1 Winship Cancer Institute | Emory University
How I Treat Mantle Cell Lymphoma
Jonathon B. Cohen, MD, MS Winship Cancer Institute of Emory University
Assistant Professor, Hematology and Medical Oncology Emory University School of Medicine
2 Winship Cancer Institute | Emory University
Disclosures
• Consulting/Advisory Services: • Abbvie, Celgene, Novartis, Pharmacyclics, Seattle Genetics
• Research Funding: • BMS, Janssen, Novartis, Takeda, BioInvent, Atara, Seattle Genetics
3 Winship Cancer Institute | Emory University
Outline
• Mantle cell lymphoma review • Prognostic indices and implications for outcome and treatment • Selection of approach to untreated patients
4 Winship Cancer Institute | Emory University
Mantle Cell Lymphoma- Background
• < 10% of cases of NHL • Characterized by:
• CyclinD1 positivity by IHC • Immunophenotype:
• CD5+, CD20+, CD23- • t(11;14)
• Frequently Stage IV • Bone Marrow Involvement • Peripheral Blood Lymphocytosis • Spleen • GI Tract
Source:Na+onalCancerDatabase
5 Winship Cancer Institute | Emory University
• WBC Count • Performance
Status
• Age • LDH
MCL International Prognostic Index Calculatedpre-treatmentandassociatedwithOS
Hosteretal,Blood2008 Hosteretal,JClinOncol2014
6 Winship Cancer Institute | Emory University
MCL International Prognostic Index
HighRiskMIPIassociatedwithbeJerOSinaddi+onalseries
Eskelundetal,BritJHaem2017 Statonetal,ASH2016
7 Winship Cancer Institute | Emory University
Ki67 Proliferative Index
• Measurable by IHC but can vary within a patient • Cutoff of 30% frequently utilized
Hoster,JClinOncol2016
8 Winship Cancer Institute | Emory University
Ki67 + MIPI: The MIPI-C MIPI-CRISKGROUP MIPIRISK
(Low,Intermediate,orHigh)Ki67 MedianOS
Low Low <30% 9.4years
Low-Intermediate
LowIntermediate
≥30%<30%
4.9years
High-Intermediate IntermediateHigh
≥30%<30%
3.2years
High High ≥30% 1.8years
Hosteretal,JClinOncol2016
9 Winship Cancer Institute | Emory University
Cytogenetics in MCL
• Complex karyotype (> 3 abnormalities) • ~20% of patients
• Associated with inferior PFS in MCL • Multi-center study in US
Greenwelletal,Cancer2018
MedianOS:4.5vs11.6years
MedianPFS:1.9vs4.4years
10 Winship Cancer Institute | Emory University
Genomic Aberrations & Clinical Outcome
TP53orCDKN2ADele+ons–RCHOP/RDHAP TP53muta+on–NordicMCL2/3
NOTCH1-Bri+shColumbiaDelfau-Larue,Blood2015;NordstromBrJHaematol2014;Kridel,Blood2012
• TP53likelyimportantandassociatedwithpoorprognosis• Assessmentofindividualabnormali+eschallengingandofques+onableu+lity
• Newgenesandassociatedprognos+cimportancecon+nuetobeiden+fied
• Mul+-genepanelneededtobeJerintegrateprognos+cimportanceofindividualabnormali+es
11 Winship Cancer Institute | Emory University
“Traditional” Approach to Treatment
NewDx–ConfirmDiagnosisandCompleteStaging/Prognos+cWork-up
Candidate for Transplant?
Yes No
“Intensive”Induc+ontherapy
AutologousTransplant
“LessIntensive”Induc+ontherapy
Maintenance
Observa+on
12 Winship Cancer Institute | Emory University
My general approach and considerations <60andHealthy 60-70andHealthy 70+andHealthy Frail
Considera+ons:• Symptoms• Stage/TumorBurden• Prognos+cMarkers
Considera+ons:• Symptoms• Stage/TumorBurden• Prognos+cMarkers• Pa+entPreference
Considera+ons:• Symptoms• Stage/TumorBurden
Considera+ons:• Symptoms• Stage/TumorBurden• Candidacyfortreatment• Pa+entPreference
Standardfront-line:• Cytarabine-based
therapies• AutoSCTin1stRemission• MaintenanceRituximab
Intensiveapproach:• Cytarabine-based• AutoSCTin1stremission• MaintenanceRituximab
Less-Intensiveapproach:• Bendamus+ne-based• R-CHOP-based• ?MaintenanceRituximab
Standard:• Bendamus+ne-based• R-CHOP• ?MaintenanceRituximab
Consider:• R-Lenalidomide
NoStandardApproach:• R-Lenalidomide(if
feasible)• R-monotherapy• ?Ibru+nib(notindicated)• Suppor+vecare
13 Winship Cancer Institute | Emory University
Front-line considerations
• Observation should be considered in all asymptomatic patients regardless of age
• Ibrutinib / Acalabrutinib not indicated in the front-line alone or combination
• Consider in frail patients who cannot tolerate chemotherapy • Clinical trial enrollment preferred in all settings
14 Winship Cancer Institute | Emory University
Identification of Patients with Indolent MCL
• Patients with indolent MCL can potentially be observed.
Mar+netal,JClinOncol2009 Cohenetal,Cancer2016 Calzadaetal,LeukLymphoma2018
15 Winship Cancer Institute | Emory University
Consistent Predictors of Deferred Therapy
• Lack of B-symptoms • Normal LDH • Leukemic, non-nodal presentation (i.e., CLL-like) • Good ECOG Performance Status • Ki67 < 30% • Lack of blastoid variant
NOTE: MIPI risk score has not been associated with selection of deferred therapy.
Mar+netal,JClinOncol2009;Cohenetal,Cancer2016;Calzadaetal,ASCO2016;Kumaretal,ASH2016;Abrisquetaetal,ASH2015
16 Winship Cancer Institute | Emory University
Outcomes of Deferred Therapy Series NumberofDeferred
PaLents(%)MedianLmetotreatment(Range)
MedianOS(DeferredPts)
MedianOS(ImmediatePts)
Mar+n2009(Cornell)
31/97(32) 12months(4-128) NotReached(4.6years)
5.3years
Abrisqueta2017(B.C.)
74/439(17) 35.5months(5-79) 5.5years 4.2years
Cohen2016(NCDB) 492/8029(6) 4months(3-38)* 6.6years -
Kumar2015(MSKCC)
91/404(23) 23months 10.6years 9.4years
Calzada2016(Mul+center)
72/395(18) 7.8months(3-121)* 11.8years 11.6years
*Convertedfromdaysasreportedinreference
• Allretrospec+veprojects–Norandomizedstudies• Successfuliden+fica+onoflowriskpa+ents
17 Winship Cancer Institute | Emory University
• R-CHOP/R-DHAP (MCL Younger)
• R-MaxiCHOP / R-AraC (Nordic)
Front-line Options (Intensive)
Hermine,Lancet,2016 Eskelund,BrJHaematol,2016
18 Winship Cancer Institute | Emory University
Other front-line approaches
• R-DHAP (Lyma) • R-HyperCVAD (+/- SCT)
• 2 year PFS (w/ SCT): 82% • Challenges with collection • Toxic in patients > 60
• 15-year FFS (w/o SCT): 30% in patients < 65 years • R-BAC • BR/R-AraC
Chen,BrJHaematol,2017;Chihara,BrJHaematol,2016
19 Winship Cancer Institute | Emory University
Role of ASCT in 1st Remission • Use based on older study with CHOP (+/- R)
Dreyling,Blood,2005
20 Winship Cancer Institute | Emory University
EA4151: MRD-based assessment of SCT
21 Winship Cancer Institute | Emory University
EA4181: Randomized phase 2 trial < 70
22 Winship Cancer Institute | Emory University
Triangle Study
23 Winship Cancer Institute | Emory University
• Bendamustine-Rituximab • R-Lenalidomide
Non-intensive Approaches
Rummel,Lancet,2013;Ruan,NEJM,2015
24 Winship Cancer Institute | Emory University
Rituximab Maintenance
• LyMa trial: R-DHAP x 4 - > ASCT • Patients randomized to rituximab maintenance x 3 years vs observation • 4year PFS 83% vs 64%, p< 0.001
• Non-transplant setting • Benefit after R-CHOP (MCL Older) • Unclear benefit after B-R
LeGouilletal,NEJM2017;Kluin-NelemansASH2017;RummelASCO2017
25 Winship Cancer Institute | Emory University
Summary
• Mantle cell lymphoma is heterogeneous and management is based on disease biology, patient fitness, comorbidities, and other factors.
• Upfront approaches range from observation to intensive therapy w/ ASCT
• Trials pending may markedly alter our approach to treatment by addressing:
• Role of ASCT • Minimal Residual Disease • Role of novel therapies including ibrutinib
26 Winship Cancer Institute | Emory University
THANK YOU!
27 Winship Cancer Institute | Emory University
Question 1
• A 50 year old male with newly diagnosed mantle cell lymphoma presents for initial evaluation. He is feeling well with no symptoms. He was diagnosed with MCL based on a mild lymphocytosis that was identified during a routine physician visit. He is otherwise healthy.
• A PET/CT shows some scattered adenopathy measuring between 1.5 and 2.5 cm.
• Bone marrow biopsy is positive for MCL with a Ki67 of 20%. How would you approach this patient? 1) Initiate cytarabine-based therapy followed by auto transplant 2) Initiate treatment with R-Bendamustine 3) Observe with close follow-up 4) Initiate treatment with ibrutinib
28 Winship Cancer Institute | Emory University
Question 2
• The 50 year old male in question 1 was observed for 18 months but ultimately developed symptomatic disease and received R-DHAP x 4 followed by consolidation with stem cell transplant. He is in complete remission and has recovered from the transplantation.
What do you recommend to improve his overall survival? 1) No further therapy is indicated – initiate observation protocol 2) Rituximab maintenance 3) Ibrutinib maintenance 4) Lenalidomide maintenance