Mantle Cell Lymphoma

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Mantle Cell Lymphoma

• Jan 7 2009
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• CT
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Lymphoma Response Criteria
Invisible CR Very small but no biopsy CRu
lt0.7 PR
0.71.2 SD
gt1.2 PD
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Mantle cell lymphoma

• 6 of NHL (2-3/100,000yrs)3,000 new cases/yr in
  US
• MF31, Median age 63
• B-symptoms 33
• Generalized LAD 90
• Extranodal involvement 80, GI tract 9-20
• 80-90 stage III/IV, BM involved 64,
  Splenomegaly 60
• Median OS 3 - 4 yrs
• WHO classified as indolent and aggressive
• 25 behavior as indolent (unable to predict)
• 75 behavior as aggressive

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5-yr Overall Survival
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Histology

• Lymphocytes in the primary lymphoid follicles and
  mantle zones of secondary follicles
• Histologic progression is common, transformation
  rare
• Express
• Cyclin D1
• CD19, CD20, CD22
• CD5
• BCL-2
• CD79a, FMC7
• Surface IgM / IgG
• Negative
• CD10
• CD23

CD148 is a potential marker D/D MCL()/CLL(-)ASH
2008, Miguet et al, Abstract 1766
Palutke M et al. Blood 1996 June87(11)4483
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Histology
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Cytogenetics

• t(1114)(q13q32) deregulated expression of
  cyclin D1.
• MM20-30 of cases
• MCLvirtually all cases

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Mantle Cell Lymphoma Biology
Cell cycle
DNA damage response (gt 80 MCL have secondary
alterations)
Deletion 11q22-23 Mutations ATM locus
ATM
ATR
RB1
Stabilization of p53
p14
CHK1-2
M
G1
INK4/ARF
Deletion 9q21
cdk4/cyclin D1
G2
p16
MDM2
G1/S arrest
p21
S
Deletion 17q/ mutation p53
p53
p27
RB1 P
Apoptosis
G1/S arrest
DNA repair
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Clinical risk factors MIPI clinical
(PALL PS, age, LDH, leucocyte count)
Hoster, Blood 2008
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Mantle cell lymphoma treatment
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Rituximab (Meta-analysis)
Response rate
Overall survival
J Natl Cancer Inst 200799 706 14
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First Line Induction Regimens

• Standard R-CHOP
• Woward, CR48, PFS16.6m
• GLSG, CR34, PFS15m
• Intensive R-HyperCVAD/R-MTX-AC
• MDACC, CR87, FFSnot reached (67_at_3yr)
• Maxi-CHOP/HDAC (Nordic-2)
• CR54, PFSnot reached
  (66_at_6yr)
• Purine analog R-FCM

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R-CHOP vs CHOP (GLSG trial)
OS
86 vs 82_at_2yrs
CR () ORR () TTF (m) 2 yr PFS 2 yr OS
CHOP 7 75 14 25 77
R-CHOP 34 94 21 25 77
P value 0.00024 0.0054 0.0131 0.31 0.93
Lenz, G. et al. J Clin Oncol 231984-1992 2005
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OS of GLSG (1996-2004) vs KLSG (1975-1986)
4.8 yrs vs 2.7 yrs
Hermann et al, Published Ahead of Print on
December 15, 2008
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Phase 2 R-HyperCVAD/R-MTXAC (MDACC)
alternate cycles 1 and 2 Q21D
cycle 1, 3, 5, 7R-hyperCVAD
cycle 2, 4, 6, 8R-M-A
day 1
day 21

• 29 pts not complete scheduled C/T cycles
• Poor prognostics gt65yo, high LDH, lack of GI
  involvement, B2gt3mg/L
• 8 deaths and 4 t-AML/MDS

Romaguera et al. JCO 2005 Oct 123(28)7013-23
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R-HyperCVAD/R-MTXAC (MDACC)
CR87, ORR97
Romaguera, J. E. et al. J Clin Oncol
237013-7023 2005
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R-HyperCVAD/R-MTXAC (MDACC)

• Too toxic! TRM8

Romaguera, J. E. et al. J Clin Oncol
237013-7023 2005
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Mantle cell lymphoma and transplantation
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Upfront ASCT European MCL NetworkPhase 3 trial
61 CHOP 26 R-CHOP
Dreyling et al, Blood, 2005, Vol. 105, No. 7, pp.
2677-2684
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PFS Benefit, no OS Benefit
Dreyling et al, Blood, 2005, Vol. 105, No. 7, pp.
2677-2684
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Upfront ASCT Nordic-1 vs Nordic-2

• Phase 2
• CR54, ORR96
• NRM5

Geisler et al, Blood. 20081122687-2693
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Upfront ASCT Nordic-1 vs Nordic-2

• PFS 66_at_6yrs, No relapse after 5 yrs
• OS 70_at_6yrs

Geisler et al, Blood. 20081122687-2693
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Retrospective EBMT and ABMT Registry supports
ASCT in CR1

• 195 patients (new diagnosis and relapsed)
• Chemotherapy varied/not reported
• Conditioning regimens varied
• Pts not transplanted in CR1 were 3x more likely
  to die from MCL
• Median survival 59 months

2yr PFS 2yr OS 5yr PFS 5yr OS
All patients 55 76 33 48
CR1 Patients 65 88 52 65
Vandenberghe, E., Ruiz, C., et al., BJH
2002120793
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EBMT Registry ASCT improves OS in CR1
Patients transplanted in CR1 2 year PFS 65 5
year PFS 52 2 year OS 88 5 year OS 65
Vandenberghe, E., Ruiz, C., et al., BJH
2002120793
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ASCT in CR1 OS by B2 Microglobulin
B2m lt 3 (N18)
B2 m gt 3 (N9)
Khouri et al. Cancer 982630-2635, 2003
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The MD Anderson1 and Fred Hutchinson2 Experience

• Allo may have a role as salvage in MCL
• Differed by conditioning regimen

n Median f/u (Months) ORR CR Measurable dz at transplant Outcome
MDA1 18 26 89 94 9 Est 3yr OS 86 Est 3yr PFS 82
FHCRC2 33 24.6 85 75 20 2yr OS 64 2yr PFS 60
1. Khouri, I., Lee,M., et al., JCO
200321(3)4407 2. Maris, M., Sandmaier, B., et
al., Blood 2004104(12)3535
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Novel Agents

• Proteosome inhibitors
• Mammalian target of rapamycin (mTOR) inhibitors
• Thalidomide

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Relapsed MCL
Regimen N CR PR ORR
Foran19 Rituximab 35 14 23 37
Gressin20 VAD Chlorambucil 30 43 30 73
Kaufmann21 Rituximabthalidomide 16 31 50 81
Dang22 Ontak 8 12.5 25 37.5
Cohen23 Cyclophosphamidefludarabine 30 30 33 63
Goy24 Bortezomib 29 21 21 42
O'Connor25 Bortezomib 11 9 36 45
McLaughlin26 Fludarabinemitoxantronedexamethasone 5 20 80 100
Seymour27 Fludarabinecisplatincytarabine 8 88
Forstpointner28 Fludarabinecyclophosphamidemitoxantrone 24 0 46 46
Forstpointner28 Fludarabinecyclophosphamidemitoxantronerituximab 24 29 29 58
Levine29 Fludarabinemitoxantronerituximab 5 80 0 80
Rummel30 Bendamustinerituximab 16 50 25 75
Fisher31 Bortezomib 141 8 25 33
Robak32 2-CdArituximab or rituximab with cyclophosphamide 9 22 45 67
Rupolo33 Rituximaboxaliplatincytarabine 9 NA NA 100
Drach34 Rituximabbortezomibdexamethasone 12 25 50 75
Wang R-HyperCVAD/R-MTXAC 29 45 48 93
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2 Line-- Single Agent Bortezomib

• Phase 2 studies in relapsed MCL
• Velcade 1.31.5mg/m2 days 1,4,8,11 Q21D

N CR PR SD PD Outcome Median follow-up
PINNACLE1 141 8 25 40 10 OS NR DOR 9.2m TTP 6.2m 13.4m
MSKCC2 10 10 40 40 10 DOR 6-19m
MDACC3 29 20.5 20.5 20.5 38 PFS 42_at_6m 9.3m
Strauss4 24 4 25
Belch5 28 4 42 TTP 12.5m

1. Fisher R et al. JCO 200624early release online
   10.1200/JCO.2006.07.9665
2. OConnor, O., Wright, J., et al., JCO 2005
   23(4)676
3. Goy, A., Young, A., et al., JCO 200523(4)667
4. Strauss et al, JCO 2006
5. Belch et al, Ann Onc 2007

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Phase 2 PINNACLE
PINNACLE
CR or CRu Continue treatment for 4 cycles beyond
initial documentation, up to 17 cycles
EVALUATE
Bortezomib 1.3 mg/m2 D1, 4, 8, 11 Q21D
PR or SD maxi 17 cycles
PD Discontinue
Enroll completed in June 2005 (N 155) 35
centers in the US, UK and Germany
Fisher et al. JCO 2006 24 4867-4874
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Phase 2 PINNACLE
()
N
Parameter
No. of prior lines of therapy for MCL
(54)
84
1
(42)
65
2
(4)
6
3
Received prior regimen containing
(98)
152
Anthracycline/mitoxantrone
(97)
150
Alkylating agents
(96)
149
Rituximab
(100)
155
At least 2/3 of the above
(91)
141
All 3 of the above
(37)
58
Prior high intensity therapy
(5/19)
8/29
Prior radioimmunotherapy / radiation therapy
High-intensity regimens defined as stem cell
transplant, Hyper-CVAD/ICE/ESHAP/DHAP all
rituximab
Fisher et al. JCO 2006 24 4867-4874
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Important Things

• CR rate8
• ORR rate33
• Median time to response 1.3m (2 cycles)

Fisher et al. JCO 2006 24 4867-4874
OConnor et al. JCO 2005 OConnor et al. ICML 2005
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Bortezomib is Synergistic with Cytarabine

• Case 1 B 1.5mg/m2, D1, D4
• Ara-C 1000mg/m2, D2, D3
  /Q21D
• Case 2 B 1.5mg/m2, D1,
  D4
• Ara-C 1000mg/m2, D2, D3
  
• Rituximab 375mg/m2, D0
  /Q28D

Weigert et al, Germany, Leukemia (2007) 21,
524528
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Bortezomib is Synergistic with Rituximab/
Cyclophosphamide in vitro and in vivo
Wang et al, MDACC, Leukemia (2008) 22, 179185
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Bortezomib Combination in MCL
Study Bortezomib Regimen Evaluable Patients (n) CR PR ORR Outcome
Blum(ASH 2006) Bortezomib Rituximab 6 33 - 33
Drach (ASH 2006) Bortezomib Rituximab Dex (BoRiD)) 16 19 56 75 PFS 9m
Weigert(ASH 2006) Bortezomib Cytarabine Dex /- Rituximab 4 25 75 100
All PET- negative evaluable following 4 cycles
Blum et al. ASH 2006, abstract 2768
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2-Line Single Agent Temsirolimus (Torisel)

• Phase 2

Dose N CR PR SD PD Outcome
Witzig (Mayo Clinic)1 250mgweekly 34 3 35 40 TTP6.5m DOR6.9m
Ansell (Mayo Clinic)2 25mg weekly 27 4 37 TTP6m DOR6m
1.JCO. 2005 Aug 1023(23)5347-56 2. Cancer. 2008
Aug 1113(3)508-14
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2-Line Single Agent Temsirolimus (Torisel)

• Phase 3

N CR PR SD PD Outcome
T 175mg QW3, then 75mg QW 54 2 20 PFS4.8m DOR7.1m OS13.6m
T 175mg QW3, then 25mg QW 54 0 6 PFS3.4m DOR3.6m OS10.0m
Investigators choice 54 2 0 PFS1.9m NA OS9.7m
ASCO 44th annual meeting, 2008 Jun
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compromised patient
elderly patient (gt65)
young patient (lt65)
First line
conventional R-chemo (e.g. R-CHOP) Rituximab
maintenance ? radioimmunotherapy ?
Dose-intensifiedR-chemo (either sequential
e.g. R-CHOP gtASCT or R-HyperCVAD/MTXAC)
watch wait ? Rituximab monotherapy Chlorambucil
Bendamustin

First relapse
R-chemo (e.g. R-FC, R-Bendamustin) molecular
approaches ASCT radioimmunotherapy ? Rituximab
maintenance ?
High tumor load R-chemo (e.g. R-FC)
allo-transplant ? radioimmunotherapy ? Rituximab
maintenance ?
R-chemo (e.g. R-Bendamustin) molecular approaches
Higher relapse
molecular approaches Bortezomib, CCI-779,
Thalidomide/Lenalidomide, Flavopiridol
(preferable in combination) repeat previous
therapy (long remissions)
Dreyling ASCO 2006
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NCCN 2008 V3