2012/3/23

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Mantle Cell Lymphoma (MCL):

Focused On Treatment

Bor-Sheng Ko, M.D., Ph.D.

Attending Physician and Assistant ProfessorDepartment of Internal Medicine

National Taiwan University Hospital, Taiwan2012-Mar-17

The incidences of MCL is changing.

US: Annual adjusted incidence ~ 0.6/100,000

Stage IV disease is increasing

Cancer 2008;113:791

2012/3/23

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The classification of MCL is also changing:

• Diagnostic hallmark:

– CD5+CD23- mature B-cell neoplasm

– CCND1 gene/cyclin D1 protein overexpression;

t(11;14)(q13;q32)

• WHO classification:

– Classic: Sox11 nuclear over-expression

– Blastoid (pleomorphic)

– Marginal-zone like

– Small cell

Small-cell MCL represents a CLL-like clinical

phenotype:

• Still CCND-1/cyclin D1 overepxression

• Still CD5+CD23-

• Low Ki-67 index

• Low proliferation signature in

microarray

• Low Sox11 expression

• Good survival

Cancer Sci 2011;102:1734

2012/3/23

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I am MCL !?

MCL is a disease with poor prognosis.

Take dis-advantages of both:

• Low-grade NHL: No cure

• High-grade NHL: Rapid progression

Overall survival

Overall survival

Blood 2000;95:2253

2012/3/23

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Prognostic index for MCL

Simplified score:

LR: 0-3

IR: 4-5

HR: 6-11

IPI MIPI

Blood 2008;111: 558

Treatment scheme of MCL

InductionInduction ConsolidationConsolidation MaintenanceMaintenance

Proper induction Proper induction

regimens?regimens?

Role of AutoRole of Auto--HSCT?HSCT?

Role of Role of AlloAllo--HSCT?HSCT?Role of Role of

RituximabRituximab??

Roles of novel Roles of novel

agents?agents?

Risk

Stratification

2012/3/23

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Choices of Induction Regimens..

Stepping from CHOP:

Rituximab improved response, but6666

TTF: All patients

encountered

PFS: CR+PR

encountered

P=0.013 P=NS

• German Low Grade Lymphoma

Study Group (GLSG)

• R-CHOP vs CHOP, N=62 vs 60

• Advanced MCL

• Prospective randomized trial

J Clin Oncol 2005;23:1984

2012/3/23

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Evolving for intensive chemotherapy:

MDACC concepts with dose-intensive C/T

• Hyper-CVAD/MA regimen

Later changed to

16.7 mg/m2 x 3d

J Clin Oncol 1998;16:3803

MDACC cohort:

Hyper-CVAD+HSCT improved MCL outcome.

• Phase II study, age<65 y/o

• 55 cases with Stage II/IV MCL,

25 untreated

• 38% CR and 55.5% PR

• All responding cases go to

HSCT: 26 auto- and 8 allo-

• All them went to CR after

HSCT

• Overall 3-yr PFS 42% and 3-yr

OS 56%

• Allo- better than Auto-

• Untreated better than relapsed

J Clin Oncol 1998;16:3803

Historical control

Previously untreated cohort

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MDACC cohort:

Long-term results for Hyper-CVAD+auto-HSCT

Cancer 2003;98:2630

• N=33

• TBI+Cy for conditioning

• B2-microglobin and Anderson tumor score(TS) are with prognostic

significance

Upgrading MDACC cohort:

R-Hyper-CVAD/R-MA further improved outcome. (1)

Overall survival• Phase II trial, N=97

• 6-8 cycles

• Subtype: blastoid 18%,

nodular 16%

• CR rate 87%, response rate

97%P=0.047

J Clin Oncol 2005;23:7013

2012/3/23

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Upgrading MDACC cohort:

R-Hyper-CVAD/R-MA further improved outcome. (2)

High b2m and elder age indicated

worse PFS

Progression-free survival

J Clin Oncol 2005;23:7013

Upgrading MDACC cohort:

R-Hyper-CVAD/R-MA further improved outcome. (3)

• 10-year follow-up

Br J Haematol 2010;150:200

2012/3/23

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Problems in R-hyper-CVAD/R-MA

• Outside MDACC: inferior outcome6.

• Higher toxicity:

– 8% treatment-related death

– Increased 2nd malignancies:

Urological cancers,

AML/MDS

Eu J Haematol 2010;85:371

In J Haematol 2010;92:25

Ann Oncol 2002;12:318

N=154,

A.D.1994-2000 for Hyper-CVAD/MA

Omitting HDMTX may reduce toxicity.

• CALGB phase II trial, N=78, 2001-2004

• High M-IPI: 12%

• R-maxiCHOP6.R-EA6..CBV/autoHSCT6.R-maintenance

• 2 treatment-related death

J Clin Oncol 2009;27: 6101

2012/3/23

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Early treatment of MCL may not result in better

outcome6.

• N=31 (observation) vs 66 (early treatment)

• Higher M-IPI in early treatment

J Clin Oncol 2009;27: 1209

Does upfront auto-HSCT work??

2012/3/23

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Upfront auto-HSCT improved PFS.

• European MCL network

• Phase III randomized control trial

PFS OS

Blood 2005;105: 2677

Those who has CR before auto-HSCT benefited

the most.

CR before auto-HSCT PR before auto-HSCT

Blood 2005;105: 2677

2012/3/23

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MDACC cohort6again:

Upfront auto-HSCT+R provided survival plateau6

but delayed auto-HSCT+/-R not!

Blood 2009; 113:4144

• Auto-HSC mobilization frequently failed after 6 cycles of R-HyperCVAD/R-MA

Nordic Group:

Impacts of rituximab and Ara-C on MCL treatment

Blood 2008;112: 2687

2012/3/23

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Who is the candidate for allo-HSCT??

Still MDACC cohort6.:

G-V-L effects documented in NST

• Myeloablative protocol (TBI+Cy/BEAM) resulted in high TRM (38%)

and 55% 3-yr OS in advanced MCL.

• NST by FCR conditioning

• N=18, relapsed and refractory MCL after C/T and/or auto-HSCT

• 89% in chemo-sensitive relapse

J Clin Oncol 2003;21: 4407

Ann Oncol 1999;10: 1293

2012/3/23

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Blood 2009; 113:4144

Leuk Lymphoma 2009;50:1239

Allo-HSCT provided the last chance to be cured

in relapse/refractory MCL.

FHCRC experiences of NST in MCL:

•NST with TBI (2Gy)+F

• MUD (n=17) and sibling donors (n=16) for relapsed/refractory MCL

• Most chemo-resistant

Blood 2004;104: 3535

2012/3/23

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Is rituximab maintenance required?

Rituximab maintenance prolonged PFS in MCL.

• GLSG study, Phase III randimized control trial

• Induction with R-FCM

• N=29 (observation) vs 28 (maintenance)

• R maintenance: 4 times weekly on 3rd and 9th month

P=0.049

Blood 2006;108: 4003

2012/3/23

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MDACC cohort:

Auto-HSCT or rituximab maintenance may be

equally effective.

• Retrospective analysis,

2005-2009

• RHCVAD alone (n=16) vs

autoHSCT (n=17) vs

R maintenance (n=11)

• R: q6m for 2 yr

Bone Marrow Transplant 2011 Nov 14, doi:10.1038/bmt.2011.218

Summary

InductionInduction

ConsolidationConsolidation

MaintenanceMaintenance

•• Intensive regimen Intensive regimen

requiredrequired

•• RituximabRituximab requiredrequired

•• RR--HyperCVADHyperCVAD/R/R--MA is MA is

good, but can be better.good, but can be better.

•• Upfront autoUpfront auto--HSCT is HSCT is

required if no R.required if no R.

•• If R added, autoIf R added, auto--HSCT? HSCT?

may still be required.may still be required.

•• AlloAllo--HSCT is the only HSCT is the only

way to cure way to cure

relapse/refractory MCLrelapse/refractory MCL

•• R R maintmaint. can . can

improve outcome if improve outcome if

no no autoHSCTautoHSCT..

•• But after autoBut after auto--

HSCT?HSCT?

•• Maybe preMaybe pre--emptive emptive

strategystrategy

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Novel Agents

Cyclin D1 over-expression is the key factor of

MCL pathogenesis.

Blood 2011;117: 26

2012/3/23

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Classification of novel drugs:

Semin Cancer Biol 2011;21: 335

Novel targeted drugs for MCL

• Proteasome inhibitors

• mTOR inhibitors

• Other chemotherapeutic agents

• Radio-immunotherapy

• Other monoclonal antibodies (anti-CD22, etc)

• Serine/threonine or tyrosine kinase inhibitors

• HiDAC inhibitors

• PI3K/Akt inhibitors

• IMiDs

2012/3/23

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Bortezomib is effective in relapsed/refractory MCL.

• Bortezomib single agent for relapsed/refractory MCL

• N=155

• Response rate 32%, with 8% CR/CRu

Ann Oncol 2009;20: 525

VcR-HyperCVAD is effective for induction in MCL.

• Phase II study, multi-center in USA

• N=27, 80% M-IPI intermediate to high

• Median age = 61 y/o

• Overall response 90%, CR/CRu rate 77%

• No TRM

• 9 with Gr3/4 polyneuropathy

PFSOS

Br J Haematol 2011;155: 190

2012/3/23

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Temsirolimus is also effective in relapsed/refractory

MCL.

• Phase III randomized double-blinded trial, multi-nation

• N=54 for each, with 8% blastoid

• OR: 22% vs 6% vs 2%, CR rate: 2% vs 0% vs 2%

• ~60% experienced Gr 3/4 thrombocytopenia in 175/75 group.

Ann Oncol 2009;20: 525

Bedamustine is also effective in treating MCL.

• DNA Alkylators with durable effects..

Anti-metabolite effects

• Single agent for phase II trial in Japan:

ORR =100%, CR/Cru rate 73% (n=11)

• B+R: phase II trial in USA

n=12

ORR 92%, CR/CRu rate 59%

Cancer Sci 2010;101: 2059

J Clin Oncol 2008;26: 4473

2012/3/23

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Radioimmunotherapy (RIT)

• 90Y-ibritumomab tiuxetan (Zevalin)131I-tositumomab (Bexxar)

• Zevalin: 30% ORR and 6m EFS in relapsed/refractory MCL

• Frontline therapy with zevalin: increased CR rate (55% vs 13%) and 31m EFS

• Bexxar: combined in auto-HSCT conditioning in FHCRC for relapsed/refractory MCL

3-yr PFS 61% and 3-yr OS 93%

Blood 2007;110: 389

Clin Oncol 2009;27: 5213

J Clin Oncol 2007;25: 1396

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