1. Relapsed/Refractory 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
The title of this presentation is “Mantle Cell lymphoma: Is There a Potential for Cure?” I am Andrew C. Zelenetz, MD, PhD, the Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center.
This program is supported by an educational grant from
Image: 3D4Medical.com/Copyright©2010 Getty Images, Inc. All Rights Reserved.

2. Management of Relapsed Mantle Cell Lymphoma
This presentation will focus on the management of relapsed mantle cell lymphoma.

3. Treatment Approach to Relapsed MCL
Essentially all patients will relapse
No treatment standards/algorithms
What is the most appropriate goal of therapy?
CR?
PFS?
OS?
Palliation?
Role of allogeneic BMT still controversial
BMT, bone marrow transplantation; CR, complete response; MCL, mantle cell lymphoma; PFS, progression-free survival; OS, overall survival.
In the treatment of the patient with relapsed mantle cell lymphoma, there are several points to remember. Essentially all patients will relapse. In addition, there are no standard treatments or standard treatment algorithms in this setting.
One major question in the relapsed setting is what is the most appropriate goal of therapy? Are we aiming to achieve a complete response? Do we want the best progression-free survival? Are we aiming for the best overall survival? Or is the goal of treatment in this setting palliation? There is no clear correct answer to this question, and the goal will vary from patient to patient.
The role of allogeneic bone marrow transplantation is still controversial; however, in selected patients, it may be a very appropriate treatment choice.

4. Transplantation for Relapsed MCL
MCL, mantle cell lymphoma.
What is the role of transplantation for relapsed mantle cell lymphoma?

5. Registry and Institutional Data Suggest ASCT Is Less Useful at Relapse
1.00
1.00
PFS
0.75
0.75
1st CR
0.50
1st CR
0.50
1st PR
0.25
Other
0.25
Other 2 4 6 8 5 10 15
ASCT, autologous stem cell transplantation; CR, complete response; EFS, event-free survival; PR, partial response; UNMC, University of Nebraska Medical Center.
The role of high-dose therapy with autologous stem cell rescue has been evaluated in the setting of relapsed and refractory mantle cell lymphoma. The data from both single-center studies as well as registry data suggest that in contrast to the experience with high-dose therapy and autologous stem cell rescue in first remission, the use of this treatment modality at relapse is associated with a significantly inferior outcome. The event-free survival of patients who have received 3 or more previous therapies was 0% at 12 months according to data from the University of Nebraska Medical Center in Omaha, Nebraska.
Yrs From Transplant
Yrs
Pts at Risk, n:
1st CR
Other
Pts at Risk, n:
1st CR
1st PR
Other
EFS of pts with ≥ 3 previous regimens: 0% at 12 mos (UNMC)
Vose JM, et al. Biol Blood Marrow Transplant. 2000;6:
Vandenberghe E, et al. Br J Haemaotol. 2003;120:

6. Allogeneic SCT at Relapse in MCL
Potential option for young/fit patients with relapsed but chemosensitive disease
Limited by the usual considerations
Advanced age
Comorbidities
Lack of appropriate donor
Less robust graft-vs-lymphoma effect compared with FL
FL, follicular lymphoma; MCL, mantle cell lymphoma; SCT, stem cell transplantation.
By contrast, allogeneic stem cell transplantation has been shown to be active in the management of patients with relapsed mantle cell lymphoma and is a potential option for patients with chemosensitive disease who are young or fit enough and who have a suitable donor. However, the availability of allogeneic stem cell transplantation is limited by the usual considerations: advanced age, comorbidities, and the lack of an appropriate donor. The literature indicates that the graft vs lymphoma effect is less robust in mantle cell lymphoma than in follicular lymphoma and more closely resembles what is observed in diffuse large B-cell lymphoma.
Maris MB, et al. Blood. 2004;104:
Khouri IF, et al. J Clin Oncol. 2003;21:

7. Allogeneic SCT in Relapsed MCL
1.0
First remission, ASCT with rituximab
P = .04*
First remission, ASCT without rituximab
Relapsed/refractory, NST
P < .01
0.8
Relapsed/refractory, ASCT
*At 2-yr landmark
0.6
Proportion Alive Without Progression
0.4
ASCT, autologous stem cell transplantation; MCL, mantle cell lymphoma; NST, nonmyeloablative stem cell transplantation; SCT, stem cell transplantation.
A study from Tam and colleagues comparing the results of allogeneic stem cell transplantation with high-dose therapy and autologous stem cell rescue suggests that in the relapsed/refractory setting there is a substantially greater likelihood of long-term disease-free survival with an allogeneic stem cell source than with an autologous stem cell source.
0.2 12 24 36 48 60 72 84 96
108
120
132
Mos
Tam CS, et al. Leuk Lymphoma. 2009;50:

8. Relapsed/Refractory MCL: Approved and Investigational Agents
Bortezomib
Cytarabine
Bendamustine
Lenalidomide
mTOR inhibitors
Monoclonal antibodies
Anti-CD20 (rituximab, ofatumumab)
Radioimmunotherapy
MCL, mantle cell lymphoma; R/R, relapsed/refractory.
However, if one is going to consider transplantation as an option for therapy, one needs to achieve a minimal disease state; several treatment options are available for patients with relapsed and refractory disease. These include the following: bortezomib, a drug that is approved for the treatment of relapsed and refractory disease; cytarabine; bendamustine; lenalidomide; mTOR inhibitors; monoclonal antibodies, including rituximab and ofatumumab; radioimmunotherapy; and other treatments that include combination chemotherapy regimens.
Approved for R/R MCL
Off-label/investigational use in R/R MCL

9. Bortezomib in MCL
Single-agent bortezomib is active in multiple relapsed FL, MZL, and MCL
Strategies need to be developed to integrate this active agent earlier into treatment
R-CBorP for indolent lymphoma
Bortezomib maintenance in MCL
FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; R-CBorP, rituximab, cyclophosphamide, bortezomib, prednisone.
Bortezomib has been approved as a single agent for the treatment of relapsed mantle cell lymphoma and is active in patients with relapsed follicular lymphoma and marginal zone lymphoma as well. Single-agent responses are not very durable, and the overall response rates are relatively modest, at approximately 30% to 40%. Therefore, strategies are needed for determining how to integrate bortezomib into combination chemotherapy to optimize use of this agent. Several approaches have been examined, including the integration of bortezomib into regimens such as standard cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy; the substitution of vincristine with bortezomib in the rituximab plus cyclophosphamide, bortezomib, and prednisone regimen; or consideration of the use of bortezomib for the treatment of minimal residual disease after chemotherapy as a maintenance strategy.
Goy A, et al. Ann Oncol. 2008;20: ; Gerecitano JF, et al. ASCO Abstract 8512.

10. Bortezomib and Proteasome Inhibition
β2*
Asp/Glu
Phe/Tyr/Trp
Post-
glutamyl
Tryptic
20S Proteasome
(four 7-membered rings) a
β1*   β7 β3
19S Proteasome
Regulatory complex + ATP
Bortez β6 β4
Chymo-
tryptic
26S Proteasome 
Bortezomib was the first in class of a novel group of chemotherapy agents that are targeted at the inhibition of the proteasome. The proteasome is the structure within the cell that is responsible for the metabolism of damaged and useless proteins. After a process called “ubiquitinization,” proteins are moved to the top of the proteasome and are subject to protease cleavage so that the amino acid constituents can be recycled and reused for peptide synthesis.
Bortezomib is a boron-based small molecule inhibitor of the chymotryptic-like activity of the proteasome.
β5*
Lys/Arg
(Hydrolysis mediated by N-terminal
Threonine, ie, threonine protease)
Strauss SJ, et al. Cancer Res. 2007;67:

11. Bortezomib Is Active in Relapsed MCL: Phase II Data
Reference
Patients, N
Regimen
ORR/CR
Outcome, Mos
Median DOR
Goy A, et al.
Ann Oncol. 2009; 20:
155 MCL
B 1.3 mg/m2 on Days 1, 4, 8, 11 q21 days
32% ORR
8% CR/CRu
TTP 6.7 TTNT 7.4 PFS 6.5
CR pts have not yet reached med DOR or med TTP; 9.2 mos in all responders
Fisher RI, et al.
J Clin Oncol. 2006; 24:
33% ORR 8% CR
TTP 6.2
9.2 mos
Gerecitano J, et al. Br J Haematol. 2009;146:
10 MCL
16 FL
B 1.8 mg/m2 wkly x 4, q6w
18% ORR
0% CR
PFS 6.7
6.7 mos
O’Connor OA, et al. Br J Haematol. 2009;145:34-39.
40 MCL
B 1.5 mg/m2 on Days 1, 4, 8, 11 q21 days
50% ORR 13% CR
PFS 5.3
7.8 mos
O’Connor OA, et al. J Clin Oncol. 2005; 23:
11 MCL
3 SLL
2 MZL
10 FL
58% ORR
5/11 MCL pts with response (1 CR)
Survival NR
6-19+ mos
Belch A, et al.
Ann Oncol. 2007; 18:
29 MCL (13 Rx-naive)
46% (1 CRu)
TTP 12.5
10 mos
Strauss SJ, et al. J Clin Oncol. 2006; 24:
24 MCL
13 FL
14 other
29% ORR in MCL (1 CR)
Not assessable (d/t consolidative treatments)
B, bortezomib; CR, complete response; CRu, unconfirmed CR; DOR, duration of response; FL, follicular lymphoma; MCL, mantle cell lymphoma; MZL, marginal zone lymphoma; NR, not reported; PFS, progression-free survival; q, every; ORR, overall response rate; SLL, small lymphocytic leukemia; TTNT, time to next treatment; TTP, time to progression.
Much evidence now exists supporting the role of bortezomib in the treatment of relapsed mantle cell lymphoma. The original data were obtained from phase II studies using 1.3 mg/m2 or 1.5 mg/m2 on Days 1, 4, 8, and 11; overall response rates in the range of 30% to 60% were reported.
For more information, please go online to:

12. Updated Analyses of the PINNACLE Study: Bortezomib in Relapsed MCL
Key eligibility criteria
MCL, cyclin D1+, or t(11;14)+ PD
≤ 2 previous therapies
Previous anthracycline and rituximab
No > grade 2 toxicity from previous therapy
Bortezomib 1.3 mg/m2 for 4 cycles beyond CR/CRu or, if no CR/CRu, up to 17 cycles until PD or toxicity
1 yr
Day 1 4 8 11
Restaging
Every 2 cycles x first 6 cycles
Then every 4 cycles/3 mos until PD or alternate therapy
Week 1 2 3 4 5 6
CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; PD, progressive disease.
The large, phase II PINNACLE study included 155 patients with relapsed or refractory mantle cell lymphoma. In this trial, patients were treated with a standard dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 of a 21-day cycle.
Goy A, et al. Ann Oncol. 2008;20:

13. Bortezomib in Relapsed/Refractory MCL: Efficacy
Patient Group
ORR, %
CR, %
Median DOR, Mos
Response evaluable (n = 141) 32 8
9.2
Refractory MCL (n = 58) 29 6
5.9
Previous high-intensity therapy (n = 58) 25 10
Not reached
CR, complete response; DOR, duration of response; MCL, mantle cell lymphoma; ORR, overall response rate.
The PINNACLE trial results were updated by Goy and colleagues and published in the Annals of Oncology in The overall response rate from this clinical trial group was 32%, with an 8% complete response rate. In the updated data, the median duration of response was 9.2 months. In patients who had refractory mantle cell lymphoma, having failed to respond to previous chemotherapy or having a response duration of < 6 months, the overall response rate was still 29% and the median duration of response was 5.9 months. These data suggest that bortezomib is acting in a way that is distinct from the treatments that these patients had previously received, because both relapsed and refractory patients had very similar response rates.
Goy A, et al. Ann Oncol. 2008;20:

14. Bortezomib in Relapsed/Refractory MCL: Efficacy
TTP by treatment response, median mos
All patients
6.7
CR/CRu NR PR
9.1
OS (median): by treatment response
23.5 mos
Responders
35.4 mos
1-yr survival
69%
91%
OS from initial diagnosis, mos
61.1
CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; NR, not reported; OS, overall survival; PR, partial response; TTP, time to progression.
The time to progression was relatively short for all patients at 6.7 months, but the median overall survival duration from treatment was approximately 2 years among all patients and approximately 3 years among the responders.
Goy A, et al. Ann Oncol. 2008;20:

15. Bortezomib, Rituximab, Dexamethasone in Relapsed/Refractory MCL
Patient characteristics
N = 16 patients
Median age: 66 yrs
Median no. of previous therapies: 3 (range: 1-7)
Rituximab: 88%
Thalidomide: 50%
Stage IV: 100%; IPI 4, 5: 10 patients (62.5%), LDH above normal (50%)
Efficacy
ORR: 13/16 (81%)
CR: 7/16 (44%)
PR: 6/16 (37%)
Median PFS: 12.1 mos
Median OS: 25.7 mos 1 2 3 4 8 11 21
Days
≥ Grade 2 Toxicity, n
Patients
Hyponatremia 2
Diarrhea 3
Infections
H. zoster
Bacterial pneumonia
Mucosal candidiasis 1
Peripheral neuropathy 7
Fatigue 6
Thrombocytopenia
Skin toxicity
CR, complete response; IPI, International Prognostic Index; LDH, lactate dehydrogenase; MCL, mantle cell lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.
As mentioned, a major goal has been to build on the single-agent activity of bortezomib, and one of the regimens investigated is the combination of bortezomib, rituximab, and dexamethasone, the so-called BORID regimen. The preliminary results with the BORID regimen suggest a high overall response rate of 81% in a small study including only 16 patients. The median number of previous therapies was 3. Eighty-eight percent of the patients had received previous rituximab, and half of the patients had received previous thalidomide. As mentioned, the overall response rate was 81% and the complete response rate was 44%. The median progression-free survival was 12.1 months. This was a relatively well-tolerated treatment, although peripheral neuropathy and thrombocytopenia were relatively common toxicities, as was fatigue.
Drach J, et al. ASH Abstract 2578.

16. Phase I/II Trial of R-CBorP in NHL: Treatment Schema
Bortezomib IV push
Cyclophosphamide + Rituximab
Prednisone 100 mg
Cycle Repeats
Days
IV, intravenous; NHL, non-Hodgkin’s lymphoma; R-CBorP, rituximab, cyclophosphamide, bortezomib, prednisone.
At Memorial Sloan-Kettering Cancer Center in New York, Gerecitano and colleagues conducted a trial investigating rituximab plus cyclophosphamide, bortezomib, and prednisone, which is a regimen in which bortezomib is substituted for vincristine in the standard rituximab plus cyclophosphamide, vincristine, and prednisone chemotherapy regimen. This was a phase I trial that initially assessed bortezomib on a weekly basis and then, in a second cohort, investigated bortezomib on a twice-weekly basis.
Days
Gerecitano JF, et al. ASCO Abstract 8512.

17. Wkly vs Twice-Wkly Bortezomib: Schedules and Hematologic Toxicities
Grade 1
Grade 2
Grade 3
Grade 4
Wkly
Twice Wkly 70 70 60 60 50 50 40 40
Percent
Percent 30 30
ALC, absolute lymphocyte count; ANC, absolute neutrophil count; Hb, hemoglobin; Plats, platelets; WBC, white blood cell count.
The toxicities were as expected for this combination. The hematologic toxicity was relatively modest and certainly acceptable for patients with mantle cell lymphoma. 20 20 10 10
WBC
ALC
ANC Hb
Plats
WBC
ALC
ANC Hb
Plats
Gerecitano JF, et al. ASCO Abstract 8512.

18. Grade 3/4 Nonhematologic Toxicities
Wkly
Diarrhea/dehydration (n = 1)
Febrile neutropenia (n = 1)
Hypomagnesemia (n = 1)
Hypokalemia (n = 2)
Hypophosphatemia (n = 1)
Hyperglycemia (n = 1) and hypoglycemia (n = 1)
Incontinence (with rectal prolapse) (n = 1)
Cellulitis (n = 1) and dental abscess (n = 1, same pt)
Sinus tachycardia (n = 1)
Autonomic insufficiency (n = 1)
Second malignancy (n = 2)
Twice Wkly
Febrile neutropenia (n = 2)
Constipation (n = 1)
Fever (n = 1)
Hyperglycemia (n = 1)
Autonomic insufficiency (n = 1)
Pneumonia (n = 1)
Neuropathy (n = 2) (1 was grade 4)
Grade 3/4 nonhematologic toxicities included infectious complications and 2 cases of neuropathy with the twice-weekly schedule. However, this was a highly active treatment regimen.
Gerecitano JF, et al. ASCO Abstract 8512.

19. Responses to R-CBorP in NHL
Wkly
Twice Wkly 40
ORR: 54%
(n = 13)
ORR: 70%
(n = 20) 20
-20
-40
CR, complete response; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PR, partial response; R-CBorP, rituximab, cyclophosphamide, bortezomib, prednisone.
Among all patients in the phase I cohort treated with the weekly schedule, the overall response rate was 54%; among patients treated with the twice-weekly regimen, the overall response rate was 70%. It is not clear whether these response rates are in fact different because there were selection biases in the patients who entered the 2 parts of the study.
-60
-80
PR: 4/13
PR: 10/20
-100
CR: 3/13
CR: 4/20
Gerecitano JF, et al. ASCO Abstract 8512.

20. Induction Plus Maintenance Rituximab and Bortezomib in FL and MCL
Phase II study (N = 23)
Rituximab
375 mg/m2 on Day 1 of Wks 4, 5, 7, 8, 10, 11, 13, 14
Bortezomib
1.5 mg/m2 on Days 1 and 4 of Wks 1, 2, 4, 5, 7, 8, 10, 11, 13, 14
Median follow-up : 12 mos
PFS, median mos
5.9
ORR, %
39.1
Grade 3/4 neurotoxicity
64% patients receiving 1.5 mg/m2
50% patients receiving 1.3 mg/m2
Grade 3 neuropathy
56.5% despite dose reductions
R-bortezomib is active in patients with relapsed or refractory MCL but toxicity profile was problematic
FL, follicular lymphoma; MCL, mantle cell lymphoma; ORR, overall response rate; PFS, progression-free survival; R, rituximab.
Another approach that has been investigated with bortezomib is bortezomib maintenance. Blum and colleagues at Ohio State University presented data at the 2008 American Society of Hematology annual meeting from a study examining the combination of rituximab and bortezomib in follicular and mantle cell lymphoma. This trial was a small, phase II study involving only 23 patients, and the treatment schedule was rituximab 375 mg/m2 on Day 1 of Weeks 4, 5, 7, 8, 10, 11, 13, and 14 and bortezomib 1.5 mg/m2 on Days 1 and 4 of Weeks 1, 2, 4, 5, 7, 8, 10, 11, 13, and 14. The median follow-up at the time of reporting was approximately 1 year. The median progression-free survival was 5.9 months. Grade 3/4 neurotoxicity was a significant problem in patients receiving bortezomib 1.5 mg/m2, but the incidence was somewhat lower when the bortezomib dose was reduced to 1.3 mg/m2. The conclusion from this study was that rituximab/bortezomib was an active regimen in patients with relapsed or refractory mantle cell lymphoma, but the incidence of neuropathy presented a significant barrier to further development of the regimen.
Blum KA, et al. ASH Abstract 3053.

21. Bendamustine Is Active in MCL
Trial N
Patient Characteristics
Treatment
ORR, %
DOR, Mos
PFS, Mos
Kahl et al[1]
100
Rituximab-refractory indolent NHL B 84
9.3
9.7
Friedberg et al[2] 76
Rituximab-refractory indolent and transformed NHL 77
6.7
7.1
Rummel et al[3] 63
Relapsed indolent NHL and MCL
B + R 90
N/A 24
Robinson et al[4] 66 92 21 23
B, bendamustine; DOR, duration of response; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PFS, progression-free survival; R, rituximab.
Another agent that is active in mantle cell lymphoma is bendamustine. Bendamustine is a bifunctional alkylator that is related to nitrogen mustard and cyclophosphamide but appears to have activity in cells that are resistant to other similar alkylators.
One of the first studies to examine the role of bendamustine was presented by Kahl and colleagues. The study included 100 patients with relapsed and rituximab-refractory indolent lymphoma including mantle cell lymphoma and demonstrated an overall response rate of 84% with a progression-free survival of 9.7 months. Similar data were obtained from other studies in the United States and Europe with overall response rates ranging from 77% to 92% and with progression-free survival ranging from 7.1 months to 2 years.
1. Kahl B. et al. ASH Abstract 1351.
2. Friedberg JW, et al. J Clin Oncol. 2008;26:
3. Rummel MJ, et al. J Clin Oncol. 2005;23:
4. Robinson KS, et al. J Clin Oncol. 2008;26:

22. Previously treated indolent B-cell lymphoma and MCL patients
Phase II Study: Bendamustine + Rituximab in Relapsed Indolent B-Cell and MCL
Previously treated indolent B-cell lymphoma and MCL patients
(N = 66)
A S S E S S
Rituximab 375 mg/m2 IV on Day 1 of each cycle + Bendamustine 90 mg/m2 IV over min on Days 2 and 3 of each cycle x 4-6 cycles
IV, intravenous; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma.
A multicenter phase II study of the combination of bendamustine and rituximab was conducted among patients with indolent B-cell lymphoma and mantle cell lymphoma. The dosing schedule was rituximab 375 mg/m2 on Day 1 and bendamustine 90 mg/m2 on Days 2 and 3. Treatment was repeated every 4 weeks for 4-6 cycles as tolerated. The study included 66 patients.
Objective: To evaluate the efficacy and safety of bendamustine in combination with rituximab in patients with relapsed NHL
Robinson KS, et al. J Clin Oncol. 2008;26:
Kaufmann et al. Blood. 2004;104:2269.

23. Phase II Study: Bendamustine + Rituximab in Relapsed Indolent B-Cell and MCL
ITT, All Patients (N = 66)
Patients, %
ORR 92
CR/CRu
41/14 PR 38 SD 8
MCL (n = 12)
Patients, %
ORR 92
CR/CRu
42/17 PR 33 SD 8
CR, complete response; CRu, unconfirmed CR; ITT, intent to treat; MCL, mantle cell lymphoma; ORR, overall response rate; PFS, progression-free survival; PR, partial response; SD, stable disease.
The overall response rate was 92%. The complete response rate was 41%, and the unconfirmed complete response rate was 14%. Among the small cohort of 12 mantle cell lymphoma patients, the overall response rate was 92%, similar to the overall population. The complete response rate and the unconfirmed complete response rates were 42% and 17%, respectively, in this group. Therefore, the responses in mantle cell lymphoma were very similar to the responses observed in other indolent B-cell lymphomas.
At a median follow-up of 20 mos, the median duration of response was 21 mos and median PFS was 23 mos
Robinson KS, et al. J Clin Oncol. 2008;26:

24. Phase II Study: Bendamustine + Rituximab in Relapsed Indolent B-Cell and MCL
Adverse Event
Patients, %
Grade 3
Grade 4
Common nonhematologic
Fatigue 5 --
Diarrhea 3
Common hematologic
Neutropenia 23 14
Febrile neutropenia 2
Thrombocytopenia 8
Anemia
MCL, mantle cell lymphoma.
The common grade 3/4 nonhematologic toxicities included fatigue and diarrhea, and, not surprisingly, neutropenia was a frequent grade 3/4 hematologic adverse event in this study. However, grade 3/4 febrile neutropenia occurred in only 7% of patients.
Robinson KS, et al. J Clin Oncol. 2008;26:

25. Bendamustine, Bortezomib, and Rituximab for Relapsed NHL
Phase II multicenter study in relapsed/refractory indolent lymphomas and MCL
BVR regimen
Bendamustine 90 mg/m2 on Days 1 and 4
Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11
Rituximab 375 mg/m2 on Day 1
Responses: 5/7 MCL and 11/11 FL (7 CR)
Responses in patients with previous SCT, nucleoside analogue, RIT
Toxicity: PN 18 patients, varicella zoster in 5 (not prophylaxed; now recommended)
Conclusion: active but more toxic than BR
No data yet in frontline setting
BR, bendamustine, rituximab; BVR, bendamustine, bortezomib, rituximab; CR, complete response; FL, follicular lymphoma; MCL, mantle cell lymphoma; NHL, non-Hodgkin’s lymphoma; PN, peripheral neuropathy; RIT, radioimmunotherapy; SCT, stem cell transplantation.
Another approach used has been to combine bendamustine and bortezomib with rituximab. Friedberg and colleagues presented data from a phase II multicenter trial examining this approach in patients with relapsed or refractory indolent lymphoma and mantle cell lymphoma at the American Society of Hematology annual meeting in The bendamustine, bortezomib, and rituximab regimen included bendamustine at a dose of 90 mg/m2 on Days 1 and 4, bortezomib at the standard dose of 1.3 mg/m2 on Days 1, 4, 8, and 11, and rituximab at 375 mg/m2 on Day 1. Among the 7 patients with mantle cell lymphoma, 5 responded, and this number included responses in patients who had received previous stem cell transplantation, purine analogue therapy, or radioimmunotherapy. Peripheral neuropathy was a common toxicity, as was reactivation of varicella zoster. The conclusion was that this was an active but more toxic regimen compared with the combination of bendamustine and rituximab and that further investigation of this regimen was warranted.
Friedberg J, et al. ASH Abstract 924.

26. Lenalidomide in Relapsed/Refractory Aggressive NHL: Results
Histology n
ORR, %
PFS, Mos
DLBCL
108 28
2.3
Mantle cell 57 42
5.7
Follicular (grade 3) 19
6.3
T-cell 33 45
4.6
ORR in patients with previous SCT: 37% (27/73)
Grade 3/4 neutropenia: 41%; thrombocytopenia: 19%
DLBCL, diffuse large B-cell lymphoma; NHL, non-Hodgkin’s lymphoma; ORR, overall response rate; PFS, progression-free survival; SCT, stem cell transplantation.
Another class of agent that has been used in the treatment of relapsed and refractory non-Hodgkin’s lymphoma is the immunomodulatory drug lenalidomide; this agent has been used in diffuse large B-cell lymphoma, T-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. At the 2009 annual meeting of the American Society of Hematology, Witzig and colleagues presented the results of a trial investigating lenalidomide in a large group of patients with aggressive lymphomas including 57 patients with mantle cell lymphoma. The single-agent response rate was 42%, and the progression-free survival was 5.7 months for patients with mantle cell lymphoma. Responses were observed across a wide range of patients including 37% of the patients who had received a previous stem cell transplant. The toxicities observed in this study were as expected with lenalidomide, including neutropenia in 41% of patients and thrombocytopenia in 19%.
Witzig TE, et al. ASH Abstract 1676.

27. Lenalidomide Monotherapy in Relapsed/ Refractory MCL: Phase II Study Design
Treatment: lenalidomide 25 mg
PO QD on Days 1-21 every 28 days; continue for 52 wks
Patients with relapsed/refractory MCL: N = 39
Median age: 66 yrs (range: 33-81)
Median number of previous therapies: 3 (range: 1-8)
23% (9/39) had previous bortezomib therapy
MCL, mantle cell lymphoma.
The activity of lenalidomide in this setting was confirmed by the results of a study conducted by Zinzani and colleagues in which the investigators administered lenalidomide at a dose of 25 mg/day orally on Days 1-21 of each 28-day cycle with cycles continued for 52 weeks. Thirty-nine patients with relapsed/refractory mantle cell lymphoma were treated. The median age of the patient population was 66 years, and the median number of previous therapies was 3.
For more information, please go online to:
Zinzani PL, et al. ASH Abstract 262.

28. Lenalidomide Monotherapy in Relapsed/ Refractory MCL: Efficacy and Safety
Response
1.0
PFS 50 45 41
0.8 40 35
0.6 30 28
Survival Probability 26
Patients (%) 25
0.4 20 15 13 10
0.2 5
CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; ORR, overall response rate; PFS, progression-free survival; PR, partial response; SD, stable disease.
The overall response rate was 41%, and the complete/unconfirmed complete response rate was 13%. The median progression-free survival was 216 days.
For more information, please go online to:
ORR
CR/CRu PR SD
100
200
300
Day
Patients, n
Events, % (n)
Censored, % (n)
Median PFS Days (95% CI) 39
49 (19)
51 (20)
216 (75-344)
Zinzani PL, et al. ASH Abstract 262.

29. Lenalidomide in MCL Patients Previously Treated With Bortezomib
25 mg of lenalidomide PO QD on Days 1-21 of every 28-day cycle
Median age: 66 yrs
N = 14
Median time from diagnosis to treatment: 3.3 yrs
ORR: 57%
CR/CRu: 21%
PR: 36%
SD: 7%
Grade 3/4 Adverse Events, %
Neutropenia 50
Thrombocytopenia 43
Anemia 21
Fatigue
Leukopenia
CR, complete response; CRu, unconfirmed CR; MCL, mantle cell lymphoma; ORR, overall response rate; PR, partial response; SD, stable disease.
Lenalidomide has also been examined in patient subset analyses, particularly in patients who have been treated with previous bortezomib. In a small study of 14 patients previously treated with bortezomib and with a median age of 66 years, the same dose of lenalidomide used in the previously discussed study, 25 mg/day on Days 1-21 of each 28-day cycle, resulted in a overall response rate of 57% and a complete/unconfirmed complete response rate of 21%.
Therefore, as with bortezomib, lenalidomide activity appears to be maintained regardless of previous treatment, suggesting that lenalidomide might have a unique mechanism of action as compared with conventional chemotherapy.
Reeder CB, et al. ASH Abstract 1560.

30. mTOR/AKT Pathway PI3k PTEN AKT Cell growth mTOR 4E-BP1 BAD NFKB S6K1
Inhibit apoptosis
Cell growth
HIF1-α
Glycolytic enzymes
PTEN
S6K1
4E-BP1
mTOR, mammalian target of rapamycin.
Another promising area in the treatment of relapsed and refractory mantle cell lymphoma is the use of mammalian target of rapamycin (mTOR) inhibitors. The mTOR pathway has increasingly become recognized as a critical pathway in not only lymphomas but also a wide variety of cancers, and the AKT/mTOR pathway has been a target for treating both lymphoid malignancies and solid tumors.

31. Temsirolimus: Single-Agent Activity in MCL
250 mg
25 mg
Patient characteristics
Median age, yrs (range)
70 (38-79)
68 (51-85)
Previous treatments, n 3
≥ 2 extranodal sites, % 69
Refractory disease, % 54 48
Results
ORR, % (n/N)
38 (13/34)
41 (11/27)
CR, % (n/N)
3 (1/34)
4 (1/27)
DR, mos
6.9
6.2
Toxicity
Dose reduction needed, % (n/N)
88 (30/34)
59 (16/27)
CR, complete response; DR, duration of response; MCL, mantle cell lymphoma; ORR, overall response rate.
Witzig and colleagues investigated temsirolimus, initially at a high dose of 250 mg/day orally in a group of 34 patients who had a median age of 70 years. The overall response rate was 38%. Although this result was promising, there was substantial toxicity, and dose reductions were required in 88% of the patients.
Witzig and colleagues conducted a second clinical trial involving 27 patients treated at one-tenth the temsirolimus dose, 25 mg/day orally. The second study included a very similar patient population, with a median age of 68 years and with 48% of the patients having refractory disease. In this study, the overall response rate was 41% with a response duration of 6.2 months. These results were very similar to the findings of the previous study at a 10-fold higher dose. Although toxicities were observed, the toxicity level was much more acceptable in this lower-dose study. Dose reductions still were required in 59% of the patients.
Witzig TE, et al. J Clin Oncol. 2005;23:

32. Phase III Trial in MCL: Temsirolimus vs Investigator’s Choice
MCL confirmed locally
Relapsed/refractory to 2-7 previous therapies
Required: Rituximab Anthracycline Alkylating agent
(N = 162) R A N D O M I Z E
Temsirolimus 175 mg/wk x 3
then 75 mg/wk
Temsirolimus 175 mg/wk x 3
then 25 mg/wk
Investigator’s choice
single agent
MCL, mantle cell lymphoma; PFS, progression-free survival.
This promising single-agent activity led to a randomized, phase III trial evaluating temsirolimus against the investigator’s choice. Because there was no standard of care regimen, a variety of single agents were acceptable in the investigator’s choice arm. Patients had to have received 2-7 previous therapies and previous exposure to rituximab, an anthracycline, and an alkylating agent was required.. In total, 162 patients were randomized to 3 treatment arms: temsirolimus weekly for 3 weeks followed by 75 mg weekly, temsirolimus weekly for 3 weeks followed by 25 mg weekly, or the investigator’s choice of a single agent. The randomization was 1:1:1 for the 3 arms, and the investigators evaluated overall response rate and the primary endpoint of progression-free survival.
Temsirolimus treatment to continue until progression, death, or unacceptable toxicity
Primary endpoint: PFS
Hess G, et al. J Clin Oncol. 2009;27: 32

33. Treatment With Temsirolimus Compared With IC: Efficacy and Toxicity
Temsirolimus 175/75 mg
Temsirolimus 175/25 mg IC
PFS
Median, mos
Increase in median PFS, %
HR (97.5% CI)
P value
4.8
153
0.44 ( )
.0009
3.4 79
0.65 ( )
.0618
1.9 OS
Median, mos (95% CI)
HR (95% CI)
12.8 ( )
0.80 ( )
.3519
10.0 ( )
0.96 ( )
.8714
9.7 ( )
ORR, % (95% CI)
22 (11-33)
.0019
6 (0-12)
.6179
Most common grade 3/4 adverse events, %
Thrombocytopenia
Anemia
Neutropenia
Asthenia 59 20 15 13 52 11 22 19 36 17 26 8
CI, confidence interval; HR, hazard ratio; IC, investigator’s choice; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
There was a significant improvement in median progression-free survival with temsirolimus 175 mg/wk for 3 weeks followed by 75 mg weekly relative to investigator’s choice (P = .0009) and a trend toward prolonged progression-free survival for the lower dose–temsirolimus arm relative to investigator’s choice (P = .0618). The median progression-free survival in the high-dose arm was 4.8 months compared with 3.4 months in the low-dose arm and 1.9 months in the investigator-choice arm. The overall response rate was significantly higher in the high dose–temsirolimus arm at 22% vs 2% in the investigator-choice arm (P = .0019). The overall response rate was 6% in the low dose–temsirolimus arm.
In my opinion, these data suggest that the drug is active. However, the dataset is not sufficiently compelling to suggest the use of this agent in the relapsed and refractory setting. What I believe should happen is that this agent should be integrated with other active agents in the relapsed and refractory setting, and new combinations should be explored to build on this potential promising activity.
Hess G, et al. J Clin Oncol. 2009;27:

34. Single-Agent Rituximab in MCL
Study
Patients*
Rituximab Regimen
Outcome
DR/PFS/TTP
Foran et al[1]
Untreated (n = 34) Relapsed (n = 40)
375 mg/m2 x 4
38% ORR
37% ORR (10% CR)
DR 1.2 yrs
Coiffier et al[2]
Relapsed (n = 13)
375 mg/m2 x 8 or 375 mg/m2 x mg/m2 x 7
33% ORR
TTP > 8.2 mos
Ghielmini et al[3]
Untreated (n = 34) Rel/ref (n = 54)
375 mg/m2 x 4 ± MR q8w x 4
27% ORR
2% CR
PFS 6 mos without MR
PFS 12 mos with MR
CR, complete response; DR, duration of response; MCL, mantle cell lymphoma; MR, maintenance rituximab; ORR, overall response rate; PFS, progression-free survival; Rel/ref, relapsed/refractory; TTP, time to progression.
Single-agent rituximab also has been investigated in the setting of relapsed and refractory mantle cell lymphoma and has not demonstrated a high level of activity, although the activity is on par with some of the other single agents discussed earlier in this presentation. In 3 separate studies, the single-agent activity of rituximab in relapsed/refractory disease ranged from 27% to 37%, with a median duration of 6-12 months.
*Nearly all patients were rituximab naive.
1. Foran JM, et al. J Clin Oncol. 2000;18:
2. Coiffier B, et al. Blood. 1998;92:
3. Ghielmini M, et al. J Clin Oncol. 2005;23:

35. Conclusions
The treatment of relapsed/refractory mantle cell lymphoma remains a substantial challenge
There are no standard treatment regimens; however, there are several agents that exhibit good activity
There are emerging data demonstrating that the combination of some of these novel agents has resulted in very high response rates with the potential for significant prolongation of progression-free survival compared with conventional chemotherapy
In summary, the treatment of relapsed/refractory mantle cell lymphoma remains a substantial challenge. There are no standard treatment regimens. However, there are several agents that exhibit good activity. There are emerging data showing that the combination of some of these novel agents has resulted in very high response rates with the potential for significant prolongation of progression-free survival compared with conventional chemotherapy.
In returning to the case patient and the question of what I would have chosen for this patient, based on the high response rate, the ease of use, and the likelihood of a successful bridge to transplantation, in my opinion the combination of rituximab/bendamustine would have been a good choice for this patient who would subsequently receive an allogeneic stem cell transplantation.

36. Go Online for More Information on Lymphomas
Medical Meeting Coverage: key data plus Expert Analysis panel discussions exploring clinical implications Treatment Updates: comprehensive programs covering the most important new concepts Interactive Cases: test your ability to manage patients
clinicaloptions.com/oncology 36