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Lymphomas in 2010 Prof Paul Ruff Division of Medical Oncology
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Most Common Lymphomas: ~90% B-cell and ~10% T-cell
Armitage JO, et al. J Clin Oncol. 1998;16:2780-2795.
Diffuse large B cell: 31%
Follicular: 22%
Marginal zone, extranodal: 8%
Peripheral T cell: 7%
Small lymphocytic/CLL: 7%
Mantle cell: 6%
Mediastinal large B cell: 2%
Anaplastic large cell: 2%
Burkitt: 2%
Marginal zone, nodal: 2%
T lymphoblastic: 2%
Other: 9%
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B- Cell Lymphoproliferative Disorders (~90%)
“Low Grade”:
CLL/SLL
Follicular
Marginal
Mantle Cell
Hairy Cell Leukaemia
Multiple Myeloma
“High Grade”:
Diffuse Large B-Cell
B-Lymphoblastic/ALL
Burkitt’s Lymphoma
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Lymphomas: Ann Arbor Staging (1971)
Stage I: One lymph node group
Stage II: >1 lymph node group on same side of diaphragm
Stage III: Lymph nodes on both sides of diaphragm
Stage IV: Extralymphoid spread eg. marrow, lung, liver, brain
A/B: presence or absence of symptoms: Night sweats, repeated fever >38ºC, >10% weight loss
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Staging of Lymphomas
Radiological staging essential for prognostic and therapeutic reasons
Chest X-ray
Spiral Chest CT if CXR suggests mediastinal or hilar adenopathy
Spiral CT head and neck also be needed in some lymphoma patients
MRI brain needed in AIDS lymphomas
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Staging of Lymphomas
Spiral CT abdomen and pelvis essential today
Ultrasound sub-optimal for retroperitoneal structures and in obese patients
Lymphangiogram obsolete but was used in Hodgkin’s lymphoma pre-1990s when CT scanning was limited and inadequate
Staging laparotomy no longer important with advent of better chemotherapy and reduced role of radiation in Hodgkin’s lymphoma
?role of 18FDG PET/CT scan in staging newly diagnosed patients
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Staging of Lymphomas: Follow-up
Spiral CT chest/abdomen to assess extent and size of lymph glands during and after completion of chemotherapy +/- radiation
Exact tumour size essential in clinical trials
Residual glands may not be malignant therefore a 18FDG PET/CT scan very useful to define active tumour tissue versus residual fibrosis
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Follicular NHL Common indolent NHL
24,000 new cases diagnosed annually in USA
Rising in incidence
Variable clinical course Incurable with standard therapy;
multiple remissions and relapses
Histological transformation
Median survival improving
t(14;18)(q32;q21) Oncogene: bcl-2
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Follicular Lymphoma Classification
Grade Characteristic
Grade 1 0-5 centroblasts/hpf
Grade 2 6-15 centroblasts/hpf
Grade 3 > 15 centroblasts/hpf
3a Centrocytes present
3b Solid sheets of centroblasts
Blood. 1997;89:3909-3918.
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FLIPI Prognostic Score Characteristic RR (Death)
Older than 60 yrs of age 2.38
Stage III-IV 2.00
Hemoglobin < 12.0 g/dL 1.55
Elevated LDH 1.50
Nodal sites > 4 1.39
Solal-Céligny, et al. Blood. 2004;104:1258-1265.
FLIPI and OS
Risk Group Risk Factors, n 5-Yr OS, % 10-Yr OS, %
Low 0-1 91 71
Intermediate 2 78 51
High ≥ 3 53 36
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Dave SS, et al. N Engl J Med. 2004;351:2159-2169. Copyright © 2004 Massachusetts Medical Society. All rights reserved.
Gene Expression: Follicular NHL
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Predictive Power of Gene Expression Signature in Follicular Lymphoma
Dave SS, et al. N Engl J Med. 2004;351:2159-2169.
Expression Signature (Prognosis) RR of Death P Value
Immune response 1 (favorable) 0.15 < .0001
Immune response 2 (unfavorable) 9.35 < .0001
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Follicular Lymphoma:
Indications for Therapy
Cytopenias secondary to bone marrow infiltration
Threatened end-organ function
Symptoms attributable to disease
Bulk at presentation
Steady progression during > 6 mos of observation
Presentation with concurrent histologic transformation
Massive splenomegaly
Patient preference
Candidate for clinical trial
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Treatment Options in 2010:
Observation (watch and wait)
Radiation
Single-agent therapy
Combination chemotherapy
Interferon-α
Monoclonal antibodies:
especially rituximab
Hematopoietic transplantation
Antisense molecules
Vaccines
Targeted agents
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Monoclonal Antibodies in B-Cell Lymphoma
Rituximab: Naked chimeric monoclonal antibody against CD20 antigen
CD20 on cell surface of most B-cell malignancies except primitive B-cell ALL and post-mature myeloma cells
Licensed as Mabthera® (RSA/Europe) or Rituxan® (USA) in CD20+ B-cell lymphomas
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Key features of Rituximab
Chimeric anti-CD20 MoAb
Activates complement mediated cytotoxicity & antibody dependent cellular cytotoxicity (ADCC)
Direct anti-tumor effects
Synergistic activity with chemotherapy
Sensitizes chemoresistant cell lines
CD20+ cell
Human
Mouse
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CVP versus CVP + Rituximab for Stage III-IV Follicular Lymphoma
Observation 1 4 7 10 13 16 19 22
Wks CVP arm
R-CVP arm
RANDOMI Z
AT ION
Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.
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CVP versus CVP + Rituximab for Advanced Follicular Lymphoma
Outcome CVP CVP + Rituximab
CR, % 10 41
Duration of response, mos 14 38
4-yr survival, % 77 83
Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.
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Prolonged Survival With Chemo + Rituximab for FL
CVP vs R-CVP[1]
CHOP vs R-CHOP[2]
MCP vs R-MCP[3]
1. Marcus R, et al. J Clin Oncol. 2008;26:4579-4586. 2. Hiddemann W, et al. Blood. 2005;106:3725-3732. 3. Herold M, et al. J Clin Oncol. 2007;25:1986-1992.
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0
60
0 2 4 6 8
4-Year
N Death Estimate
CHOP + Mab 179 18 91%
ProMace 425 189 79%
CHOP 356 226 69%
Years After Registration
OS by Treatment
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23:8447-8452.
1980s
1990s
Overa
ll S
urv
ival
(%)
1990s-2000s
40
20
100
80
10
Improving Survival of Follicular NHL: Impact of Antibody-Based Therapy
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Treatment of FL: Summary
Rituximab prolongs PFS and OS in patients requiring treatment Despite progress, relapsing patterns continue to be observed
Maintenance rituximab improves PFS Longer-term follow-up will be of interest to determine whether there is a
survival advantage
Many unanswered questions Role of watchful waiting
Role of maintenance therapy
Role of FLIPI or risk stratification in choosing therapy
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Potential Antibody Targets for B-Cell Lymphomas
Cheson BD, et al. N Engl J Med. 2008;359;613-626. Copyright © [year of publication] Massachusetts Medical Society. All rights reserved.
CD5
CD19
CD20
CD22
CD23
CD37 CD40 CD52
CD74
CD80
Death receptors
HLA-DR
Surface immunoglobulin
B cell
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New Antibodies for Follicular Lymphoma
Antibody Type
Epratuzumab (humanized) Anti-CD22
Ofatumumab (human) Anti-CD20
Galiximab (chimeric) Anti-CD80
Dacetuzumab (humanized) Anti-CD40
Inotuzumab-ozogamicin (humanized) Anti-CD22
Veltuzumab (humanized) Anti-CD20
GA-101 (humanized) Anti-CD20
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Rituximab-Refractory Indolent NHL
Patients treated with rituximab who then
Fail to respond to rituximab therapy
Progress within 6 months of rituximab therapy
In the US, often includes patients refractory to an R-chemo regimen or who progress during maintenance therapy
Outcome of this group of patients has not been well evaluated, and optimal therapy is unknown
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Rituximab-Refractory Indolent NHL: “Standard” Therapy Options
Radioimmunotherapy On label Response rate high, time-to-progression variable
ASCT Randomized trial suggests benefit over standard therapy Applicable to minority of patients May be difficult with extensive previous therapy or marrow involvement
AlloSCT Potentially curative option High transplantation-related mortality and morbidity Donor a requirement
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clinicaloptions.com/oncology
Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment
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clinicaloptions.com/oncology
Advances in Lymphoproliferative Disease: From Molecular Pathogenesis to Multitargeted Treatment
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Diffuse Large B-Cell Lymphoma
Most common NHL: 31%
Peak incidence in 6th decade
Curable in 50% or more of cases
Median survival: wks to mos if not treated
Clinical outcomes and molecular features highly heterogeneous
Large cells with loss of follicular architecture of node
30% to 40% present with rapidly enlarging, symptomatic mass with B symptoms
May present as extranodal disease (stomach, CNS, testis, skin)
Michallet AS, et al. Blood Rev. 2009;23:11-23.
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DLBCL: Prognostic Factors (IPI)
Risk Group Risk
Factors, n
CR,
%
5-Yr
OS, %
Patients (all ages)
Low 0-1 87 73
Low intermediate 2 67 51
High intermediate 3 55 43
High 4-5 44 26
Patients 60 yrs of age or younger
Low 0 92 83
Low intermediate 1 78 69
High intermediate 2 57 46
High 3 46 32
Adverse risk factors correlated with response to chemotherapy and survival
Older than 60 yrs of age
LDH > normal
PS ≥ 2
Ann Arbor stage III/IV
Extranodal involvement > 1 site*
International NHL Prognosis Factors Project. N Engl J Med. 1993;329:987-994.
*Prognostic for patients older than 60 yrs of age only.
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Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL
Diffuse Large B- Cell Lymphoma
Dave SS, et al. N Engl J Med 2006;354:2431-2442.
Copyright © (2006) Massachusetts Medical Society. All rights reserved.
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Yrs
OS
Diffuse Large B- Cell Lymphoma
DLBCL Subgroup 5-Yr OS, %
PMBL 64
GCB DLBCL 59
ABC DLBCL 30
Gene Expression Defines Molecularly and Clinically Distinct Subgroups in DLBCL
1.0
0.8
0.6
0.4
0.2
0
0 2 4 6 8 10
Rosenwald A, et al. J Exp Med. 2003;198:851-862.
Originally published in The Journal of Experimental Medicine.
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Lenz G, et al. N Engl J Med. 2008;359:2313-2323.
DLBCL Subtype Retains Prognostic Value With R-CHOP Therapy
CHOP-Rituximab OS
1.0
0.8
0.6
0.4
0.2
0
Pro
babili
ty
0 1 2 3 4 5 6
Yrs
P = 4 x 10-3
CHOP-Rituximab PFS
CHOP OS
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5 6
Yrs
P = 1 x 10-4
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5
Yrs
6
P = 8 x 10-6
GCB DLBCL ABC DLBCL
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DLBCL Treatment
Localized stage I/II disease:
Abbreviated course of chemotherapy with immunotherapy followed by radiation or a full course of chemotherapy
Advanced-stage disease:
Chemoimmunotherapy plus combination of rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy for 6-8 cycles
NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010. Available at:
http://nccn.org/professionals/physician_gls/PDF/nhl.pdf.
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CHOP q3w for 8 cycles
(n = 201)
CHOP q3w for 3 cycles
(n = 200)
Untreated
patients with
localized
intermediate/high
grade NHL
(N = 401)
Stratified by age (< vs ≥ 65 yrs), histology (DLBCL vs others), disease site (GI vs other), stage (I vs
II), resection of all visible tumors (y vs n)
SWOG 8736: CHOP ± Radiotherapy in NHL in Localized DLBCL (Stage I and II)
Endpoints: PFS, OS, toxicity
IFRT
Miller TP, et al. N Engl J Med. 1998;339:21-26.
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Yrs After Registration
Miller T, et al. ASH 2001. Abstract 3024.
OS
(%
)
SWOG 8736: OS for DLBCL Patients Treated With CHOP ± Radiotherapy
100
80
60
40
20
0 0 3 6 9 12
5-Yr Estimate, %
82 71
Death, n 53 61
N 152 149
CHOP + RT CHOP
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R-CHOP q3w for 8 cycles
(n = 202)
CHOP q3w for 8 cycles
(n = 197)
Untreated elderly
patients with
stage II-IV DLBCL
(N = 399)
Stratified by center and risk factors (0-1 vs 2-3)
Assessment
CHOP ± Rituximab in Advanced-Stage DLBCL: GELA LNH-98.5 Phase III Study
Primary endpoint: EFS
Secondary endpoints: OS, RR Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126.
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CHOP ± Rituximab in DLBCL: 3-Yr Survival Results (GELA LNH-98.5 Study)
Coiffier B, et al. N Engl J Med. 2002;346:235-242. Copyright © (2002) Massachusetts Medical Society.
All rights reserved.
EFS
Pro
babili
ty o
f E
FS
CHOP plus rituximab
CHOP
P < .001
1.0
0.8
0.6
0.4
0.2
0
0 0.5 1.0 1.5 2.0 2.5 3.0
Yrs After Randomization
Pts at Risk, n CHOP plus 202 177 137 108 63 19 rituximab CHOP 197 144 101 72 42 17
OS
Overa
ll P
robabili
ty
of
Surv
ival
CHOP plus rituximab
CHOP
P = .007
1.0
0.8
0.6
0.4
0.2
0
0 0.5 1.0 1.5 2.0 2.5 3.0
Yrs After Randomization
Pts at Risk, n CHOP plus 202 187 167 118 64 21 rituximab CHOP 197 171 136 96 58 16
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CHOP ± Rituximab in DLBCL: 7-Yr Survival Results (GELA LNH-98.5 Study)
Coiffier B, et al. ASCO 2007. Abstract 8009.
OS (N = 399)
Surv
ival P
robabili
ty
Yrs
0
0.2
0.4
0.6
0.8
1
0 1 3 5 7 8 2 4 6
CHOP
R-CHOP
P = .0004
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Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.
MInT: Phase III Study of CHOP-like Chemo ± Rituximab in Adv. DLBCL (Younger Pts)
Patients with
untreated CD20+
stage II-IV DLBCL
(or bulky stage I),
IPI 0-1, 18-60 yrs
of age
(N = 823)
CHOP-Like Regimen* + 30-40 Gy radiotherapy
(n = 410)
CHOP-Like Regimen* + Rituximab 375 mg/m
2
+ 30-40 Gy radiotherapy (n = 413)
Cycle 6
*CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO.
Stratified by age-adjusted IPI score (0 vs 1), bulky disease, treatment center, and regimen
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Pfreundschuh M, et al. Lancet Oncology. 2006; 7: 379-391.
Impact of Rituximab: The MInT Trial Group
For rituximab plus chemotherapy vs chemotherapy alone, the impact of rituximab that was demonstrated in the GELA trial also held true in the MInT trial with benefits in:
EFS
PFS
OS
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Diffuse Large B-Cell Lymphoma: Nodal Response
Before Treatment After Treatment
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Guideline Recommendations for Treatment of Relapsed DLBCL
Second-line therapy in candidates for high-dose therapy + ASCT
DHAP ± rituximab
ESHAP ± rituximab
GDP ± rituximab
GemOx ± rituximab
ICE ± rituximab
MINE ± rituximab
Second-line therapy for patients who are not candidates for high-dose therapy
Clinical trial
Rituximab
CEPP ± rituximab
Lenalidomide
EPOCH ± rituximab
NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010.
Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf.
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PARMA Study: ABMT vs Conventional Chemotherapy in Relapsed NHL
Philip T, et al. N Engl J Med. 1995;333:1540-1545.
D H A P
D H A P
Bone marrow harvest
Sensitive (n = 109)
Resistant (n = 90)
BEAC ± RT
(n = 55)
DHAP ± RT
(n = 54)
ABMT
Salvage Tx ABMT
Patients with chemosensitive
NHL (int or high grade) in 1st
or 2nd relapse following
doxorubicin regimen and CR
to initial induction regimen
(N = 215)
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PARMA Study: Bone Marrow Transplantation versus Salvage Chemotherapy
P = .001
0
20
40
60
80
100
EF
S (
%)
0 15 30 45 60 90 75
Mos After Randomization
P = .038
0
20
40
60
80
100
OS
(%
)
0 15 30 45 60 90 75
Mos After Randomization
Transplantation
Conventional treatment
Philip T, et al. N Engl J Med. 1995;333:1540-1545. Copyright © (1995) Massachusetts Medical Society. All rights reserved.
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Investigational Therapies for DLBCL
Bevacizumab: recombinant, humanized, monoclonal anti-VEGF antibody
Epratuzumab: humanized, monoclonal anti-CD22 antibody
Everolimus: mTOR inhibitor
Lenalidomide: immunomodulator, antiangiogenic
Radioimmunotherapy
Tamatinib: inhibitor of Syk in B-cell signaling pathway
Bortezomib: proteasome inhibitor
Enzastaurin: PKCβ-selective inhibitor
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DLBCL Treatment: Summary
Eminently curable with chemoimmunotherapy approaches, both for patients with limited-stage disease and for those with advanced-stage disease/localized stage I/II disease
Modern era treatment
Combination of rituximab and chemotherapy, typically using the R-CHOP for an abbreviated course of therapy plus radiation for patients with limited-stage disease or possibly R-CHOP for 6-8 cycles for those patients without radiation
For patients with advanced-stage disease, R-CHOP chemotherapy for 6-8 cycles total
NCCN practice guidelines in oncology: non-Hodgkin’s lymphomas V.1.2010.
Available at: http://nccn.org/professionals/physician_gls/PDF/nhl.pdf.
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PET to Determine Treatment Approach in DLBCL Following 3 R-CHOP Cycles Retrospective analysis of PET-guided treatment in
patients with limited-stage DLBCL
Median follow-up: 20 months
Patients from BC Cancer Lymphoid Database aged ≥ 16 years with newly
diagnosed, limited-stage DLBCL and biopsy proven disease
(N = 50)
*1 patient received subsequent IFRT because of chemotoxicity and 1 died prior to receiving further therapy.
R-CHOP x 3
PET Neg
(n = 37)
PET Pos
(n = 13)
R-CHOP x 1*
IFRT
Sehn LH, et al. ASH 2007. Abstract 787.
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PET to Determine Treatment Approach in DLBCL Following 3 R-CHOP Cycles
Progression-Free Survival
0 1.0 2.0 .5 2.5 1.5
Years
0
0.2
0.4
0.6
0.8
1.0
Pe
rce
nt
Su
rviv
al
PET negative
PET positive
Sehn LH, et al. ASH 2007. Abstract 787.
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Mantle Cell Lymphoma: Clinical Features
Accounts for ~ 6% of B-cell NHL cases
Moderately aggressive course
74% male
Median age: 63 yrs
> 90% stage III/IV, including marrow involvement
Extranodal sites common
GI (upper and lower, can present as lymphomatous polyposis coli)
Leukemic phase, PB flow commonly positive Armitage JO. Oncology (Williston Park). 1998;12(10 suppl 8):49-55. Fisher RI, et al. Hematology Am Soc Hematol Educ Program. 2004:221-226. O’Connor OA, et al. Leuk Lymphoma. 2008;49(Suppl 1):59-66.
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MCL: Pathology
Typical immunophenotype: CD20+, CD5+, CD23-, CCND1+, FMC7+, BCL2+
Morphological variants Diffuse histology: 75% Nodular: 10% to 15% Mantle zone: 5% to 7% Blastoid: 5%
t(11;14)(q13;q32) → CCDN1 driven by IgH locus Occasion amplification; CCDN2 or CCDN3 translocation
CD20 CD5
Cyclin D1 BCL2
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P = .0002
MCL: Critical Role of Cyclin D1
Most cases of lymphoma that are CD20+, CD5+, and CD23- and lack expression of cyclin D1 are not MCL but rather variant CLL
This research was originally published in Blood. Yatabe Y, et al. Blood. 2000;95:2253-2261 © the American Society of Hematology.
Cyclin D1 Cyclin D1
H&E H&E
All patients
Cyclin D1+
Cyclin D1-
O
S (
%)
100
80
60
40
20
0
0 5 10 15
Yrs
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Improvement of OS in MCL During the Last Decade
Median OS of patients with advanced MCL significantly increased from 2.7 to 4.8 yrs (HR: 0.44; P < .0001)
5-yr survival increased from 22% to 47%
Patients with advanced MCL benefit from progress in medical treatment
Rituximab?
New agents?
Aggressive therapy with transplant?
Herrmann A, et al. J Clin Oncol. 2009;27:511-518.
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MCL: Conventional Therapy
CHOP ± rituximab
Median FFS: 15-18 mos
Few long-term survivors
Howard and colleagues[1] showed improved CR with rituximab but no improvement in PFS
Fludarabine
Lower response rate than CHOP, similar FFS
Highly active when combined with cyclophosphamide but increased toxicity
1. Howard OM, et al. J Clin Oncol. 2002;20:1288-1294.
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SWOG 0213: HyperCVAD + Rituximab in Newly Diagnosed MCL Multicenter, nonrandomized,
prospective, phase II trial
Recruited October 2002-September 2006 (N = 49)
8 cycles of hyperCVAD (fractionated cyclophosphamide, vincristine, doxorubicin, + dexamethasone) alternating every 21 days with rituximab + high-dose methotrexate/ cytarabine
Prophylactic anti-infectious agents, G-CSF given
Epner EM, et al. ASH 2007. Abstract 387.
Disease type
– Nodular: 3 (6%)
– Diffuse: 13 (27%)
– Mantle zone: 28 (57%)
– Blastic: 4 (8%)
– Too early: 1 (2%)
Stage III/IV disease: 49 (100%)
Zubrod performance status
– 0: 29 (59%)
– 1/2: 20 (41%)
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SWOG 0213: HyperCVAD + Rituximab in Newly Diagnosed MCL
Survival Outcome At Risk, n Progression/Death, n 1-Year Estimate, %
Progression-free 49 13 89
Overall 49 9 91
Epner EM, et al. ASH 2007. Abstract 387.
Survival Outcomes
Years From Registration
0
20
40
60
80
100
0 1 3 5 2 4
Overall survival
Progression-free survival
Pe
rce
nta
ge o
f P
ati
en
ts
6
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PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL
Open-label, prospective, international, multicenter, phase II trial
Bortezomib 1.3 mg/m2 on Days 1, 4, 8, and 11 of 21-day cycle Upon CR/CRu
Treatment continued for 4 additional cycles
If no CR/CRu
Treatment continued up to 17 cycles or until disease
progression or toxicity
Goy A, et al. ASH 2007. Abstract 125.
Characteristic Patients
(N = 155)
Median age, years (range) 65
(42-89)
Median time from diagnosis, yrs
(range)
2.3
(0.2-11.2)
Median prior therapies 1
Stage IV MCL, % 77
IPI score ≥ 3, % 44
KPS < 90%, % 29
LDH > upper limit of normal, % 36
Bone marrow involvement, % 55
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PINNACLE: Bortezomib in Patients With Relapsed/Refractory MCL
0
0.2
0.4
0.6
0.8
Even
t-F
ree P
rob
ab
ilit
y
Time (Months)
1.0
CR/CRu: not yet reached
PR: 9.1 months
All patients: 6.7 months
3 6 9 12 15 18 21 24 27
Goy A, et al. ASH 2007. Abstract 125.
Time to Progression Median Time to Progression
0
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Conclusions Lymphomas are amongst the most curable adult
malignancies
Predominantly B-cell phenotype (~90%)
CHOP-type chemotherapy standard since 1970s
Radiation useful in localized disease
Advent of rituximab, a chimeric anti-CD20 monoclonal antibody has revolutionized the treatment of most B-cell lymphomas
T-cell lymphomas have a more aggressive course and are more difficult to treat.
Evolving role of 18FDG PET/CT scanning in monitoring lymphoma treatment