Dr. Romaguera MCL

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Strategies in Mantle cell lymphoma:

Chemotherapy

Jorge E. Romaguera, M.D.

Professor of Medicine

Department of Lymphoma/Myeloma

U.of Texas M. D. Anderson Cancer Center

Disclosures

Millenium – research

Celgene - research

12 Dec 2004

Mantle Cell NHL

Clinical Characteristics MDACC EMCLN

M:F ratio 3:1 3.2:1Median age (range) 60(41-80) 64(27-86)

Age > 65 33%

PS (ECOG) 0-1 98% 84%

AA Stage IV 99% 92%(III-IV)

Bone marrow involved 91% 72%

GI tract involved 88%

Peripheral blood involved 49%

Splenomegaly 40%

Elevated LDH 25% 29%

IPI score 0-1 12% 17%Histology Diffuse 89% 81% Nodular 11% 18%Blastoid cytology 14% 3%

Strategies in the Treatment of Mantle cell lymphoma

1- When to treat

a- Stratify

2- What to treat with

Conservative management of MCL

Martin et al. J Clin Oncol. 2009

95 patients 1997-2007; median follow up 4.5 years

Retrospective, single institution, known date of Diagnosis and date of first Tx

Observed X 3 months to define 2 groups: observationVs. early treatment

Median time to treatment 1 yr in observation group Mostly treated with CHOP (5 with HCVAD or SCT)

Conservative management of MCL

Martin et al. J Clin Oncol. March 2009

Strategies in the Treatment of Mantle cell lymphoma

1- When to treat

a- Stratify

3- What to treat with

Mantle cell International PrognosticIndex (MIPI)

GLSG 1996 CHOP, MCPGLSG CHOP + R, Ifn Vs ASCT

438 patientsCHOP – 56%R-CHOP – 31%MCP - 11%Other - 2%

ASCT – 80 ptsIFN maintenance – 199 ptsNo therapy in remission – 72

ptsHoster et al. Blood Jan 2008

Simplified MIPI prognostic index

For each prognostic factor, 0 to 3 points were given to each patient and points were summed up to a maximum of 11. Patients with 0 to 3 points in summary were classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with 6 to 11 points as high risk. ECOG performance status was weighted with 2 points if patients were unable to work or bedridden (ECOG 2-4). LDH was weighted according to the ratio to the ULN. Thus, for an ULN of 240 U/L, the cutpoints were 180 U/L, 240 U/L, and 360 U/L, for example.

 Points 

 Age, y 

 ECOG   LDHULN   WBC, 109/L 

 0   <50   0-1   <0.67   < 6.700 

 1   50-59   —   0.67-0.99   6.700-9.999 

 2   60-69   2-4   1.000 -1.49 

 1.000-14.999 

 3      70   —      1.5000      15000 

Overall Survival according to MIPI – GLSG

Hoster et al. Blood Jan 2008

Conservative management of MCL

Martin et al. J Clin Oncol. 2009

Other prognostic variables

Pre- Treatment1- Lack of adenopathy2- Early stage3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-115- b2 microglobulin

Post- Treatment1- MRD

Other prognostic variables

Pre- Treatment1- Lack of adenopathy2- Early stage3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-115- b2 microglobulin

Post- Treatment1- MRD

Chemotherapy + XRT forStage I-IIA untreated MCL: 26 pts

Leitch et al, Ann Oncol 14:1555-1561, 2003

Chemotherapy + XRT forStage I-IIA untreated MCL: 21 pts

Bernard M et al. ICML 2011

62% stage II; 73% head and neck5 patients with blastoid variant17 patients with chemotherapy (R-CHOP in 13 )-XRT

ORR 95%With median follow up 5 yrs, 5 yr relapse rate 46%

Prognostic factors for worse outcome: stage II, blastoid variant

Other prognostic variables

Pre- Treatment1- Lack of adenopathy2- Early stage3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-115- b2 microglobulin

Post- Treatment1- MRD

Other prognostic variables

Pre- Treatment1- Lack of adenopathy2- Early stage3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-115- b2 microglobulin

Post- Treatment1- MRD

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-value= 0.0003

HH ( E / N = 18 / 23 )HL ( E / N = 10 / 30 )LH ( E / N = 4 / 9 )LL ( E / N = 11 / 35 )

Time (Months)

Pro

ba

bili

tyOverall Survival by B2M and Age

Other prognostic variables

Pre- Treatment1- Lack of adenopathy2- Early stage3- Proliferation, Blastoid cytology 4- Other Molecular, SOX-115- b2 microglobulin

Post- Treatment1- MRD

8 x R-CHOP

IFN- maintenance(3 x 3 M IU/week)

or Peg-IFN(1mg/kg week)

PR, CR6 x R-FC

Rituximabmaintenance(all 2 months)

First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)

Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review

Kluin-Nelemans et al: ICML 2011

MRD (minimal residual disease)

MRD clearance mid-therapy rapid for R-FC 67% vs only 31% for R-CHOP

Sustained molecular remission beyond 1 year from end of treatment predicted for improved chances of maintaining clinical remission at 2 years (84% vs. 35%)

Pott et al. IMCL 2011

Strategies in the Treatment of Mantle cell lymphoma

1- When to treat

a- Stratify

3- What to treat witha- conventionalb- new non-transplant approaches

i- combination with newer drugsii- consolidation/maintenance

Should treatment include Rituximab?

Rituximab in Overall Survival of MCL

Schultz et al. J Natl Can Inst. 2007

Meta-analysis of seven randomized controlled trials

1990-2005, 1943 patients

R- chemotherapy improved OS in MCL

But heterogeneity made data less reliable (p = .07)

Griffith et al, Blood 2011; SEER data

Rituximab improves Survival in the elderly

Overall Survival for MCL in 2 periods

Abrahamsson et al, ICML 2011

785 patients from 2000-2010

For 2006-2010, 3-yr OS better (62% vs. 47%, p < 0.01)These patients received High dose AraC and rituximab as part of induction regimen

OS improvement persisted when groups corrected for prognostic factors (age, PS, B symptoms)

Should it be more intense?

Improvement in Survival of MCL

Herrmann et al. J Clin Oncol. 2008

Kiel Lymphoma Study Group (KLSG) – 1975-1986German low-grade Study Group (GLSG) – 1996-2004

520 patients (370 from GLSG)

Frequency matching for age, LDH, Performance statusnon-blastoid,advanced stage

Median overall Survival improved from 2.7 y to 4.8 y

Overall Survival for MCL in 2 periods

Herrmann et al J Clin Oncol Dec 2008

A – Initial cohorts B – matched cohorts

Reference RegimenAge

(years)

No. of Patients

CR/CRu (%)

Relapse/failure

Overall Survival

Median Follow-Up Time (months)

•Kahl et al •Modified R-Hyper-CVAD¥

•40-81 •22 •64 •50% 3-year PFS

•73% •37

•Neelapu et al •EPOCH-R •22-73 •26 •92 •Median EFS, 22 months

•89% •46

•Dreyling et al RCHOP/interf •28 •25% 3-year PFS

•52% •60*

RCHOP/autoSC transplant

•35-65 •81 •54% 3-year PFS

•67% •60*

•Romaguera et al

•Hyper-CVAD-R+methotrexate-cytarabine-R

•41-65 •65 •89 •46% 8-year FFS

•67% •96

R-HCVAD/R-MAOverall Survival

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

Overall Survival

Time (Months)

Pro

ba

bility

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-value= 0.0003

HH ( E / N = 18 / 23 )HL ( E / N = 10 / 30 )LH ( E / N = 4 / 9 )LL ( E / N = 11 / 35 )

Time (Months)

Pro

ba

bili

tyOverall Survival by B2M and Age

R-HyperCVAD/R-MA10 year follow-up

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-value= 0.0046

0 ( E / N = 14 / 49 )1-2 ( E / N = 29 / 48 )

Time (Months)

Pro

ba

bility

Overall Survival by MIPI

R-HCVAD/R-MATime to Failure

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

Time to Failure

Time (Months)

Pro

bability

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-v alue= 0.0064

<3 ( E / N = 25 / 44 )>=3 ( E / N = 40 / 53 )

B2M

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-v alue= 0.0004

HH ( E / N = 21 / 23 )HL ( E / N = 19 / 30 )LH ( E / N = 6 / 9 )LL ( E / N = 19 / 35 )

B2M and Age

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-v alue= 0.0207

Low ( E / N = 49 / 78 )High ( E / N = 16 / 19 )

LDH

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-v alue= 0.5139

0 ( E / N = 28 / 44 )1 ( E / N = 35 / 51 )2 ( E / N = 2 / 2 )

ECOG

Time (Months)

Pro

babi

lity

Time to Failure

Time (Years)

Pro

ba

bili

ty

0 20 40 60 80 100 120

0.0

0.2

0.4

0.6

0.8

P-v alue= 0.0159

0 ( E / N = 28 / 49 )1-2 ( E / N = 37 / 48 )

Time to Failure by MIPI (0 vs. 1-2)

Strategies in the Treatment of Mantle cell lymphoma

1- When to treat

2- Stratify

3- What to treat witha- conventionalb- new non-transplant approaches

i- combination with newer drugsii- consolidation/maintenance

Bortezomib in untreated MCL

• 13 patients, stage III-IV

• Bortezomib 1.3mg/m2 on days 1, 4, 8, and 11 every 21 days

• 46% Overall response rate (all PR’s)

• Duration of response – 8 months

Belch et al. Ann Oncol 2007

Bortezomib + R-AD + chlorambucil in Untreated Elderly MCL

• 39 patients, stage III-IV, median age 72 yrs

• 35-day cycle of B 1.3 mg/m2 days 1, 4, 8, 11; R 375 mg/m2 days 1, 8 cycle 1; day 1 cycles 2-6; doxorubicin 9 mg/m2 days 1-4; dexamethasone 40 mg days 1-4, chlorambucil 12 mg days 20-29

• ORR 74% (59 % CR/Cru)

• Median PFS 26 months; Median OS NR

• Mild toxicityHouot et al, Ann Oncol 2011

Bortezomib + R-CHOP in untreated MCL

• 36 patients, stage III-IV

• Bortezomib 0.7, 1.0, 1.3mg/m2 on days 1, 4, every 21 days

• • ITT Overall response rate 81%

(64% CR/Cru)

• 2-year PFS 44%, MIPI correlates with OS

• Neurotoxicity – 8% grade 2; 4% grade 3Ruan J et al, J Clin Oncol 2011

Bortezomib + R-CVAD in MCL

• Bortezomib-Rituximab-CVAD in MCL, n=30

• Bortezomib dose was initially 1.5 mg/m2 on days 1 & 4 only Went down to 1.3 mg/m2

• Likewise, Vincristine dose went down to a total of 1mg

• CR/CRu 23(77%), PR 4(13%)

• 3-yr PFS 63 months (50 months without bortezomib)

Chang JE et al; Br. J Haem. 2011

Bortezomib + R-DA-EPOCH in MCL

• 38 patients

• 1 cycle bortezomib alone 1.3 mg or 1.5 mg/m2 days 1, 4, 8, 11

• 6 cycles R-DA-EPOCH with bortezomib 1.5 mg/m2 (reduced to 1.3 mg/m2 days 1 and 4

• Responders randomized to 1.3 mg/m2 d1, 4, 8, 11 every 2 months vs. observation

Grant et al, ASCO 2011, abstract #8022

Bortezomib + R-DA-EPOCH in MCL

• ORR to bortezomib alone = 11% (38 pts)

• ORR to regimen 92% (63% CR)

• 3-year PFS 48% observation vs. 63% maintenance

• 50% grade > 2 neurotoxicity

Grant et al, ASCO 2011, abstract #8022

Alternate cycles 1 & 2 every 21 days:

CYCLE 1• Rituximab 375 mg/m2 D1• • Cyclophosphamide 300 mg/m2 IV

over 3 hrs q 12 hrs x 6 D2-4• Bortezomib 1.3 mg/m2 D2 after 1st

dose cyclophosphamide• Doxorubicin 50 mg/m2 /d IVPB

D5• Vincristine 1.4 mg/m2 IV

(maximum 2 mg) D5 after doxorubicin IV & D12

• Bortezomib 1.3 mg/m2 D5 immediately after vincristine

• Dexamethasone 40 mg IV or PO Days 2-6 and 12-16

CYCLE 2:• Rituximab 375 mg/m2 D1• Bortezomib 0.7/1/1.3 mg/m2 D1

after rituximab• Methotrexate 200 mg/m2 IV over

2 hrs D2• Methotrexate 800 mg/m2 IVCI 22

hrs D2 • Cytarabine 3,000 mg/m2 IV over

2 hrs q 12 hrs x 4 D3-4• Bortezomib 0.7/1/1.3 mg/m2D6

Untreated MCL < 79 years BR-HCVAD Phase I-II

Bortezomib + R-HCVAD/R-MA in MCL

• ORR = 100% (87% CR)• Toxicity (188 cycles) Grade 3 (%) Grade 4(%)

HematologicThrombocytopenia 13 (7%) 48 (26%)Neutropenia 15 (8%) 54 (29%)Neutropenic fever 0 9 (5%)

Non-hematologicFatigue 0 0Pulmonary 0 0Mucositis 0 0Nausea 0 0Vomit 0 0Neuropathy (sensory) 1 (1%) 0Arrhythmia 3 (2%) 0

Romaguera et al ICML 2011

Bendamustine Plus Rituximab Versus CHOP Plus Rituximab in the First-Line-Treatment of Patients with Follicular, Indolent and MCLs

Rummel, ASH 2008 # 2596

Histology Benda-R(ORR / CR)

CHOP-R(ORR / CR)

FL 94 / 44 94 / 34

MCL 89 / 32 95 / 35

IC / LPL 100 / NE 95 / NE

MZL 90 / 52 96 / 36

StiL: Study Group Indolent Lymphomas

MJRMJR

PFS, mantle cell, B-R vs CHOP-RPFS, mantle cell, B-R vs CHOP-R

00 1212 2424 3636 48480.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

Pro

babi

lity

Pro

babi

lity

CHOP-RCHOP-R

B-RB-R

Bendamustine Plus Rituximab Plus Cytarabine for MCL

28 patients (15 untreated)Median age 71 yrs, high MIPI 54%; blastoid 18%

R 375/m2 day 1; B 70 mg/m2 days 2,3; Cytarabine 800 mg/m2 daily days 2, 3, 4

4-6 cycles every 4 weeks.

ORR 96% (92% CR)Median follow up 1 year; 2 patients relapsed

Visco et al; ICML 2011

Lenalidomide + R-CHOP

• R-CHOP 21; lenalidomide 5 to 25 mg (phase I) daily X 14 days per cycle; pegfilgrastin day 4; aspirin 100 mg/d

Tilly et al; ASCO 2011

R-CHOP and 90Y-RIT

Stages II-IV, > 18 years old.

R-CHOP 21 X 4 cycles

CR/PR/SD patients get 0.4 mCi/kg 90Y-RIT

Endpoint – time to treatment failure

MIPI – Low 51%, Int. 26%; high 21%

Smith et al. ICML 2011

R-CHOP and 90Y-RIT

57 patients

Response after R-CHOP – 81% (56% CR/Cru)

23/57 patients with improved response after 90Y-RIT

(16 PR to CR/Cru; 3 SD to PR)

Median F/U 64 months; median TTF 28 months; median OS not reached

Estimated 3-yr OS 86% for > 65 y/o; 67% for > 65 y/o

Smith et al. ICML 2011

Maintenance Strategies in MCL

• Modified R-HCVAD (+ Bortezomib) + maintenance R

• DA R-EPOCH + Bortezomib

R-CHOP alternating with R-Cytarabine X 5 cyclesThen Cytarabine-fludarabine cycles 6-8Then Rituximab q 2 months X 2 yrs

50 untreated patients, median age 74 yrs; high MIPI in 50%ORR 96% (86% CR/Cru)At median follow up 3 yrs, 86% OS, 70% EFS18% patients (9) improved during cytarabine/fludarabine Toxicity: one MDS, one gr 4 infection, 19 patient with transient

gr 4 neutropenia during maintenance. More dose reductions during fludarabine.

Raty et al. ICML 2011

R-GIFOX q 2 weeks X 6 plus Rituximab q 2 months maintenance

16 untreated patients, median age 66 yrsGemcitabine 1200 mg/m2 D1, Oxaliplatin 120 mg/m2 D2,

Ifosfamide 5 g/m2 D2, R 375 mg/m2 q 2 months

ORR 100% (88% CR)5-year PFS of 56% without plateau

Toxicity: Gr 4 thrombocytopenia in 43% patients; Gr 3 infection in 37% patients

Corazzelli et al. ICML 2011

8 x R-CHOP

IFN- maintenance(3 x 3 M IU/week)

or Peg-IFN(1mg/kg week)

PR, CR6 x R-FC

Rituximabmaintenance(all 2 months)

First RCT for MCL Elderly 8 countries, n = 560 (Jan 2004-Oct 2010)

Newly diagnosed, >60-65 yr; performance 0-2, Stages II-IV, central PA review

Kluin-Nelemans et al: ICML 2011

MCL Elderly: Baseline Characteristics evaluable patients

Parameter R-CHOP (%) R-FC (%)Age median (range) 71 (61-87) 70 (60-85)% male 67 72Stage IV 85 82% pos. BM 76 74B-Symptoms 36 38

Performance 0-1 92 92

Elevated LDH 41 42MIPI low risk 8 11MIPI intermediate risk 44 40MIPI high risk 48 50

n 215 216Kluin-Nelemans et al: ICML

2011

Maintenance Strategies : RBL

• Patients > 65 years old• Rituximab 375 mg/m2 day 1; bendamustine 90 mg/m2

days 1-2 q 28 days X 6; lenalidomide 5 to 25 mg (phase I) daily X 21 days per cycle

• Maintenance lenalidomide 25 mg/day X 21 days q 28 days X 7 cycles

• Goal: improve PFS by at least 6 months over B-R (36 months vs. 30 months)

Jerkeman et al; ASCO 2011

Improvement in survival is also a measure

of the effectiveness of salvage therapy,

and over the last few years there has been

marked improvement in options available.

LYMPHOMA DEPARTMENTLUIS FAYAD, MDFREDERICK HAGEMEISTER, MDNEELAPU, SATTVA, M.D., PH.D.M ALMA RODRIGUEZ, MDFELIPE SAMANIEGO, MDANAS YOUNES, MDMICHAEL WANG, MDDONNA WEBER, M.D.RAYMOND ALEXANIAN, M.D.QING YI, Ph.D.ROBERT ORLOWSKI, M.D., Ph.D.JATIN SHAH, M.D.NATHAN FOWLER, M.D.Andre Goy, M.D.LARRY KWAK, MD, Ph.D.

PAMELA WEAVER, R.N.KIMBERLY HARTIGCHRISTINE SAMUELMARIA BADILLO

SANDY HOROWITZ, PHARM D

KATHLEEN SHANNON-MCADAMS, RN, ANP ELLEN MULLEN, RN, ANPMATHAI VARGHESE, PA

SHAPATRA PARKER

HEMATOPATHOLOGYJEFFREY L MEDEIROS, MDJOHN MANNING, MDJEFFREY JORGENSENRICHARD FORD, M.D. Ph.DRAJA LUTHRA, MD, Ph.D.

CYTOPATHOLOGYRUTH L KATZ, MDNANCY CARAWAY M.D.ABHA KHANNA

Acknowledgements

AMANDA WEDGWOOD, RN, CNSAMYE MOSHIER, PAHONGYAN WANG, PAMARIA GUERRERO, ANPWENDY CHEN, PAPETER LAI, PASHIRLEY GEORGE, APN

BMT DEPARTMENTRICHARD CHAMPLIN, M.D.ISSA F.KHOURI, M.D.CHITRA HOSING, M.D.

12 Dec 2004

Thank you!