how i treat mantle cell lymphoma - oncology leanring network...72 / 395 (18) 7.8 months (3-121)*...

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