Mantle Cell LymphomaManagement Updates 2017g p

Robert Chen, MDAssociate ProfessorAssociate Director of Toni Stephenson Lymphoma CenterAssociate Director of Toni Stephenson Lymphoma CenterCity of Hope

DISCLOSURES

I am a consultant for BMS, Merck, Seattle Genetics,Merck, Seattle Genetics, Pharmacyclic, and on the Speaker’s Bureau withSpeaker s Bureau with Genentech, Seattle Genetics.

Overview

• Case presentation• BackgroundBackground • Prognostic factors

U f t t t t• Upfront treatment• Relapsed/refractory• Novel therapies/clinical trials

Case presentation

• A 54-year-old male right cervical LAD• + fever, chills, and night sweats• PE: right cervical, bilateral axillary, and right inguinal LAD• LAB: elevated WBC with lymphocytosis and several unclassified y p y

cells. • FDG-PET scan. The scan shows increased SUV uptake and

discrete masses in the right cervical, bilateral axillary, g , y,retroperitoneal, and right inguinal LAD.

• Pathology: mantle cell lymphoma, blastoid variant type• BM biopsy: MCL involvementBM biopsy: MCL involvement. • Flow cytometry: CD19+, CD20+, and CD51+/ CD10-, CD23-,

and BCL6-negative phenotype. • This patient was diagnosed with stage IVB mantle cell• This patient was diagnosed with stage IVB mantle cell

lymphoma.

Background

• MCL is an aggressive B cell non-Hodgkin lymphoma and id d i blconsidered incurable.

• 4% of lymphomas in the US • Median age is ~60 years• male disposition• ~80% advanced stage disease• Splenomegaly and lymphomatous polyposisSplenomegaly and lymphomatous polyposis• B symptoms such as fever, chills, and night sweats are

common.

The Non-Hodgkin’s Lymphoma Classification Project. Blood. 1997;89:3909-18.Samaha H, Dumontet C, Ketterer N, et al.. Leukemia. 1998;12:1281-7.

Pathology

• Pathology: sheets of• Pathology: sheets of monomorphic lymphoid cells that are small to medium sized

• Four cytologic variants including• Four cytologic variants, including small cell, mantle zone, diffuse, and blastoid variant

Swerdlow SH, Campo E, Harris NL, et al: WHO Press; 2008.Bertoni F, Rinaldi A, Zucca E, Cavalli F.. Hematol Oncol. 2006;24:22-7.

Cyclin D1

• The pathognomonic feature of MCL is the overexpressionof MCL is the overexpressionof cyclin D1 due to chromosomal translocation t(11;14)(q13;32)t(11;14)(q13;32)

CCND1 overexpression

Clinical Prognostic Factors• The Mantle Cell International Prognostic Index (MIPI)

– Age, ECOG, LDH, and WBC count. g , , ,– Low risk patients tend to do well, with a median overall survival (OS) not reached– Intermediate risk patients have a median OS of 51 months, – High risk patients have a median OS of 29 months.

Hoster E, Dreyling M, Klapper W, et al. Blood. 2008;111:558-65.

Biological Prognostic Factorsg g• SOX 11

– SOX 11 is a transcription factor, and absence of SOX 11 has been p ,associated with an indolent form of MCL

• Ki-67/P53/P16– High Ki-67 proliferation and p53 and p16 deletion have been shown g p p p

to be associated with blastoid variant MCL and worse OS outcome. • Gene expression profiling (GEP)

– RAN, MYC, TNFRSF10B, PLE2, and SLC29A2 as predictors. , , , , pPatients who had increased expression of all five genes had inferior survival.

• Cyclin D1 truncation/MicroRNAs: – Truncated cyclin D1 3’UTR as having inferior outcomes. – Altered mir-16-1 regulation as shown by Chen et al.

Bernard M, Gressin R, Lefrere F, et al. Leukemia. 2001;15:1785-91.Hartmann E, Fernandez V, Moreno V, et al.. J Clin Oncol. 2008;26:4966-72.Wiestner A, Tehrani M, Chiorazzi M, et al.. Blood. 2007;109:4599-606.Chen RW, Bemis LT, Amato CM, et al.. Blood. 2008;112:822-9.

Upfront Treatmentp

• Younger patients who are fit vs. Elderly patients with co-biditimorbidities

• Aggressive induction chemotherapy followed by autologousstem cell transplantation (ASCT).

• European MCL network showed the benefit of ASCT. – ASCT vs. maintenance interferon – Improved PFS, 39 months vs. 17 months. P=0.01

• Choice of induction chemotherapy – R-HyperCVAD– Nordic Regimen (R-Maxi-CHOP)– RCHOP– R-bendamustine– VR-CAP

Dreyling M, Lenz G, Hoster E, et al.. Blood. 2005;105:2677-84.Romaguera JE, Fayad L, Rodriguez MA, et al. J Clin Oncol. 2005;23:7013-23.

R-HyperCVAD

R t l t MDACC• Romaguera et al. at MDACC• Hyperfractionated cyclophosphamide, vincristine, doxorubicin,

and dexamethasone alternating with high dose cytarabine and th t t f 6 8 lmethotrexate for 6-8 cycles.

• ORR 97%, CR 87%, 3 year FFS of 64% and OS of 82%. • SWOG 0213 multicenter

– ORR 86%, CR of 55%, and 3 year PFS 66%.

• 90% grade IV hematological toxicities, and 61% finished the full course of treatment.

Romaguera JE, Fayad L, Rodriguez MA, et al.. J Clin Oncol. 2005;23:7013-23.Bernstein SH, Epner E, Unger JM, et al.. Ann Oncol. 2013;24:1587-93.

Other Intense Regimens

• R-Maxi-CHOP – RCHOP alternating with high dose cytarabine without

methotrexate) followed by ASCTmethotrexate) followed by ASCT– CR 54%, ORR 96%, a 6 year PFS of 66% and OS of 70%.

• RCHOP/RDHAP– 3 cycles of RCHOP followed by 3 cycles of RDHAP

(rituximab, cisplatin, cytarabine, and dexamethasone) followed by ASCT.

– CR of 57%, ORR of 93%, and 5 year OS of 75%.

Geisler CH, Kolstad A, Laurell A, et al.. Blood. 2008;112:2687-93.Delarue R, Haioun C, Ribrag V, et al. Blood. 2013;121:48-53.

Less Intense Regimens

• RCHOP– ORR of 96% and CR of 48%, and a PFS 17 months.

• VR-CAP (rituximab, bortezomib, cyclophosphamide, doxorubicin, and prednisone)

– Compared VR-CAP vs. RCHOP– Primary endpoint PFS– No ASCT consolidation

• R-Bendamustine– Compared R-B vs. RCHOP– Primary endpoint was EFS

N ASCT lid ti– No ASCT consolidation

Howard OM, Gribben JG, Neuberg DS, et al. J Clin Oncol. 2002;20:1288-94.Kluin-Nelemans HC, Hoster E, Hermine O, et al.. N Engl J Med. 2012;367:520-31.Robak T, Huang H, Jin J, et al.. N Engl J Med. 2015;372:944-53.

VR-CAP LYM-3002

59% improvement in59% improvement in PFS,

median OS was 56.3% vs. not reached in favor of VR-CAP

CR 42% 3%CR 42% vs. 53%, not stat. significant

Kaplan–Meier Analysis of Progression-free Survival According to Independent Review (Intention-to-Treat

Population).p )

More th b t i ithrombocytopenia in VR-CAP

Peripheral neuropathy was similar

Robak T et al. N Engl J Med 2015;372:944-953.

BR vs. R-CHOP

BR (× 6 cycles)

RAN

( y )Bendamustine: 90 mg/m2:

day 1-2, q4w+

Rituximab: 375 mg/m2

260 pts

Untreated pts with indolent

and MCL(n = 546)

NDOMI

day 1, q4w

R-CHOP (× 6 cycles)IZE

Rituximab: 375 mg/m2

day 1, q3w+

CHOP (standard)

253 pts

day 1, q3w

• Primary end point: To prove a noninferiority of BR vs R-CHOP in EFSEFS

Rummel et al. ASH 2009, ASCO 2012. StiL study

Progression free survival Progression free survival 45 months follow45 months follow--up up

1.01.0 Median (months)Median (months)

0 70 7

0.80.8

0.90.9 BB--RR 69.569.5

CHOPCHOP--RR 31.231.2

ORR (93% vs. 91%)CR (40% vs. 30%)

0.50.5

0.60.6

0.70.7

0.30.3

0.40.4

Hem toxicities (30% vs. 68%)Infections (37% vs. 50%)

0 00 0

0.10.1

0.20.2Hazard ratio, 0.58 (95% CI 0.44 Hazard ratio, 0.58 (95% CI 0.44 -- 0.74)0.74)

p = 0.0000148 (stratified log rank)p = 0.0000148 (stratified log rank)

0.00.0

0 12 24 36 48 60 72 84 96 months0 12 24 36 48 60 72 84 96 months

Pre-Transplant R-Bendamustine Induces High Rates ofPre Transplant R Bendamustine Induces High Rates of Minimal Residual Disease in MCL Patients: Updated Results of S1106: US Intergroup Study of a Randomized Phase II Trial of R HCVAD Vs R BendamustineRandomized Phase II Trial of R-HCVAD Vs. R-BendamustineFollowed By Autologous Stem Cell Transplants for Patients with Mantle Cell Lymphoma

R Chen H Li S H Bernstein L M Rimsza S Forman L S Constine T C Shea R. Chen, H. Li, S. H. Bernstein, L. M. Rimsza, S. Forman, L. S. Constine, T. C. Shea, A. F. Cashen, K. Blum, T. S. Fenske, P. Barr, M. Leblanc, R. I. Fisher, B.D. Cheson, S. M. Smith, M. Faham, J. Wilkins, J.P. Leonard, B.S. Kahl, J. W. Friedberg

US intergroup S1106: SWOG, CALGB/Alliance, ECOG

SchemaFirst

Registration

Randomize forRandomize for Induction

R HCVAD cycle 1 R Bendamustine xR-HCVAD cycle 1R-MTX/Ara-C cycle 2

R-Bendamustine x 4 cycles

Restaging Restaging

<PR ≥PR <PR≥PR

OFF STUDYFollow for survival

R l h h id 3 / 2

OFF STUDYFollow for survival

R-HCVAD Cycle 3Stem cell collection

R-bendamustine x 2 cycles

R-cyclophosphamide 3 gm/m2

Stem Cell CollectionR-MTX/Ara-C cycle 4

Restaging

Second Registration

STEM CELL TRANSPLANT<61 yrs: BCV, BEAM or TBI/VP16/Cy

61-65 yrs: BCV or BEAM

Results

N= 51 evaluable ptsR-HyperCVAD

(N=17)R-Bendamustine

(N=35)N 51 evaluable pts (N 17) (N 35)Response

ORRCR

94.1% 35%

82.9% 40%CR

PRInadequate

35%59%6%

40%43%17%

Median F/UMedian F/U (months) 34 (10.0-41.0) 27.3 (1-39.5)

Survival2-year PFS2-year OS

82% 88%

81% 87%

CT/PET not mandated

S1106:PFS

80%

100%

60%

20%

40%

R B d tiAt Risk

35Failed

8

2-year Estimate

81%

0%0 12 24 36 48

Months After Registration

R-BendamustineR-HCVAD/MTX/Ara-C

3517

84

81%82%

g

S1106:OS100%

80%

40%

60%

20%R-BendamustineR HCVAD/MTX/Ara C

At Risk3517

Deaths42

2-Year Estimate

87%88%

0%0 12 24 36 48

Months After Registration

R-HCVAD/MTX/Ara-C 17 2 88%

R-HCVAD: PD 1, suicide 1R-Bendamustine: PD 3, unknown 1

Safety

Grade 3/4 Toxicities(induction phase)

R-HyperCVAD(N=17)

R-Bendamustine(N=35)( p ) ( ) ( )

Anemia 59% 8.6%Neutropenia 65% 34%Febrile neutropenia 29% 14%Th b t i 71% 17%Thrombocytopenia 71% 17%Hypokalemia 29% 5.7%Hypophosphatemia 24% 2.9%Hyperglycemia 12% 0%yp g yALT increased 5.9% 0%AST increased 5.9% 0%Catheter related infection 5.9% 2.9%D h d ti 5 9% 0%Dehydration 5.9% 0%Diarrhea 5.9% 0%Epistaxis 5.9% 0%Nausea 5.9% 0%ausea 5 9% 0%Rash 5.9% 2.9%Syncope 5.9% 0%

Off-TreatmentReasons for going off-Txor not going on to ASCT

R-HyperCVAD (17)12/17

R-Bendamustine (35)14/35g g

Failure to collect stem cells 5 2

Thrombocytopenia 5Patient choice 4Progressive disease 2Pancytopenia 1Neutropenia 1Allergy 1Seizure 1Insurance denial 1Others 1 2

RH ASCT: 9 (53%), 4 off protocolRB ASCT: 23 (66%), 2 off protocol

Conclusions

B th R h CVAD d R b d ti ti i• Both R-hyperCVAD and R-bendamustine arm are active regimens with similar response rates and 2-year PFS and OS.

• R-hyperCVAD is not an ideal platform for building future multicenter trials in MCL with ASCT (marrow toxicity and inadequate stem cell mobilization).

• R-Bendamustine arm achieved a 2-year PFS of 81%, which isR Bendamustine arm achieved a 2 year PFS of 81%, which is higher than the target of 75%. Premature study closure limits the precision around the PFS estimates.

European MCL network

RAN

RCHOPx 3/R-DHAP x3Followed by ASCT 248 pts

Untreated pts with MCL

NDOMIIZE

R-CHOP (× 6 cycles)Followed by ASCT 249 pts

• Primary end point: Treatment Failure Rate

Hermine O et al. Lancet 2016

Results

N= 51 evaluable pts R-CHOP RCHOP/DHAPN 51 evaluable pts R CHOP RCHOP/DHAPResponseORRCR

90% 39%

94% 55%CR

MRD negative39%47%

55%79%

Median F/U 6 1 6 1(months) 6.1 years 6.1 years

5 year treatment5 year treatmentfailure rate 65% 40%

Safety

Grade 3/4 Toxicities RCHOP RCHOP/RDHAPAnemia 8% 29%Neutropenia 65% 34%Febrile neutropenia 8% 17%Thrombocytopenia 9% 73%Renal Toxcity 10% 43%Renal Toxcity 10% 43%

N/V (all grades) 33% 57%

Collection Failure 16% 34%

Conclusion

• Cytarabine including induction regimen can lead to higher CR, MRD negative g , gstatus

• Cytarabine plus MTX or Cytarabine plusCytarabine plus MTX or Cytarabine plus Cisplatin lead to higher adverse events, including stem cell collection failuresincluding stem cell collection failures

MRD (minimal residual disease)( )

• In ALL, MRD has been shown to be an independent predictive factor

• 1) Real time quantitative PCR – junctional regions of rearranged immunoglobulin heavy chain (IGH) is a

highly sensitive method.

• 2) Multicolor flow cytometry– Bottcher et al. showed 18% of patients were negative by flow cytometry but

positive for MRD by consensus IGH PCRpositive for MRD by consensus IGH-PCR.

• 3) Next generation sequencing (NGS) can identify clonogenic B cells with high sensitivity and specificity.

– The novel method can overcome disadvantages of PCR-based methods– The novel method can overcome disadvantages of PCR-based methods and avoid the need for patient-specific agents.

– It also has the potential to operate at a higher level of sensitivity (1 x 10-6), which is superior to flow cytometry

– Incorporated into all induction trialStow P, Key L, Chen X, et al.. Blood. 2010;115:4657-63.Raff T, Gokbuget N, Luschen S, et al.. Blood. 2007;109:910-5.

Elderly patients

• RCHOP/VRCAP/R-Bendamustine• R-lenalidomide (Ruan et al)

– Single arm multicenter trial (38 pts)– Induction: 25 mg lenalidomide daily x 21 days x 12 cycles.Induction: 25 mg lenalidomide daily x 21 days x 12 cycles.

Rituximab on weeks 1, 2, 3, 4, 13, 21, 29, 37.– Maintenance: 15 mg lenalidomide daily x 21 days. Rituximab once

every 8 weeks.– Low or intermediate MIPI or high MIPI but can’t tolerate chemo– ORR of 92%, CR of 64%, median time to CR 11 months– 2 year PFS of 85%– 50% grade III and IV hem toxicities, 42% required dose reduction.

• Watchful waiting (Martin et al)– Asymptomatic, low MIPI, or elderly MCL patients. y p , , y p– Median time to treatment was about 12 months (4-128 months)

Ruan J, Martin P, Shah B, et al. N Engl J Med. 2015;373:1835-44.Martin P, Chadburn A, Christos P, et al.. J Clin Oncol. 2009;27:1209-13

Regimen ORR/CR PFS/OSR-HyperCVAD (no ASCT) MDACC

SWOGORR 97%CR 87%ORR 86%

3 yr FFS 64%3 yr OS 82%3 PFS 66%ORR 86%

CR 55%3 yr PFS 66%

RCHOP (no ASCT) Dana FarberGerman Group

ORR 96%CR 48%

Median PFS 17 monthsMedian PFS 31 months

ORR 91%CR 30%

R-bendamustine (no ASCT)

German Group ORR 93%CR 40%

Median PFS of 70 months)

RMaxiCHOP Nordic ORR 96%CR 54%

6 year PFS 66%6 year OS 70%

RCHOP/RDHAP French Group ORR 93%CR 57%

5 year OS 75%

VR-CAP Swiss lead multicenter ORR 92%CR 53%

Median PFS 25 monthsMedian OS not reachedCR 53% Median OS not reached

R-lenalidomide Cornell Lead multicenter ORR 92%CR 64%

2 yr PFS 85%2 yr OS 97%CR 64% 2 yr OS 97%

Case

• The patient in our initial case presentation received 6 cycles of R-p ybendamustine followed by ASCT. He also enrolled on our trial using rituximabgplus bortezomib as maintenance therapy post ASCT. He is currently py p ydoing well and still in remission.

Relapsed/Refractory diseasep y

• RICE, R-ESHAP, RDHAP, or gemcitabine-based strategies. • R-bendamustine alone or + cytarabine (R-BAC). • The ORR of these agents appears high (80-90%) with a CR of• The ORR of these agents appears high (80-90%), with a CR of

60-70% • However, grade III and IV adverse events are common,

including cytopeniasincluding cytopenias.

Rummel MJ, Al-Batran SE, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. to c ty p o e t e t eat e t o a t e ce a d ow g ade o odg s y p o a. J C O co .2005;23:3383-9.Visco C, Finotto S, Zambello R, et al. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologoustransplantation. J Clin Oncol. 2013;31:1442-9.

Molecular Pathways

Lenz and Staudt NEJM 2010

Novel TherapiesDrug Mechanism of

actionORR/CR Duration of

ResponseToxicities

B t ib P t i hibit ORR 33% DOR 9 2 th 13% i h lBortezomib Proteosome inhibitor ORR 33%CR 8%

DOR 9.2 months 13% peripheral neuropathy

Lenalidomide Immunomodulator ORR 35%CR 12%

Median PFS 9 months

46% grade 3-4 neutropenia, 30% grade 3-4 thrombocytopeniathrombocytopenia

Temsirolimus mTOR inhibitor ORR 41%CR 4%

MTP 6 months 54% grade 3-4 hem toxicities

Ibrutinib BTK inhibitor ORR 68%CR 21%

MDR 18 months 16% grade 3-4 hem toxicities44% grade 1-2 diarrhea

Idealisib PI3K inhibitor ORR 40%CR 5%

MDR 3 months 18% grade 3-4 diarrhea20% grade 3-4 AST/ALT elevation

Venetoclax BCL-2 inhibitor ORR 85%CR 21%

Median PFS 14 months

16% grade 3-4 anemia12% grade 3-4 gneutropenia

Ph 2 St d f B t ' T i Ki (BTK) I hibitPhase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell

Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up

Michael Wang, M.D.1, Simon A. Rule, MD*,2, Peter Martin, MD3, Andre Goy, MD4, Rebecca Auer, MD*,5, Brad S. Kahl, M.D.6,

Wojciech Jurczak7, Ranjana H. Advani, MD8, Jorge Enrique E Romaguera, MD9, Jesse McGreivy, MD10, Fong Clow, ScD*,11, g y gMichelle Stevens-Brogan*,12, Lori Kunkel, MD10 and Kristie A.

Blum, MD13

ASH 2012 abstract 904

PCI-32765 (Ibrutinib)

• Orally available inhibitor of BTK

• Once daily dosingO

NN

NH 2

N NN

NN

O

39Wang et al, NEJM 2013

ORR

The median PFS is 13 months, DOR 17.5 months.2-year PFS was 31%, and 2-year OS was 47%.y , y

Wang et al, NEJM 2013 Wang et al. Blood 2016

AEs in >10% of pts

Post Ibrutinib Failure• Median OS

2 9 months2.9 months

• Median OS 5 8 months5.8 months Tx

Martin P et al. Blood 2016

Venetoclax

• Oral BCL-2 inhibitor• Phase I study 200 mg to 1200 mgy g g• No MTD established in MCL, dose moving

forward is 800 mg• ORR 75% and CR 21%• Median PFS 14 months• 1 year OS 87%

Davids et al. JCO 2016 .

Venetoclax

Davids M et al. JCO 2016

Venetoclax

ASCT/Allo-HCT• Rituximab maintenance

– Fred Hutchinson Cancer Center showing post transplant rituximab was g p passociated with improved PFS (HR 0.44) and OS (HR 0.46).

• Bortezomib maintenance– CALGB showed consolidative bortezomib or maintenance bortezomib post

ASCT i d PFS d t hi t i l t lASCT improved PFS as compared to historical controls

• Bortezomib plus rituximab– COH, phase II multicenter trial.

Interim analysis shows a only 1/23 patients had progressed after ASCT– Interim analysis shows a only 1/23 patients had progressed after ASCT

• Tam et al. (RIC allo) in patients with relapsed/refractory MCL. – 6 year PFS was 46% and 6 year OS was 53%.

Chen R, Palmer J, Holmberg L, et al. Interim analysis of a phase 2 study of bortezomib plus rituximabChen R, Palmer J, Holmberg L, et al. Interim analysis of a phase 2 study of bortezomib plus rituximabmaintenance therapy in patients with mantle cell lymphoma status post autologous stem cell transplantation. Blood. 2015;126:abstr 1961.Tam CS, Bassett R, Ledesma C, et al. Mature results of the M.D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma. Blood. 2009;113:4144-52.

Future directions

• The median OS of MCL has been extended from 2.7 years to 4.8 years from the time period of 1975-1996 to 1996 to 2004to 1996 to 2004

• Questions that remain to be answered include the following:g– the optimal induction regimen– the role of ASCT in MRD-negative patients post induction– optimal maintenance therapy post induction– optimal maintenance therapy post induction– optimal combinations of novel therapeutics

Herrmann A, Hoster E, Zwingers T, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511-8

COH MCL Guidelines

• Newly Diagnosed– 60 < age < 75, R-Bendamustine followed by AHCT– Age < 60, Maxi-CHOP followed by AHCTAge 60, Maxi CHOP followed by AHCT– > 75, R-Bendamustine followed by R or R-Lenalidomide

R l d/R f t• Relapsed/Refractory– Clinical Trials (Ibrutinib + venetoclax, CAR-T)– Ibrutinib– Bortezomib/Lenalidomide based therapy

Clinical Trials at COHStudies Phase Patient population

Maintenance bortezomibplus rituximab post ASCT

Phase II COH lead multicenter IST

in patients with MCL

Ibrutinib plus ABT 199 in patients with

Phase I Collaboration with U of Virginiapatients with

relapsed/refractory MCLVirginia multicenter IST

CAR-T cells Phase I/II COH ISTCAR T cells Phase I/II COH ISTKITE

Lenalidomide/ ABT199 in upfront MCL

Phase I/II Collaboration with U Michigan IST

Ibrutinib vs. Ibrutinib plus Rituximab in upfront MCL

Phase III Industry

Ibrutinib vs. Ibrutinib plus ABT 199 in patients with

Phase III IndustryABT 199 in patients with R/R MCL