapy after chemotherapy or after

transplant

Elderly, Less Fit, Indolent Disease Improve chemotherapy by addition of targeted therapies Eliminate chemotherapy all together and study

combination of immune therapies and targeted therapies Trying different maintenance therapies


Research – Initial Therapy Younger and Healthy Ibrutinib + Chemo Ibrutinib maintenance after transplant Transplant vs no transplant Newer antibodies combined with aggressive chemo +

transplant

Elderly, Less Fit, Indolent Disease BR or BRV chemotherapy followed by maintenance

therapy with rituximab or rituximab + lenalidomide BR+Ibrutinib followed by ibrutinib maintenance Rituximab + Lenalidomide + Ibrutinib/Aclabrutinib Newer antibodies with bendamustine


Triangle add on vs head to head comparison

TRIANGLE _ Prof. M. Dreyling / D. Gözel

ObservationR-CHOP/ R-DHAP x 6 ASCT

2 yrs I-maintenance

2 yrs I-maintenance

R R-CHOP/ R-DHAP x 6 + I

R-CHOP/R-DHAP x 6 + I

ASCT Observation

Observation

A:

A + I:

I:

Age ≤ 65PRIMARY ENDPOINT TTF


RANDOMIZATION

Primary• PET/CT CR• MRD

assessmentSecondary• Toxicity

MRD- CR

PR or MRD+ CR

Arm A: 28 day cycles x 6 (BRA)Bendamustine 90 mg/m2 IV D1, 2 + Rituximab 375 mg/m2 IV Day 1Acalabrutinib 100 mg po twice daily

Arm B: 28 day cycles x 6 (BRC)Cycles 1, 3, 5Bendamustine 90 mg/m2 IV D1, 2 + Rituximab 375 mg/m2 IV Day 1Cycles 2, 4, 6Rituximab 375 mg/m2 IV Day 1 + Cytarabine 2000 mg/m2 Q12 hours on Days 1, 2

1:1:1

Phase III enrollment

Arm C: 28 day cycles x 6 (BRCA)Cycles 1, 3, 5Bendamustine 90 mg/m2 IV D1, 2 + Rituximab 375 mg/m2 IV Day 1Acalabrutinib 100 mg po twice dailyCycles 2, 4, 6Rituximab 375 mg/m2 IV Day 1 + Cytarabine 3000 mg/m2 Q12 hours on Days 1, 2Acalabrutinib 100 mg po twice daily

E4151:Randomized phase 2 trial


E4151:Randomized phase 3 trial of Auto SCT +MR vs. MR alone in MRD-CR MCL

PRE-REGISTRATION*

ARM AAuto-HCT + Rituximab

Clonal Marker Present?

YES

NO

Post-inductionRestaging (CR, PR, SD/PD)● Submit blood to Adaptive for MRD assessment (MRD pos or MRD neg)

MRD neg CR**

RANDOMIZATION

Submit tumor tissue to Adaptive Biotechnologies forclonal marker testing

ARM BRituximab

Arm CAuto-HCT + Rituximab

MRD neg PRMRD indeterminateMRD pos CR or PR

*Pre-registration can occur any time during induction or within 2 months after** These patients will be stratified by MIPI-c and Type of induction (containing high dose Ara-C and no Ara-C)*** Rituximab maintenance is every 8 weeks x 3 years

Primary Endpoint: OS


Rituximab-Lenalidomide-AcalabrutinibRituximab-Lenalidomide-VenetoclaxRituximab-Venetoclax-Acalabrutinib

Therapy at Relapse


Drugs in development Targeted therapies Biologic Antibody therapies Bispecific Antibodies (BiTE) Immunotherapies Chimeric Antigen Receptor T cells (CART)


• Targets Protein Specifically Expressed on The Surface of the Cells

• Different targets dependent on disease cell of origin

• CD20 antibodies approved and in trials

• CD19 antibody trials ongoing

Mouse

HumanIgG1

Antibodies

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Content and Title –gray bands with DNA element in footer

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Targeted Therapies


Drugs in development Ventoclax oral targeted therapy Inhibits a protein (bl2) that allows cell survival being tested alone and in combination therapies

Venetoclax + Ibrutinib Venetoclax + acalabrutinib + rituximab Venetoclax + lenalidomide + rituximab BR + venetoclax

Very promising but very powerful drug which has slowed the studies


Drugs in development Cyclin dependent kinase 4/6 or CDK 4/6 oral targeted therapy

Palbociclib Approval in breast cancer

Inhibits proteins in the cell cycle Cell cycle is dyregulated in MCL

being tested alone and in combination therapies palbociclib + ibrutinib

Very promising in combination Most common side effects: drop in blood counts


Drugs in development BTK inhibitors Zanibrutinib

Proteosome inhibitors Iaxozimib

PI3K inhibitors


Drugs in development Antibodies and Immunotherapy Bispecific Antibodies CAR-T cells

Own body’s t-cells engineered to recognize tumor cells Very early in development but also very promising


• Powerful: Attacks the cancer systemically

• Specific: Trains the immune system to recognize & target specific cells, including cancer cells

• Memory: Capacity for memory means durability of protection

• Universal: Treatment approach applicable to nearly all cancers

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Strategy based on ex vivo manipulation of immune cells to enhance anti-tumor activity

Own body’s t-cells engineered to recognize tumor cells

Cellular Therapy


CAR T therapy is the name given to chimeric antigen receptor (CAR) genetically modified T cells that are designed to recognize specific antigens on tumor cells resulting in their activation and proliferation eventually resulting in significant and durable destruction of malignant cells

CAR T cells are considered “a living drug” since they tend to persist for long periods of time

CAR T cells are generally created from the patients own blood cells although this technology is evolving to develop “off the shelf” CAR T cells

Chimeric Antigen Receptor (CAR) Therapy


CAR Modified T Cells as Cancer Therapy

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Source: mskcc.org

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