1. Mantle Cell Lymphoma: Is There a Potential for Cure?
Andrew D. Zelenetz, MD, PhD
Associate Professor Department of Medicine
Cornell University Medical College
Chief, Lymphoma Service
Memorial Sloan-Kettering Cancer Center
New York, New York
Welcome. I am Andrew D. Zelenetz, MD, PhD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York, New York. The subject of this presentation is “Mantle Cell Lymphoma: Is There a Potential for Cure?”
This program is supported by an educational grant from
Image: 3D4Medical.com/Copyright©2010 Getty Images, Inc. All Rights Reserved.

2. Overview
Review the biology of MCL and the central role of proliferation in prognosis
Discuss the evolution in management of MCL
Review the development of quantitative image analysis for proliferation index
Discuss the role of aggressive consolidation in the management of MCL
MCL, mantle cell lymphoma.
This presentation will review the biology of mantle cell lymphoma (MCL) and the central role of proliferation in prognosis. We will discuss the evolution of the management of MCL, review the development of quantitative image analysis for proliferation index, and discuss the role of aggressive consolidation in the treatment of MCL.

3. MCL: Diagnosis and Pathology
MCL, mantle cell lymphoma.
Let us now discuss the diagnosis and pathology of MCL.

4. Pretreatment Workup History and physical examination
Evidence of GI blood loss?
Early satiety
Pretreatment evaluation
CBC, COMP, LDH, B2M, IF, quantitative immunoglobulins
HBsAg, hep B core Ab (hep B PCR if either is positive)
Diagnostic CT with PET
GI tract involvement by PET may be unreliable
Panendoscopy
Controversial; does it change treatment?
Depends on goals of therapy
Establish bleeding risk: if negative, no need to repeat to confirm CR
Echocardiogram
When appropriate: pregnancy testing
B2M, β2-microglobulin; CBC, complete blood count; COMP, complete metabolic panel; CR, complete response; CT, computed tomography; GI, gastrointestinal; Hep B core Ab, hepatitis B core antibody; HBsAg, hepatitis B surface antigen; IF, immunofixation; LDH, lactate dehydrogenase; PCR, polymerase chain reaction; PET, positron emission tomography.
The pretreatment evaluation is relatively standard for patients with lymphoma. However, historical and physical examination should be focused with specific attention to evidence of gastrointestinal (GI) blood loss and early satiety. In addition, the pretreatment evaluation for MCL includes panendoscopy. The use of this procedure has been somewhat controversial because of the question of whether the results change the management approach and the concern that if the results are positive, is there a substantial risk for GI tract bleeding? However, the National Comprehensive Cancer Network guidelines recommend and Memorial Sloan-Kettering policy dictates that panendoscopy is performed. Only approximately one half of patients at Memorial Sloan-Kettering have GI tract involvement. At some centers, GI tract involvement is reported to be present in as high as 90% of patients; in such settings, it becomes less critical to assess for GI tract involvement because it can be assumed and assessments can be reserved for the end of treatment to ensure that the GI tract is negative.

5. MCL: 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
GI, gastrointestinal; NHL, non-Hodgkin’s lymphoma; PB, peripheral blood.
Mantle cell lymphoma accounts for approximately 6% of all B-cell non-Hodgkin’s lymphoma. It has a moderately aggressive course and an unusual male predominance, with approximately 74% of cases occurring in men. The median age at diagnosis is 63 years. The vast majority of patients (> 90%) has advanced-stage disease at diagnosis, and involvement of the bone marrow and GI tract are common.
Armitage JO. Oncology (Williston Park). 1998;12(10 suppl 8): Fisher RI, et al. Hematology Am Soc Hematol Educ Program. 2004: O’Connor OA, et al. Leuk Lymphoma. 2008;49(Suppl 1):59-66.
Fisher et al. Hematology. 2004;221.

6. MCL: Pathology
CD20
CD5
Cyclin D1
BCL2
IgH, immunoglobulin heavy chain.
The typical immunophenotype for MCL is that of a CD20-positive, CD5-positive, cyclin D1-positive, FMC7-positive, and BCL2-positive tumor. The absence of CD23 is typical. Morphologic variants of MCL include diffuse histology, which is the most common occurring in approximately 75% of patients, nodular histology occurring in 10% to 15% of patients, mantle zone histology occurring in 5% to 7% of patients, and blastoid histology occurring in approximately 5% of patients.
The translocation t(11;14), which juxtaposes the immunoglobulin heavy chain gene with the cyclin D1 gene on chromosome 11, is the most common cytogenetic abnormality observed in MCL, and it is easily detected by FISH. However, rarely cyclin D2 or cyclin D3 involvement is present.
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

7. MCL: Critical Role of Cyclin D1
H&E
100 80 60
All patients
Cyclin D1+
Cyclin D1-
OS (%) 40
P = .0002 20
CLL, chronic lymphocytic leukemia; H&E, hematoxylin and eosin; MCL, mantle cell lymphoma.
The critical role of cyclin D1 expression was reported by Yatabe and colleagues in 2000 when they demonstrated that CD20-positive, CD5-positive, and CD23-negative lymphoma that lacked expression of cyclin D1 did not exhibit behavior typical of MCL, but in fact was a variant of chronic lymphocytic leukemia. Although some cases of MCL can express cyclin D2 or D3, these cases are so rare that they are overwhelmed by variant cases of chronic lymphocytic leukemia. 5 10 15
Yrs
Most cases of lymphoma that are CD20+, CD5+, and CD23- and lack expression of cyclin D1 are not MCL but rather variant CLL
Some cases of MCL express cyclin D2 or D2
This research was originally published in Blood. Yatabe Y, et al. Blood. 2000;95: © the American Society of Hematology.

8. GEP in MCL: Characteristic Signature Includes Variant CCDN1- Disease
Gene expression patterns can identify a unique diagnostic signature for MCL
Variant cases of MCL expressing cyclin D2 or D3 do not have a distinctive natural history
However, cyclin D2 or D3 expression alone is not sufficient for diagnosis of MCL in cases of CD5+, CD23-, CCDN1- lymphoma/leukemia
Expression of SOX11 may identify CCDN1- MCL
GEP, gene expression profiling; MCL, mantle cell lymphoma.
However, recent evidence has emerged from gene expression profiling showing that the expression of SOX11 might help differentiate between CD5-positive, CD23-negative MCL that is cyclin D1-negative, and CD5-positive, CD23-negative, cyclin D1-negative chronic lymphocytic leukemia. Patients who express SOX11 in fact have the MCL variant.
Rosenwald A, et al. Cancer Cell. 2003;3:
Campo E. Personal communication.

9. MCL: Prognostication MCL, mantle cell lymphoma.
Now I would like to review prognostication in MCL.

10. Proliferation Predicts Outcome in MCL
GEP of MCL identified a signature associated with proliferation that predicted outcome
Determination of proliferation by MIB-1 (Ki-67) expression can substitute for the GEP
Clinical application is limited by extensive variability between observers
Quantitative image analysis removes intraobserver variation
GEP, gene expression profiling; MCL, mantle cell lymphoma.
The most powerful predictor for outcome in MCL was demonstrated by gene expression profiling to be a signature of genes that are involved in proliferation. This proliferation signature divides patients into 4 quartiles with dramatically different outcomes for both overall survival and progression-free survival. However, gene expression profiling is not practical in day-to-day practice, and the determination of proliferation index by MIB-1 or Ki-67 expression can substitute for the proliferation signature determined by gene expression profiling. One problem with the clinical application of Ki-67 staining is that it is limited by extensive variability between observers. Later in the presentation, we will review a new methodology with a much more precise quantitative imaging analysis that removes interobserver variation.
Rosenwald A, et al. Cancer Cell. 2003;3:

11. MCL International Prognostic Index
Prognostic score
x age + (0.6978/ECOG PS > 1) x log10 (LDH/ULN) x log10 (WBC)
Optimal cut points: 5.7, (maximal log-rank statistics)
Risk group definitions
Low risk (< 5.7)
Int. risk (≥ 5.7 to < 6.2)
High risk (≥ 6.2)
Risk groups are well separated
Survival in MCL by MIPI Risk Group
1.0
0.8
Low
0.6
Probability of OS
0.4
Int
0.2
High
ECOG PS, Eastern Cooperative Oncology Group performance score; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; OS, overall survival; ULN, upper limit of normal; WBC, white blood cell.
Prognosis in MCL can also be dictated by the MIPI. The full index involves a complex weighted algorithm that includes age, performance score, LDH, and white blood cell count. However, this index includes complicated logarithms and coefficients that are difficult to remember, and one needs to use a Web site calculator for determining this value on a regular basis. The risk groups are defined as follows: low risk as < 5.7, high risk as ≥ 6.2, and intermediate risk as everyone in between. 12 24 36 48 60 72 84 96
Mos Since Registration
This research was originally published in Blood. Hoster E, et al. Blood. 2008;111: © the American Society of Hematology. Online MIPI calculator:

12. Simplified MIPI Risk groups
Points
Age, Yrs
ECOG PS
LDH, x ULN
WBC, 109/L
< 50
0-1
< 0.67
< 6.7 1
50-59 --
6.7 ≤ 10 2
60-69
2-4
10 ≤ 15 3
≥ 70
> 1.5
≥ 15
Risk groups
Low risk: 0-3 points
Intermediate risk: points
High risk: 6-11 points
This model provides good curve separation in the dataset without calculation
LDH, lactate dehydrogenase; MIPI, Mantle Cell Lymphoma International Prognostic Index; ULN, upper limit of normal; WBC, white blood cell.
The authors realized that this was a complex calculation and suggested a simplified MIPI that takes into account age, performance score, LDH level, and white blood cell count and assigns different numerical point values to different values for these parameters. However, I would argue that the simplified index is not as simple as the International Prognostic Index that is routinely used in diffuse large B-cell lymphoma. When applying the simplified MIPI, low-risk patients have 0-3 points, intermediate-risk patients have 4-5 points, and high-risk patients have 6-11 points. When this model is applied to the case patient, the score reveals that the patient has intermediate-risk disease, with points accrued for age, LDH, and white blood cell count.
This research was originally published in Blood. Hoster E, et al. Blood. 2008;111: © the American Society of Hematology. Online MIPI calculator:

13. Initial Therapy of MCL MCL, mantle cell lymphoma.
Now we will discuss initial therapy for patients with MCL.

14. OS in MCL has Improved: 1996-2002 vs 1975-1986
KLG studies
Prospective observational trial ( )
COP vs CHOP randomized trial ( )
GLSG randomized trials
MCP vs CHOP ( )
CHOP vs R-CHOP ( )
Data from Kiel Lymphoma Group ( )
Analysis (N = 520)
Data from German Low-Grade Lymphoma Study Group ( )
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; COP, cyclophosphamide, vincristine, prednisone; MCL, mantle cell lymphoma; MCP, mitoxantrone, chlorambucil, prednisone; OS, overall survival; R, rituximab.
Recently, Herrmann and colleagues compared outcomes of patients who were treated between 1975 and 1986 with outcomes of patients in the German Lymphoma Study Group who were treated between 1996 and It is notable that these 2 groups of patients did not receive dramatically different therapy in these 2 eras. However, the outcomes were surprisingly quite different.
Herrmann A, et al. J Clin Oncol. 2009;27:

15. Improvement of OS in MCL: GLSG Cohort (1996-2004) vs KLG Cohort (1975-1986)
1.0
Median OS, Yrs
5-Yr OS, % (95% CI)
4.8
47 (38-55)
2.7
22 (13-31)
0.8
0.6
HR: 0.44
Survival Probability
0.4
GLSG
KLG
P < .0001
0.2
CI, confidence interval; HR, hazard ratio; MCL, mantle cell lymphoma; OS, overall survival.
The median overall survival for patients treated in the older Kiel Lymphoma Study Group was 2.7 years. This value increased to 4.8 years in the more recent analysis. 1 2 3 4 5 6 7 8 9 10
Yrs
Pts at Risk, n:
GLSG
202
171
145
117 82 47 20 3
KLG
134
105 74 43 30 12 2 1
Herrmann A, et al. J Clin Oncol. 2009;27: Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.

16. 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?
HR, hazard ratio; MCL, mantle cell lymphoma; OS, overall survival.
What is a possible explanation for this difference? It may be the result of improved diagnosis and the identification of patients with a slightly more favorable prognosis. Another possibility is that new agents, such as rituximab, bortezomib, or aggressive treatment with high-dose therapy and stem cell rescue, have made a difference in the overall survival of patients with MCL.
Herrmann A, et al. J Clin Oncol. 2009;27:

17. MCL: Conventional Therapy
CHOP ± rituximab
Median FFS: 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
CR, complete response; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; FFS, failure-free survival; MCL, mantle cell lymphoma; PFS, progression-free survival.
Conventional therapy with CHOP with or without rituximab results in a median failure-free survival of 15-18 months and few long-term survivors. A study by Howard and colleagues demonstrated that the addition of rituximab dramatically improved the complete response rate but unfortunately did not appear to improve progression-free survival. Additional data comparing these regimens in a randomized study will be discussed subsequently.
Fludarabine-based combinations seem to have a lower response rate than CHOP chemotherapy. However, the failure-free survival seems to be similar. Fludarabine is highly active when combined with cyclophosphamide, but the toxicity is increased.
1. Howard OM, et al. J Clin Oncol. 2002;20:

18. Initial Therapy of MCL: R-CHOP vs CHOP
Pts < 60 yrs (< 65 yrs) R a n d o m i z t R a n d o m i z t
PBSCT
6-8 x CHOP + Rituximab
CR, PR
Standard IFN maintenance
Pts > 60 yrs (> 65 yrs)
6-8 x CHOP
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; IFN, interferon; MCL, mantle cell lymphoma; PBSCT, peripheral blood stem cell transplantation; PR, partial response; R, rituximab.
One of the more important MCL trials compared CHOP with CHOP plus rituximab (R-CHOP) in a 2-by-2 trial design. The initial randomization examined the addition of rituximab to CHOP, and the second randomization was an age-stratified comparison of intensive vs standard interferon maintenance for older patients and transplantation vs standard interferon for younger patients. This discussion will focus on the initial randomization.
CR, PR
Intensive IFN maintenance
Standard IFN maintenance
Lenz G, et al. J Clin Oncol. 2005;23:

19. Initial Therapy of MCL: CHOP vs R-CHOP
Response, %
CHOP
R-CHOP
P Value CR 7 34
.0002 PR 68 60 MR 13 3 SD 5 2 PD
ORR 75 94
.0054
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; MCL, mantle cell lymphoma; MR, minimal response; ORR, objective response rate; PD, progressive disease; PR, partial response; R, rituximab; SD, stable disease.
The results of the initial randomization showed that rituximab addition was associated with a dramatic increase in the complete response rate: 34% of patients who received R-CHOP achieved a complete response compared with 7% of patients treated with CHOP chemotherapy alone, and this difference was statistically significant. Unfortunately, this dramatic improvement in complete response rate did not translate to either a progression-free survival or overall survival advantage for those patients who were treated with R-CHOP compared with CHOP alone.
Lenz G, et al. J Clin Oncol. 2005;23:

20. CHOP vs R-CHOP in MCL: Impact of Ki-67 Proliferation Index
1.0
< 10, median: 112
1.0
≥ 10, median: 59
≥ 30, median: 35
0.8
P = .0002
0.8
0.6
0.6
Probability of OS
Probability of OS
0.4
0.4
< 10, median not reached
≥ 10, median not reached
0.2
≥ 30, median: 52
0.2
P = .0126 12 24 36 48 60 72 84 96
108
120 12 24 36 48 60 72 84 96
108
120
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MCL, mantle cell lymphoma; OS, overall survival; R, rituximab.
In an analysis of patient specimens from several randomized trials, investigators used Ki-67 expression as a measure of the proliferation index to stratify patients into 3 groups: a group with a proliferation fraction of < 10%, a group with a proliferation fraction of 10% to < 30%, and a group with a proliferation fraction of ≥ 30%. Each stratification group exhibited quite different outcomes, with a median overall survival of 112 months for patients with the lowest proliferation index who received CHOP therapy vs 35 months for patients with the highest proliferation index who received CHOP therapy. Outcomes were similar with CHOP vs R-CHOP treatment.
Mos Since Registration
Mos Since Registration
Pts at Risk, n
Pts at Risk, n
< 10 ≥ 10 ≥ 30
9 9 0
6 2
2 0
< 10 ≥ 10 ≥ 30
40 11
11 6 1
7 3 0
0 1
Stratified by proliferation index score: < 10%, ≥ 10% to < 30%, ≥ 30%
This research was originally published in Blood. Determann O, et al. Blood. 2008;111: © the American Society of Hematology.

21. MCL: Chemotherapy ± Rituximab
Summary of Randomized Trials
Author N
Therapy
PFS P Value
OS P Value
Comment
Lenz[1]
122
CHOP ± R NS
Up-front
Herold[2] 90
MCP ± R
Forstpointner[3]
128
FCM ± R NR
.004
Relapsed/refractory
Forstpointner[4] 47
Obs vs R
.05*
Maintenance after FCM (relapsed/ refractory)
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; FCM, fludarabine, mitoxantrone, cyclophosphamide; MCL, mantle cell lymphoma; MCP, mitoxantrone, chlorambucil, prednisolone; NS, not significant; NR, not reported; OS, overall survival; PFS, progression-free survival; R, rituximab.
The central role of rituximab in the treatment of MCL has been a major question during the last decade. Four randomized trials have investigated the role of rituximab. The previously discussed German study comparing CHOP with or without rituximab as up-front therapy in untreated patients showed that rituximab addition resulted in neither an improvement in progression-free survival nor overall survival. Another frontline trial examining the mitoxantrone, chlorambucil, and prednisolone regimen, also with or without rituximab, similarly showed no difference in progression-free survival or overall survival. In the relapsed/refractory setting, Forstpointner and colleagues assessed the fludarabine, mitoxantrone, and cyclophosphamide regimen with or without rituximab and found that overall survival was improved somewhat with the addition of rituximab—but not progression-free survival. Of note, maintenance rituximab in that study improved progression-free survival but not overall survival.
These data are in contrast to trials conducted in follicular lymphoma and in diffuse large B-cell lymphoma where the addition of rituximab to conventional chemotherapy has consistently demonstrate important benefits in progression-free survival and overall survival. Therefore, the role of rituximab as an essential component of MCL treatment remains somewhat controversial, although practically speaking, most physicians include rituximab in the induction regimen.
For more information, go online to:
*Response duration.
1. Lenz G, et al. J Clin Oncol. 2005;23: Herold M, et al. Ann Oncol. 2008;19 (suppl 4): Abstract Forstpointner R, et al. Blood. 2004;104; Forstpointner R, et al. Blood. 2006;108:

22. R-HyperCVAD/R-MA for MCL: Schedule
Alternate cycles 1 and 2 every 21 days
Cycle 1, 3, 5, 7 R-hyperCVAD
Cycle 2, 4, 6, 8 R-MA
Day 1
Day 22
Staging every 2 cycles
If CR after 2 cycles, give 4 additional cycles
Transplantation offered if not in CR after first 6 cycles
Cytarabine dose reduced by 2/3 for ages 60 yrs or older or creatinine > 1.5 mg/dL
Prophylaxis: MESNA, G-CSF, antifungal, antibacterial, antiviral, calcium leucovorin, prednisone eye drops
CR, complete response; G-CSF, granulocyte colony-stimulating factor; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; MA, methotrexate, cytarabine; MCL, mantle cell lymphoma; R, rituximab.
One of the regimens most commonly used in the treatment of MCL is rituximab in combination with hyperCVAD alternating with rituximab and methotrexate and cytarabine. This is quite a toxic regimen originally developed for patients with acute lymphoblastic leukemia and involves alternating treatments between rituximab with hyperCVAD and rituximab with methotrexate and cytarabine. In a study of this regimen, staging was performed after 2 cycles and if there was a complete response after 2 cycles, a total of 6 cycles of therapy were given—that is, 3 cycles of hyperCVAD and 3 cycles of rituximab with methotrexate and cytarabine.
If there was not a complete response after the first 6 cycles, high-dose therapy and autologous stem cell rescue was offered. The dose of cytarabine was reduced by two thirds for patients older than 60 years or for patients with a creatinine level > 1.5 mg/dL. In addition, this regimen requires extensive prophylaxis, including the use of MESNA to prevent hemorrhagic cystitis as well as growth factors, and antifungal, antibacterial, and antiviral prophylaxis.
Romaguera JE, et al. J Clin Oncol. 2005;23:

23. R-HyperCVAD in MCL Study Author N ORR, % CR, % FFS, % Toxicity, %
Romaguera[1] 97 87
3-yr FFS in pts ≤ 65 yrs: 73
Toxic death: 5
MDS: 3
Epner[2] 49 88 58
2-yr FFS: 63
Toxic death: 2
Gr 4 heme tox: 87
CR, complete response; FFS, failure-free survival; Gr, grade; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; ORR, overall response rate; R, rituximab.
The results of the study conducted by Romaguera and colleagues at the University of Texas M. D. Anderson Cancer Center in Houston, Texas, demonstrated an overall response rate of 97% and a complete response rate of 87% in nearly 100 patients. There was a toxic death rate of approximately 5% and 3% of patients developed myelodysplasia. However, in the initial report, the 3-year failure-free survival for patients younger than 65 years of age was 73%.
The Southwest Oncology Group subsequently performed a pilot study to see if these results could be reproduced in a multicenter setting. Forty-nine patients were treated in this study. The overall response rate was still very high at 88%, but the complete response rate was significantly lower at 58% and the 2-year failure-free survival rate was only 63%, demonstrating inferior outcomes compared with the data from Romaguera and colleagues. However, these were both phase II studies, and further studies are needed to compare rituximab plus hyperCVAD alternating with rituximab plus methotrexate and cytarabine with a standard regimen to determine if it is associated with superior outcomes.
For more information, go online to:
1. Romaguera JE, et al. J Clin Oncol. 2005;23:
2. Epner EM, et al. ASH Abstract 387.

24. R-HyperCVAD in MCL
R-hyperCVAD results in high CR rates with durable responses
Hematologic toxicity is significant but expected
MDS can develop, as with other intensive therapies
Median FFS is superior than expected for CHOP alone
No plateau on EFS or OS curves
Relapses suggest persistent minimal residual disease and a need for additional therapy
Drop in efficacy seen in multicenter validation study
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; EFS, event-free survival; FFS, failure-free survival; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; OS, overall survival; R, rituximab.
However, it is reasonable to conclude that rituximab plus hyperCVAD results in a high complete response rate and the responses are durable. The toxicity is significant but expected and myelodysplastic syndrome does occur, but this outcome is also observed with other very intensive chemotherapy regimens. The median failure-free survival is superior to that expected for CHOP alone, but unfortunately the event-free survival and overall survival curves do not exhibit a plateau. Continued relapse over time suggests that there is persistent minimal residual disease, and there is a need for additional therapy.

25. E1405: Addition of Bortezomib to R-CVAD Yields High CR rates
Regimen
Bortezomib 1.3 mg/m2 on Days 1, 4
Cyclophosphamide 300 mg/m2 q12h x 6 doses on Days 1-3
Doxorubicin 50 mg/m2 CI over 48 hrs on Days 1-2
Vincristine 1 mg on Day 3
Dexamethasone 40 mg on Days 1-4
Maintenance rituximab: 4 wkly doses q6m x 2 yrs
CR: 75% (84% in completely restaged patients)
CI, confidence interval; CR, complete response; CVAD, cyclophosphamide, vincristine, doxorubicin, dexamethasone; R, rituximab.
Another approach to the treatment of MCL has been to introduce the novel agent bortezomib into the initial treatment with R-CHOP chemotherapy. A phase I/II dose escalation trial of this strategy was performed between 2004 and 2007, with results reported at the annual meeting of the American Society of Hematology in 2009.
Kahl B, et al. ASH Abstract 1661.

26. R-CHOP Plus Bortezomib for Initial Therapy of MCL
Phase I/II dose-escalation trial (6/ /2007)
Standard R-CHOP-21 plus bortezomib 1.0 or 1.3 mg/m2 on Days 1, 4 x 6 cycles
N = 36; 67% with intermediate- or high-risk MIPI scores
20 developed peripheral neuropathy, only 3 grade 2 and 1 grade 3
Results: ORR 91%, CR/CRu 72%
Median PFS: 21 mos
MIPI correlated with PFS and OS
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; MIPI, Mantle Cell Lymphoma International Prognostic Index; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, rituximab.
The regimen included standard R-CHOP given every 21 days with the inclusion of bortezomib at 1.0 or 1.3 mg/m2 on Days 1 and 4 for 6 cycles. There were 36 patients and 67% of the patients had intermediate-risk or high-risk disease according to the MIPI. Twenty patients developed peripheral neuropathy, but there was only 1 case of grade 3 neuropathy. The overall response rate was very high—91%—and the complete response/unconfirmed complete response rate was 72%. The median progression-free survival, however, was a disappointing 21 months. In this study, the MIPI did correlate with progression-free survival and overall survival.
Ruan J, et al. ASH Abstract 2682.

27. Bendamustine/Rituximab vs R-CHOP for Indolent and MCL: PFS
Mantle cell P = .0146
Lymphoma Subtype
Median PFS, Mos BR
R-CHOP FL
Not reached 46
MCL 33 23
Indolent/WM NR
~ 36
1.0
0.8
0.6
Probability of PFS
0.4 BR
(n = 45)
R-CHOP
0.2
(n = 48) 12 24 36 48 60 72
BR, bendamustine, rituximab; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; FL, follicular lymphoma; MCL, mantle cell lymphoma; NR, not reported; PFS, progression-free survival; R, rituximab; WM, Waldenström’s macroglobulinemia.
Another approach to the treatment of MCL has been the introduction of bendamustine. Patients with relapsed and refractory MCL were shown to have a very high response rate to the combination of bendamustine and rituximab. Recently, Rummel and colleagues reported the final results of a large randomized trial that compared bendamustine and rituximab with R-CHOP chemotherapy for patients with indolent lymphoma including follicular lymphoma as well as patients with MCL. In the subgroup of patients with MCL, the median progression-free survival for bendamustine and rituximab was 33 months compared with 23 months for R-CHOP, and this was a statistically significant difference with a P value of .01.
For more information, go online to:
Mos
Conclusion: BR improves PFS and CR rates vs R-CHOP, has a better toxicity profile, and can be considered as a first-line treatment option for indolent and MCL
Rummel MJ, et al. ASH Abstract 405.

28. Radioimmunotherapy for MCL
MCL, mantle cell lymphoma.
What about other approaches to the treatment of MCL? Mantle cell lymphoma is a highly radiosensitive tumor; however, typically it is a systemic disease presenting in multiple sites. This would suggest that radioimmunotherapy might be a good treatment strategy for the management of patients with MCL.

29. MSKCC 01-029: RIT→ CHOP for MCL Study Design
Tositumomab/
Iodine-131 Tositumomab
Restage
Restage
CHOP* x 6 1 2 3 4 5 6 7 8 9 10 11 12 13
Wks
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MCL, mantle cell lymphoma; MSKCC, Memorial Sloan-Kettering Cancer Center; RIT, radioimmunotherapy.
At Memorial Sloan-Kettering Cancer Center, Protocol included an interesting trial design to investigate radioimmunotherapy as induction therapy followed by CHOP in patients with untreated MCL. Patients were initially treated with iodine-131 tositumomab and, 12 weeks later, were treated with conventional CHOP chemotherapy.
Simon 2-stage design, 14 in first stage with assessment of response and safety, 24 evaluable total
*Cyclophosphamide dose: 1000 mg/m2 q3w, filgrastim supported.
Zelenetz AD, et al. ASCO Abstract 7560.

30. 01-029: RIT → CHOP for MCL— High Response to RIT
RIT (N = 24 evaluable)*
CR, confirmed 12/24 (50%)
RIT → CHOP (N = 20 evaluable)†
CR 14/20 (70%)
By ITT (N = 24)
CR 14/24 (58%)
*1 patient did not receive RIT because of drug availability.
†2 patients withdrew consent, 2 patients died (1 CVA, 1 POD)
100 90 80 70
Patients (%) 60 PR 50 CR 40 30 20
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CVA, cerebrovascular accident; ITT, intent to treat; MCL, mantle cell lymphoma; PR, partial response; RIT, radioimmunotherapy.
The overall response rate was very high with a complete response rate to radioimmunotherapy of 50%. Although the complete response rate increased to 70% following consolidation with CHOP chemotherapy, the increase was not statistically significantly. However, by intent-to-treat analysis, the complete response rate was 58% (14/24 patients) with this treatment approach. This result suggested that radioimmunotherapy had substantial single-agent activity in the treatment of MCL. 10
Post- RIT
Post- CHOP
ITT
Zelenetz AD, et al. ASCO Abstract 7560.

31. E1499 Study Design: R-CHOP Followed by 90Y-Ibritumomab Tiuxetan
Untreated patients with stage II-IV MCL (N = 57)
R-CHOP (× 4 cycles) R 375 mg/m2 CHOP: Standard q3w
R 250 mg/m2 + Imaging with 111In-Ibritumomab
CR, PR, or SD and BM < 25%
Primary endpoints
1.5-yr PFS of 60%
50% increase in 1.5-yr PFS compared with published data for R-CHOP x 6
Secondary endpoints
Response rate after R-CHOP and after 90Y-Ibritumomab
Toxicity
R 250 mg/m2 + 90Y-Ibritumomab 0.4 mCi/kg (0.3 mCi/kg if platelets ,000)
BM, bone marrow; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; MCL, mantle cell lymphoma; PFS, progression-free survival; PR, partial response; R, rituximab; SD, stable disease.
The Eastern Cooperative Oncology Group looked at a more conventional approach to integration of radioimmunotherapy using induction with R-CHOP followed by treatment with yttrium-90-ibritumomab tiuxetan.
Smith MR, et al. ASCO Abstract 7503.

32. E1499 Responses: R-CHOP Followed by 90Y-Ibritumomab Tiuxetan
After R-CHOP x 4 (n = 53)
After 90Y-Ibritumomab (n = 49) n %
ORR 37 70
CR/CRu 7 13 PR 30 57 SD 15 28 PD 1 2 n %
ORR 43 88
CR/CRu 27 55 PR 16 33 SD 3 6 PD
Incremental Improvement in CR/CRu After 90Y-Ibritumomab
After R-CHOP After 90Y-Ibritumomab 60 55 57
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; ORR, overall response rate; PD, progressive disease; PR, partial response; R, rituximab; SD, stable disease.
In this study, patients had an overall response rate of 70% with a complete response rate of only 13% following R-CHOP chemotherapy. However, after treatment with radioimmunotherapy, the overall response rate increased to 88% and the complete response rate increased to 55%. These data suggest that radioimmunotherapy was active for minimal residual disease that was left behind after R-CHOP chemotherapy, suggesting that radioimmunotherapy is active in this setting as well. 50 40 33
Patients (%) 30 28 20 13 10 6
CR/CRu PR SD
Smith MR, et al. ASH Abstract 389.

33. RIT for MCL: Summary
MSKCC trial demonstrates substantial single- agent activity
35% molecular remissions
ECOG 1499 trial demonstrates that RIT can address minimal residual disease (even in the presence of rituximab)
RIT may have a role in the management of MCL
CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; MCL, mantle cell lymphoma; RIT, radioimmunotherapy.
In summary, the Memorial Sloan-Kettering Cancer Center trial demonstrated that there was substantial single-agent activity of iodine-131-tositumomab with 35% molecular remissions. The Eastern Cooperative Oncology Group trial demonstrated that radioimmunotherapy can address minimal residual disease even in the presence of previous rituximab. These results suggest that radioimmunotherapy may have a role in the management of MCL, although additional studies are necessary.

34. Strategies for Consolidation
It is clear from the data presented to date that a number of approaches can achieve a response in MCL. However, these responses are generally followed by relapse without plateau in the survival curve. Therefore, the next question is what strategies are available for consolidation?

35. European MCL Network: HDT/ASCT vs IFN in Consolidation
6 x CHOP-like chemotherapy
PR/CR Age < 65 yrs
2 cycles
consolidation
DexaBEAM
(stem cell harvest)
Relapse
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; DexaBEAM, dexamethasone, carmustine, etoposide, cytarabine, melphalan; HDT, high-dose therapy; IFN, interferon; MCL, mantle cell lymphoma; OS, overall survival; TBI, total body irradiation.
The European Mantle Cell Lymphoma Network conducted a landmark trial that randomized patients who achieved a partial or complete response to induction with CHOP-like chemotherapy to receive either 2 cycles of additional consolidation chemotherapy followed by interferon maintenance or to receive dexamethasone, carmustine, etoposide, cytarabine, melphalan (DexaBEAM) chemotherapy for stem cell mobilization followed by high-dose cyclophosphamide and total body irradiation followed by autologous stem cell rescue. Complicating the overall survival analysis in this study was the crossover design that allowed patients who had progressed on the chemotherapy-alone arm to cross over to the high-dose therapy arm.
Cyclophosphamide 120 mg/kg + TBI
ASCT
Interferon-alfa
maintenance
Complicates OS analysis
Dreyling M, et al. Blood. 2005;105;

36. European MCL Network: ASCT vs IFN in Consolidation (ITT Analysis), TTF and OS
Time to Treatment Failure OS
1.0
1.0
ASCT, median: 2.6 IFN, median: 1.4
ASCT, median: 7.0 IFN, median: 5.3
0.8
0.8
P = .0001
P = .0308
0.6
0.6
Probability
Probability
0.4
0.4
0.2
0.2
ASCT, autologous stem cell transplantation; IFN, interferon; ITT, intent to treat; MCL, mantle cell lymphoma; OS, overall survival; TTF, time to treatment failure.
Despite the crossover design, the results from this trial demonstrated that high-dose therapy and autologous stem cell rescue significantly improved progression-free survival and overall survival. The median overall survival was 7 years in the group of patients receiving high-dose therapy and autologous stem cell rescue and 5.3 years in the group of patients receiving interferon maintenance. There is no convincing evidence of a long-term survival plateau in this dataset. However, the induction regimen used in this trial was relatively minimal with CHOP-like chemotherapy. 1 2 3 4 5 6 7 8 9 10 11 1 2 3 4 5 6 7 8 9 10 11
Yrs Since Randomization
Yrs Since Randomization
Pts at Risk, n
Pts at risk, n
ASCT IFN
77 65
66 34
43 19
32 12
19 4
10 3
6 1 5
4 0
ASCT IFN
103 97
91 86
84 73
63 55
48 36
33 28
21 14
13 6
8 5
3 1
0 0
Reproduced with permission by MH Dreyling. Dreyling MH, et al. ASH Abstract 769.

37. European MCL Network: HDT/ASCT vs IFN—Conclusions
HDT/ASCT is feasible in a cooperative group setting for relatively young patients (up to 65 yrs of age)
TRM rate (8%) is higher than would be expected for a current trial
Up-front consolidation leads to a clear improvement in time to treatment failure
Despite the crossover design, there is a survival advantage for up-front HDT/ASCT
Quality of response (CR vs PR) affects outcome
Despite aggressive consolidation, continuous relapse is seen
Is there a problem with the quality of the induction therapy?
ASCT, autologous stem cell transplantation; CR, complete response; HDT, high-dose therapy; IFN, interferon; MCL, mantle cell lymphoma; PR, partial response; TRM, treatment-related mortality.
The European MCL Network study demonstrated that high-dose therapy and autologous stem cell rescue is feasible in a multicenter setting for patients up to 65 years of age. The treatment-related mortality rate in that trial was 8%, but it is higher than what one would expect currently for this treatment modality. The up-front consolidation led to an improvement in time to treatment failure and in overall survival.
Dreyling MH, et al. ASH Abstract 769.

38. Nordic Lymphoma Group Trials: MCL1 and MCL2
Regimen
Trail no.
MCL1:
MCL2:
Induction
Maxi-CHOP-21 x 3
Maxi-CHOP-21 x 3 alternating with HD-cytarabine x 2, rituximab on Day 1 of each cycle
Stem cell mobilization
Maxi-CHOP-21
HD-cytarabine
Stem cell purging
In vitro: CD34+ cell selection when possible
In vivo: rituximab x 2 (Days 1 and 9 of the HD-cytarabine)
Consolidation
Allowed (1-2 series)
High-dose therapy
BEAM/BEAC
BEAM: 90 patients BEAC: 55 patients
Preemptive treatment at molecular relapse No
Rituximab 375 mg/m2/wk x 4
BEAC, carmustine, etoposide, cytarabine, cyclophosphamide; BEAM, carmustine, etoposide, cytarabine, melphalan; HD, high dose; maxi-CHOP, high-dose cyclophosphamide, doxorubicin, vincristine, prednisone; MCL, mantle cell lymphoma.
The Nordic Lymphoma Group has further advanced this approach by not only adding the high-dose therapy consolidation but also optimizing the induction treatment. In the MCL1 trial conducted between 1996 and 2000, the investigators used a variant of CHOP chemotherapy called maxi-CHOP that was given for 4 cycles with stem cell mobilization followed by high-dose therapy with carmustine, etoposide, cytarabine, melphalan (BEAM) or carmustine, etoposide, cytarabine, and cyclophosphamide (BEAC). A more recent trial, MCL2, conducted between 2000 and 2006, assessed a regimen of maxi-CHOP alternating with high-dose cytarabine that also included rituximab. Patients received high-dose therapy with either BEAM (in 90 patients) or BEAC (in 55 patients). In this study, the investigators also included rituximab for patients who had molecular evidence of recurrence after high-dose therapy.

39. Intensive Chemotherapy Plus ASCT in MCL (Nordic MCL2 Study): Efficacy
Nordic MCL Protocols 1 and 2
100
74% 80
MCL2 survival (n = 159)
MCL2 response duration (n = 144) 5-yr DOR
MCL2 EFS (n = 159)
72% 60
63%
Survival (%) 40
MCL1 EFS (n = 41) w/o R 20
ASCT, autologous stem cell transplantation; DOR, duration of response; EFS, event-free survival; MCL, mantle cell lymphoma; R, rituximab.
With this much more intensive approach, overall survival for patients in the MCL2 treatment program was 74% at 5 years. The event-free survival was 63% at 5 years, and these rates compare very favorably to the MCL1 outcome. The results of these studies suggest that the inclusion of a more intensive induction regimen followed by high-dose therapy and autologous stem cell rescue is associated with favorable and durable outcomes.
EFS, MCL1 vs MCL2: P < .0001
2.5
5.0
7.5
10.0
Yrs
6 (3.8%) treatment-related deaths
Geisler CH, et al. Blood. 2008;112:

40. EFS According to Ki-67 Expression
Intensive Chemotherapy Plus ASCT in MCL (Nordic MCL2 Study): Predictors of Outcome
EFS According to Ki-67 Expression
EFS According to Lymphoma Growth Pattern
100
100
< 10 (n = 10) 80 80 60
10-29 (n = 60) 60
Survival (%)
Survival (%)
> 29 (n = 50) 40 40
Nondiffuse (n = 70) 20 20
Diffuse (n = 81)
P = .008
P = .012
2.5
5.0
7.5
10.0
2.5
5.0
7.5
10.0
EFS
EFS
100
EFS According to Cytological Variant
100
EFS According to IPI 80 80
ASCT, autologous stem cell transplantation; EFS, event-free survival; IPI, International Prognostic Index; MCL, mantle cell lymphoma.
When individual factors were examined for their ability to predict outcome, one of the strongest predictors was the proliferation index as determined by Ki-67 staining. Patients with a very low proliferation index of < 10% had a long-term event-free survival rate of > 90% whereas patients with a proliferation index of 10% to 29% had a long-term event-free survival rate of approximately 60%. Patients with diffuse (common) histology fared somewhat better than patients with blastoid histology, although the difference in event-free survival was not statistically significant. In addition, patients with a diffuse lymphoma growth pattern had inferior event-free survival compared with patients whose disease exhibited a nodular (nondiffuse) growth pattern. 60 60
Survival (%)
Survival (%) 40 40
Common (n = 129) 20
IPI < III (n = 104) 20
P = .069
Blastoid (n = 31)
P = .046
IPI > II (n = 56)
2.5
5.0
7.5
10.0
2.5
5.0
7.5
10.0
EFS
EFS
This research was originally published in Blood. Geisler CH, et al. Blood. 2008;112: © the American Society of Hematology.

41. R-CHOP and R-DHAP Followed by ASCT in MCL: Phase II GELA Study
Response
After R-CHOP
(n = 60)
After R-DHAP
After PBSCT
(n = 49)
Entire Cohort
ORR
55 (92%)
52 (87%)
40 (100%) 82 CR
7 (12%)
34 (57%)
47 (96%) 78 PR
48 (80%)
18 (30%)
2 (4%) --
5-yr OS
75%
Median: not reached
5-yr EFS
64%
Median: 84 mos
ASCT, autologous stem cell transplantation; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CR, complete response; DHAP, dexamethasone, cytarabine, cisplatin; EFS, event-free survival; MCL, mantle cell lymphoma; ORR, overall response rate; OS, overall survival; PBSCT, peripheral blood stem cell transplantation; PR, partial response; R, rituximab.
The Nordic Lymphoma Group data are not unique, and the GELA has reported similar results with a sequence of R-CHOP followed by rituximab and dexamethasone, cytarabine, cisplatin (R-DHAP) chemotherapy. The complete response rate after rituximab and CHOP was only 12%. However, after consolidation with rituximab plus high-dose cytarabine and cisplatin, the complete response rate was 57%, increasing to 96% after high-dose therapy and autologous stem cell rescue. This resulted in a 5-year overall survival rate of 75% and a 5-year event-free survival rate of 64%.
The results with these 2 regimens taken together suggest that intensive treatment up-front followed by high-dose therapy and autologous stem cell rescue can result in substantial long-term outcomes for patients who can tolerate this treatment.
Reproduced with permission by R Delarue. Delarue R, et al. ASH Abstract 581. 41

42. NCCN NHL Database Prospective cohort study established in 2000
Currently > 4300 patients enrolled
Clinical, treatment, and outcome data
7 participating NCCN centers
City of Hope National Medical Center, Duarte, CA
Dana-Farber Cancer Institute, Boston, MA
Fox Chase Cancer Center, Philadelphia, PA
M. D. Anderson Cancer Center, Houston, TX
Northwestern University Feinberg School of Medicine, Chicago, IL
Roswell Park Cancer Institute, Buffalo, NY
University of Michigan Cancer Center, Ann Arbor, MI
NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma.
The National Comprehensive Cancer Network has a lymphoma database that includes 7 participating centers. A prospective cohort study examined the results of patients enrolled in this observational database with the diagnosis of MCL who were not treated on a clinical trial.
For more information, go online to:
LaCasce A, et al. ASH Abstract 403.

43. NCCN NHL Database Study: MCL Patient Selection
Patients with previously untreated MCL were eligible
Younger than 65 yrs of age
No clinical trial
Received rituximab-containing therapy
Treatment
Induction therapy defined as initial chemoimmunotherapy received within 180 days of diagnosis
HDT/ASCR consolidation defined as receipt of transplantation after achieving remission
First-line Treatment
n (%)
R-CHOP
29 (17)
R-CHOP + HDT/ASCR
34 (20)
R-hyperCVAD
104 (62)
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HDT, high-dose therapy; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; MCL, mantle cell lymphoma; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; R, rituximab.
Patients included in the analysis were required to receive first-line treatment with rituximab and hyperCVAD (104 patients), R-CHOP (29 patients), or R-CHOP followed by high-dose therapy and autologous stem cell rescue (34 patients). The final cohort included 167 patients.
For more information, go online to:
LaCasce A, et al. ASH Abstract 403.

44. NCCN NHL Database Study: Therapy and Complications
The 3 groups of patients had similar distributions of:
IPI values
Comorbidity index values
Treatments were administered with all 3 regimens
Risk of hospitalization was greatest for patients who received rituximab + hyper CVAD
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HDT, high-dose therapy; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; R, rituximab.
In general, the 3 groups of patients had similar distributions of International Prognostic Index values and similar distributions of comorbidity index values. Treatments were effectively administered with all 3 regimens. However, the risk of hospitalization was greatest for patients who received rituximab and hyperCVAD.
For more information, go online to:
LaCasce A, et al. ASH Abstract 403.

45. NCCN NHL Database Study: PFS
PFS results demonstrated that patients treated with rituximab hyperCVAD or R-CHOP followed by high-dose therapy and ASCT had equal outcomes which were superior to outcomes with R-CHOP
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HDT, high-dose therapy; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; PFS, progression-free survival; R, rituximab.
The progression-free survival results demonstrated that patients treated with rituximab and hyperCVAD or R-CHOP followed by high-dose therapy and autologous stem cell rescue had equivalent outcomes, and these outcomes were superior to outcomes with R-CHOP.
For more information, go online to:
LaCasce A, et al. ASH Abstract 403.

46. NCCN NHL Database Study: Conclusions
In the NCCN NHL outcomes database, R-CHOP alone is inferior to both R-CHOP + HDT/ASCR and R-hyperCVAD in terms of PFS and OS
R-CHOP + HDT/ASCR and R-hyperCVAD had equivalent PFS and OS in this cohort of patients
As compared to R-CHOP + HDT/ASCR, R-hyperCVAD resulted in more unplanned admissions for toxicity
Future trials should explore incorporation of novel agents rather than comparing aggressive induction strategies
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HDT, high-dose therapy; hyperCVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; NCCN, National Comprehensive Cancer Network; NHL, non-Hodgkin’s lymphoma; OS, overall survival; PFS, progression-free survival; R, rituximab.
The findings of this analysis demonstrated that in a multicenter or community-type setting outside of a clinical trial, long-term favorable outcomes could be obtained with either intensive chemotherapy such as rituximab and hyperCVAD or R-CHOP followed by high-dose therapy and autologous stem cell rescue.
For more information, go online to:
LaCasce A, et al. ASH Abstract 403.

47. MCL: Practical Application of Proliferation Index
MCL, mantle cell lymphoma.
Let us now consider a practical application of the proliferation index for the prognostication of patients with MCL.

48. Digital Image Analysis
Scan slide
Designate tumor regions
Select algorithm
Separate blue (hematoxylin) and brown (DAB)
As mentioned earlier, gene expression profiling data clearly demonstrate that proliferation is the most important predictor for long-term outcome and proliferation can be estimated by Ki-67 expression. However, Ki-67 expression assessment varies considerably among different pathologists. Therefore, we sought to remove the pathologist from the determination of Ki-67 staining by using a quantitative image analysis methodology in which the slides are scanned and areas for analysis are selected. The colored channels are then separated into a hematoxylin channel and a brown channel to assess the immunohistochemical staining and obtain a quantitative value.
Recognize objects based on blue stain
Count blue and brown objects
Export Data
% = brown objects
Brown + blue
Review results

49. Quantitative Image Analysis
Ki-67 stained slide
Color deconvolution: High PI: a, b Low PI: c, d
PI, proliferation index.
This slide shows an example of the quantitative image analysis for a highly proliferative tumor (in a and b) and a low proliferation tumor (in c and d).

50. PI Estimation by QIA Correlates With Manual Counting80 60
Quantitative Image Analysis (%) 40
PI, proliferation index; QIA, quantitative image analysis.
The correlation between the quantitative, computer-based imaging technique and manual counting of 1000 cells under the microscope is very good. 20 20 40 60 80
100
Manual Count (%)

51. PI by QIA: Ki-67 Cutoff of 30% Predicts Outcome
PFS OS
≥ 10% to 30% (n = 33, censored 24)
≥ 10% to 30% (n = 33, censored 28)
≥ 30% to 50% (n = 18, censored 9)
≥ 30% to 50% (n = 18, censored 16)
< 10% (n = 22, censored 13)
< 10% (n = 22, censored 18)
> 50% (n = 15, censored 5)
> 50% (n = 15, censored 6)
P = .042
P < .001
100
100 80 80 60 60
PFS (%)
OS (%) 40
PFS, progression-free survival; PI, proliferation index; QIA, quantitative image analysis.
An examination of different cutoffs for the proliferation index determined using quantitative image analysis demonstrates that the cutoff of 30% reported previously by the European MCL Network and confirmed by the Nordic Lymphoma Group provides accurate prediction of both progression-free survival and overall survival. 40 20 20 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10
Yrs
Yrs
Schaffel R, et al. Ann Oncol. 2010;21: by permission of Oxford University Press.

52. QIA for PI in MCL: HDT/ASCR Consolidation
ICE ± R x 2 (n = 63*)
Functional imaging*
± Rituximab
Maintenance
CHOP ± R every 14 days x 4
HDT/ASCR
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; HDT, high-dose therapy; ICE, ifosfamide, carboplatin, etoposide; MCL, mantle cell lymphoma; PI, proliferation index; QIA, quantitative image analysis; R, rituximab.
Quantitative image analysis has also been applied to a uniformly treated group of patients. Patients were treated with CHOP with or without rituximab every 14 days for 4 cycles followed by ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with or without rituximab for either 2 cycles if they were in complete response or 3 cycles if they were in partial response, as determined by functional imaging with fluorodeoxyglucose positron emission tomography. Patients then went on to receive high-dose therapy and autologous stem cell rescue.
ICE ± R x 3 (n = 16)
*In the 20 patients without functional imaging performed, 2 cycles of ICE ± R were given.
Schaffel R, et al. Ann Oncol. 2010;21:

53. Outcome of MCL With Sequential Therapy: R-CHOP/ICE/HDT-ASCR
1.0
1.0
PI < 30% (n = 37, censored 29)
0.8
0.8
0.6
0.6
Proportion Event Free
Proportion Event Free
EFS
0.4
0.4
EFS (n = 66, censored 40)
0.2
0.2
PI ≥ 30% (n = 29, censored 11) 2 4 6 8 10 12 2 4 6 8 10 12
1.0
Yrs
1.0
Yrs
ASCR, autologous stem cell rescue; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; EFS, event-free survival; HDT, high-dose therapy; ICE, ifosfamide, carboplatin, etoposide; MCL, mantle cell lymphoma; OS, overall survival; PI, proliferation index; R, rituximab.
The results of this study were similar to the findings of the European MCL Network in that there was an improvement in survival outcomes compared with historic data from studies using CHOP alone. However, there is a continuous decline in the survival curves over time.
When quantitative image analysis of the proliferation index is applied, the survival curves deconvolute into 2 very distinct populations. The patients with a proliferation index of ≥ 30% have an inevitable relapse whereas patients with a proliferation index of < 30% appear to have a potentially curative outcome; approximately 70% of these patients remain in remission beyond 5 years. It is interesting to note that there has not been a single relapse of MCL after 5 years in this group of patients. Therefore, aggressive therapy in patients with a low proliferation index might result in a long-term outcome that resembles a cure.
0.8
0.8
PI < 30% (n = 37, censored 34)
0.6
OS ( n = 66, censored 55)
0.6
Proportion Alive OS
Proportion Alive
0.4
0.4
0.2
0.2
PI ≥ 30% (n = 29, censored 21) 2 4 6 8 10 12 2 4 6 8 10 12 OS
Yrs

54. Summary PI by QIA in MCL Determination of PI by QIA is robust
More reproducible than estimation by a pathologist
Easier than manually counting 1000 cells
PI cutoff of 30% identifies a group of favorable patients with good outcome
Up-front consolidation with HDT/ASCR
Disease progression occurs for 5 yrs
With a PI of < 30%, no events have occurred after 5 yrs
With a PI ≥ 30%, no patient is progression free
ASCR, autologous stem cell rescue; HDT, high-dose therapy; MCL, mantle cell lymphoma; PI, proliferation index; QIA, quantitative image analysis.
In summary, determination of proliferation index by quantitative image analysis is robust, more reproducible than the estimation by a pathologist, and easier than manual counting. A proliferation index cutoff of 30% identifies a favorable patient subgroup with a good outcome. Up-front consolidation with high-dose therapy and autologous stem cell rescue results in disease progression that occurs for approximately 5 years, but for the favorable patient subgroup (ie, proliferation index < 30%), there have been no progression events after 5 years. Among patients with a higher proliferation index (≥ 30%), all have progressed by Year 5.

55. Proliferation in MCL: Conclusions
MCL is a disorder of dysregulated cell cycle progression
Overexpression of cyclin D1 is not sufficient to produce MCL
Lesions in the apoptotic machinery and in DNA damage repair are important in the genesis and evolution of MCL
Proliferation is a major determinant of outcome in MCL
GEP identifies a proliferation signature that can be approximated by IHC for Ki-67
QIA allows for robust and reproducible determination of proliferation index
Up-front consolidation leads to a clear improvement in PFS and EFS
Patients with a PI of < 30% may have the potential for a curative outcome
Several new agents have clinical activity in MCL and need to be integrated into curative treatment strategies
EFS, event-free survival; GEP, gene expression profiling; IHC, immunohistochemistry; MCL, mantle cell lymphoma; PFS, progression-free survival; PI, proliferation index; QIA, quantitative image analysis.
In conclusion, MCL is a disorder of dysregulated cell cycle. Although overexpression of cyclin D1 is not sufficient to produce MCL, dysregulation of the cell cycle is the critical lesion that ultimately leads to the development of the tumor.
Proliferation is a major determinant of outcome. Gene expression profiling can be used to identify a proliferation signature, although the proliferation index can also be approximated by immunohistochemical staining for Ki-67; quantitative image analysis makes this a robust and reproducible determination.
Up-front consolidation leads to a clear improvement in progression-free survival and event-free survival, and patients with a favorable proliferation index may have the potential for a curative outcome.
There are numerous new agents that have clinical activity in MCL, such as bortezomib. The integration of bortezomib into treatment with R-CHOP suggested the possibility of improved outcomes. Additional studies need to be conducted to investigate the optimal integration of a range of novel agents into the initial management of patients with MCL in order to improve outcomes, particularly in patients with a proliferation index ≥ 30% without the potential for a curative outcome with current management strategies.

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