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Mantle Cell Lymphoma (MCL): Approach to Upfront Treatment
Lauren C Pinter-Brown, MDDirector, UCLA Lymphoma Program
Clinical Professor of MedicineGeffen School of Medicine at UCLA
Copyright © 2011 Research To Practice. All rights reserved.
Interest in Topics Related to the Treatment of Patients with CTCL or PTCL (Percent Responding 9 or 10)
12%
15%
17%
18%
20%
25%
26%
27%
0% 5% 10% 15% 20% 25% 30%
Denileukin diftitox in CTCL
Classification of TCL
Romidepsin/HDAC inhibitors
Stem cell transplant
Skin treatment in CTCL
Pralatrexate in PTCL
Brentuximab vedotin in ALCL
New agents/regimens
Copyright © 2011 Research To Practice. All rights reserved.
Interest in Topics Related to the Treatment of Patients with MCL (Percent Responding 9 or 10)
30%
33%
40%
41%
50%
0% 10% 20% 30% 40% 50% 60%
Maintenancetherapy
Treatment ofrelapsed MCL
Initial therapy forpatients >70 yo
Initial therapy forpatients <70 yo
New agents/regimens
Prognostic Factors: Pathologic
• Blastoid and pleomorphic variants connote poor prognosis
• Small cell variant may have more indolent course; impact of mantle zone or nodular pattern less clear
• Overt peripheral blood involvement with adenopathy appears worse (vs. peripheral blood, marrow and possible splenic involvement without adenopathy)
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, 4th edition.
Prognostic Factors: Ki-67 Index
Determann O et al. Blood 2008;111:2385-2387.
• Median overall survival, CHOP-treated subgroup:– <10% Ki-67 index = 112 months – 10% - 30% Ki-67 index = 59 months – ≥30% Ki-67 index = 30 months – p-value = 0.0002
• Median overall survival, R-CHOP treated subgroup: – <10% Ki-67 index = not reached – 10%-30% Ki-67 index = not reached – ≥30% Ki-67 index = 52 months – p-value = 0.0126
Prognostic Factors:Simplified MIPI
Hoster E et al. Blood 2008;111:558-65.
0-3 points applied for each prognostic factor
Sum reflects MIPI score
Low risk: 0-3 points
Intermediate risk: 4-5 points
High risk: 6-11 points
Points Age, yrs ECOG PS
LDH/ULN WBC, cells/mm3
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 10,000-14,999
3 ≥70 — ≥1.5000 ≥15,000
Frontline Treatment Considerations
• Optimal frontline standard of care not yet defined• MCL not yet shown to be curable with currently available
frontline treatments • Prolongation of survival by frontline treatment has been
definitely shown• May consider treatment options separately for:
– Patients for whom a dose intensive approach is an option (65 and under without comorbidities)
– Patients for whom a dose intensive approach is not an option (older than 65 or with significant comorbidities)
– Median age is around 60
Patients for Whom a Dose-Intensive Approach is Not an Option
• In truth…– Will likely need additional treatment earlier than if the patient had an
aggressive initial therapy (NCCN database)– ? Similar OS than if the patient had aggressive therapy (Cornell
retrospective data, N=97…in selected asymptomatic patients “watch and wait” is acceptable management1)
– Many choices that include:
• R-bendamustine vs R-CHOP (Rummel data: BR has stat sig increased PFS, 33 vs 23 mo, and better tox profile than R-CHOP in MCL, N=932)
• Modified hyperCVAD (VcR-CVAD) with R maintenance (ECOG-E1405 shows high CR rate3)
• Rituximab alone, R-CVP, R-fludarabine/CDA1. Martin P, JCO 2009; 27:1209-1213.2. Rummel MJ, ASH 2009, abs 405.3. Kahl B, ASH 2009, abs 1661.
Patients for Whom a Dose-Intensive Approach is an Option
• NCCN database, prospective cohort study of pts with MCL <65 yo that R-hyperCVAD or R-CHOP → auto have similar PFS that are better than R-CHOP alone1
• Nordic regimen: R-Maxi-CHOP/R-HDAraC → auto with consolidation with R in presumptive relapse2
• GELA: R-CHOP/R-DHAP → auto3
1. LaCasce A, ASH 2009, abstract 403.2. Geisler CH, Blood 2008; 112:2687-2693.3. Delarue R, ASH 2010, abstract 581.
Consolidation or Maintenance Strategies
• ECOG-E14991: Single dose of yttrium-90-ibritumomab tiuxetan given 4-8 weeks after R-CHOP x 4 in responding patients
• 16/56 patients experienced improvement in response after RIT
• Median failure-free survival: 27 months• Maintenance rituximab: Await presentation of
European MCL Consortium randomized trial
1. Smith M et al. ASH 2007, abstract 389.
PTCL/CTCL: Approaches to Relapsed/Refractory Disease
Lauren C Pinter-Brown, MDDirector, UCLA Lymphoma Program
Clinical Professor of MedicineGeffen School of Medicine at UCLA
What’s the difference between PTCL and CTCL?
• Both groups are mature T-cell neoplasms
• Most nodal and extranodal (excluding skin) PTCLs are aggressive; most CTCLs are indolent
• Be aware that the staging system for mycosis fungoides/Sézary syndrome is a totally different staging system from the Ann Arbor system used for other lymphomas
Classification of PTCL
Mature T-NK neoplasm
Extranodal Nodal Leukemic
PTCL, NOS
ALCL (ALK +)
Angioimmunoblastic (AILT)
Adult T-cell leukemia/lymphoma (ATLL)
Aggressive NK cell leukemia
T-prolymphocytic leukemia (T-PLL)
T-large granular lymphocytic leukemia
(T-LGL)
Extranodal NK/T cell, nasal type
Enteropathy associated (EATL)
Hepatosplenic (ϒΔ)
Classification of CTCL
Cutaneous
Mycosis fungoides/Sézary syndrome (MF/SS)CD30+ lymphoproliferative disorders
Subcutaneous panniculitic T-cell lymphomaCD4+ small/medium pleomorphic T-cell lymphoma
Cutaneous PTCL, NOSCutaneous aggressive CD8+ T-cell lymphoma
Cutaneous NK/T cell lymphoma, nasal type
Outlook for patients with PTCL/CTCL
• Nodal and extranodal PTCL (excluding CTCL) have a median survival of 1-3 years with present therapy
• 5-year overall survival is approximately 25%• The exception is anaplastic large cell lymphoma
(ALCL) ALK+ where 5-year overall survival is 65-95%
• No CTCL is curable with conventional medical therapy
Denileukin diftitox Denileukin diftitox is a recombinant DNA derived cytotoxic protein
composed of IL-2 protein sequence fused to active portion of diphtheria toxin
• Targets tumor cells expressing the high and medium affinity IL-2 receptor (IL-2R); the IL-2 portion binds to the IL-2 receptor, allowing the diphtheria toxin to enter the cell and induce cell death by inhibition of protein synthesis
• Approved for use in patients with relapsed/refractory CTCL with an overall RR=30-44% (20-34% PR) with median duration of response (DOR)=6.9 mo1,2
• In relapsed/refractory T-cell malignancies (excluding CTCL), N=27, RR=48% (46% PR) with median PFS=6 mo3
• Common toxicity includes:
– Immediate: allergic, constitutional– Delayed: vascular capillary leak, primarily in first cycle– Lab: reversible liver function test abnormalities
1. Prince HM, JCO 2010; 28(11): 1870-7.2. Olsen E, JCO 2001; 19(2): 376-88.3. Dang NH, Br J Haematol 2007; 136(3): 439-47.
HDAC inhibitors• Vorinostat (po) and romidepsin (IV) are approved for treatment of
relapsed/refractory CTCL• Vorinostat in relapsed/refractory CTCL ORR = 30%; estimated median
DOR ≥ 185 days1; there is no data to support use of vorinostat in PTCL• Romidepsin in relapsed/refractory CTCL ORR = 34% (31% PR) with
median DOR = 15 mo2
• Romidepsin in relapsed/refractory PTCL ORR 38% (20% PR) with median DOR = 8.9 mo3
• The common toxicities can be classified into 4 symptom complexes: – Gastrointestinal symptoms (diarrhea, nausea, anorexia, weight decrease,
vomiting, constipation)– Constitutional symptoms (fatigue, chills)– Hematologic abnormalities (thrombocytopenia, anemia, neutropenia)– Taste disorders (dysgeusia, dry mouth)
• Abnormal laboratory values include high glucose, elevated creatinine, abnormal EKGs
1. Olsen EA, JCO 2007; 25(23): 3109-15.2. Whittaker SJ, JCO 2010; 28(29): 4485-91.3. Piekarz R, Blood 2011 epub.
Pralatrexate• Novel folate antagonist approved for treatment
of relapsed or refractory PTCL• In patients with relapsed/refractory PTCL
at dose of 30 mg/m2 six out of seven weeks, ORR = 29% (18% PR) with median DOR = 10.1 mo1
• In patients with relapsed/refractory CTCL, the optimal dose was 15 mg/m2 three out of four weeks with an ORR = 43%2
• Common toxicities include: mucositis, thrombocytopenia, neutropenia, anemia
1. O’Connor OA JCO 2011; 29(9):1182-9.2. Horwitz SM, ASH 2010, abstract 2800.
How would I sequence these drugs?
• In relapsed/refractory PTCL (if not using typical salvage chemotherapy):
• (1) Pralatrexate • (2) Romidepsin • (3) Denileukin diftitox
• In relapsed/refractory CTCL (if inappropriate for topical or other FDA-approved therapies such as bexarotene):
• (1) Romidepsin (or vorinostat)• (2) Denileukin diftitox• (3) Pralatrexate
Copyright © 2011 Research To Practice. All rights reserved.
What is your usual preferred initial systemic treatment for MCL in patients older than age 75?
9%
43%
25%
9%
3%
11%
0% 10% 20% 30% 40% 50%
Other
BR
R-CHOP
Modified R-hyper-CVAD
R-hyper-CVAD
R monotherapy
Copyright © 2011 Research To Practice. All rights reserved.
Do you generally use rituximab maintenance in MCL?
57%
25%
18%
0% 10% 20% 30% 40% 50% 60%
No
Yes, in somepatients
Yes, in mostpatients
Copyright © 2011 Research To Practice. All rights reserved.
What is your usual preferred initial systemic treatment for MCL in patients older than age 75?
9%
43%
25%
9%
3%
11%
0% 10% 20% 30% 40% 50%
Other
BR
R-CHOP
Modified R-hyper-CVAD
R-hyper-CVAD
R monotherapy
Copyright © 2011 Research To Practice. All rights reserved.
Do you generally use rituximab maintenance in MCL?
57%
25%
18%
0% 10% 20% 30% 40% 50% 60%
No
Yes, in somepatients
Yes, in mostpatients
Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know
A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical
Management of Select Hematologic Cancers
Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois
Faculty
Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD
ModeratorNeil Love, MD
Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek
Copyright © 2011 Research To Practice. All rights reserved.
28%
13%
3%
49%
6%
0% 10% 20% 30% 40% 50% 60%
I have no informationor experience
Relatively welltolerated
Somewhat welltolerated
Not well tolerated
Very poorly tolerated
What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?
Copyright © 2011 Research To Practice. All rights reserved.
18%
10%
1%
69%
2%
0% 10% 20% 30% 40% 50% 60% 70% 80%
I have no informationor experience
Relatively welltolerated
Somewhat welltolerated
Not well tolerated
Very poorly tolerated
What is your perception and experience concerning the side effects and tolerability of romidepsin in patients with TCL?
Copyright © 2011 Research To Practice. All rights reserved.
28%
13%
3%
49%
6%
0% 10% 20% 30% 40% 50% 60%
I have no informationor experience
Relatively welltolerated
Somewhat welltolerated
Not well tolerated
Very poorly tolerated
What is your perception and experience concerning the side effects and tolerability of pralatrexate in patients with TCL?
Copyright © 2011 Research To Practice. All rights reserved.
What Clinicians Want to Know
A Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical
Management of Select Hematologic Cancers
Sunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois
Faculty
Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD
ModeratorNeil Love, MD
Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek