Therapeutic Activity of Lenalidomide in Mantle Cell Lymphoma and Indolent Non-Hodgkin’s Lymphomas

Mantle cell lymphoma (MCL) comprises 3–10% of NHL, with survival times ranging from 3 and 5 years. Indolent lymphomas represent approximately 30% of all NHLs with patient survival largely dependent on validated prognostic scores. High response rates are typically achieved in these patients with current first-line chemoimmunotherapy. However, most patients will eventually relapse and become chemorefractory with poor outcome. Alternative chemoimmunotherapy regimens are often used as salvage strategy and stem cell transplant remains an option for selected patients. However, novel approaches are urgently needed for patients no longer responding to conventional chemotherapy. Lenalidomide is an immunomodulatory drug with activity in multiple myeloma, myelodisplastic syndrome and chronic lymphoproliferative disorders. In phase II studies of indolent NHL and MCL lenalidomide has shown activity with encouraging response rates, both as a single agent and in combination with other drugs. Some of these responses may be durable. Optimal dose of lenalidomide has not been defined yet. The role of lenalidomide in the therapeutic armamentarium of patients with indolent NHL or MCL will be discussed in the present paper.

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The Efficacy and Safety of Lenalidomide Oral Monotherapy in Patients with Mantle Cell Lymphoma Previously Treated with Bortezomib: Pooled Data from Two Phase II Studies (NHL-002 and NHL-003).

Blood ◽

10.1182/blood.v112.11.1560.1560 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1560-1560 ◽

Cited By ~ 4

Author(s):

Craig B. Reeder ◽

T.E. Witzig ◽

Julie M. Vose ◽

Pier Luigi Zinzani ◽

Rena Buckstein ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Prior Treatment ◽

Cell Transplant ◽

Phase Ii Trials ◽

Phase Ii Studies ◽

Mantle Cell

Abstract Introduction: Mantle-cell lymphoma (MCL) is an aggressive B-cell lymphoma that if not cured with aggressive chemoimmunotherapy and stem cell transplant is usually fatal. The intravenous proteasome inhibitor bortezomib produces an overall response rate (ORR) of 33% in patients with relapsed MCL (J Clin Oncol2006;24(30):4867–74). Unfortunately, most patients eventually relapse and new agents are needed for this disease. Two recently conducted phase II trials (NHL-002 and NHL-003) tested single-agent lenalidomide for patients with relapsed MCL. Fifty-four patients with MCL were enrolled into the two studies; 26% (14/54) had received prior bortezomib and they are the subject of this report. Methods: Patients with relapsed or refractory MCL and measurable disease 2 cm after at least one prior treatment regimen including prior bortezomib were eligible. Patients received 25 mg of lenalidomide orally once daily on days 1–21 of every 28-day cycle. Therapy was continued as tolerated or until disease progression. The 1999 IWLRC methodology was used to assess response and progression. Results: The 14 patients in this study were heavily pretreated with a median of 4 (2–6) prior treatments (including bortezomib) and 50% were bortezomib-refractory. Median age was 66 (45–84) years and 6 (43%) patients were female. Median time from diagnosis to lenalidomide treatment was 3.3 (0.7–7.6) years. The ORR with lenalidomide was 57% (8/14), including 21% (3/14) complete response (CR)/unconfirmed CR and 36% (5/14) partial responses. One (7%) patient had stable disease. The most common grade 3 or 4 adverse events were neutropenia (50%), thrombocytopenia (43%), anemia (21%), fatigue (21%), and leukopenia (21%). Neutropenic fever occurred in 7% of patients. Conclusion: These results demonstrate that lenalidomide oral monotherapy is very effective with manageable side effects in patients with relapsed or refractory MCL who had received prior treatment with bortezomib.

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Initial therapy of mantle cell lymphoma

Therapeutic Advances in Hematology ◽

10.1177/2040620711412418 ◽

2011 ◽

Vol 2 (6) ◽

pp. 381-392 ◽

Cited By ~ 4

Author(s):

David J. Inwards ◽

Thomas E. Witzig

Keyword(s):

Mantle Cell Lymphoma ◽

Median Survival ◽

Cell Lymphoma ◽

Survival Rates ◽

Central Nervous System Involvement ◽

Progression Free Survival ◽

Response Rates ◽

World Health ◽

Cell Transplant ◽

Mantle Cell

Mantle cell lymphoma is a well-recognized distinct clinicopathologic subtype of B-cell non-Hodgkin lymphoma. The current World Health Organization (WHO) classification subdivides this entity into aggressive and other variants. The disease has a predilection for older males, and patients typically present at an advanced stage with frequent splenomegaly and extranodal involvement including bone marrow, peripheral blood, gastrointestinal, and occasional central nervous system involvement. Early studies of therapy outcomes in this disease revealed that while response rates where high, relapse was expected after a limited period of time. Prolonged survival was uncommon, with initial median survival rates typically in the 3–4-year range. Those with a high proliferative rate, blastoid morphology, and selected clinical features were recognized as having a worse prognosis. Therapeutic approaches have diverged into aggressive therapies with high response rates and promising progression free survival rates, which may be applied to younger healthy patients, and less aggressive approaches. Aggressive therapies include intensive chemotherapy alone or chemotherapy followed by autologous stem cell transplant, which has been shown to be most effective when applied in first remission. Whether these more intense therapies result in improved survival as compared with less aggressive therapies is not well established. Allogeneic transplant has also been investigated, although high treatment-related mortality and the risk of chronic graft versus host disease and the relatively advanced age of this patient population have tempered enthusiasm for this approach. A number of less aggressive therapies have been shown to produce promising results. Consolidation and maintenance strategies are an active area of investigation. A number of newer agents have shown promising activity in relapsed disease, and are being investigated in the front-line setting. Overall survival rates are improving in this disease, with current studies suggesting a median survival of 5 or more years.

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Combined analysis of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8533 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8533-8533

Author(s):

Thomas E. Witzig ◽

Julie Vose ◽

Pier Luigi Zinzani ◽

Thomas Matthew Habermann ◽

Joseph M. Tuscano ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Phase Ii ◽

Cell Lymphoma ◽

Single Agent ◽

Pooled Analysis ◽

Prior Treatment ◽

Second Primary ◽

Phase Ii Studies ◽

Venous Thromboembolic Events ◽

Mantle Cell

8533 Background: Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma (NHL) with poor prognosis. The immunomodulatory agent lenalidomide shows consistent activity with tolerable safety in multiple phase II studies of relapsed/refractory aggressive NHL (NHL-002 and NHL-003) and MCL post-bortezomib (MCL-001). This pooled analysis further examined the efficacy and safety of single-agent lenalidomide in patients with relapsed/refractory MCL. Methods: Single-agent lenalidomide was given 25 mg/d PO on days 1-21 of 28-day cycles as tolerated for 52 weeks (NHL-002) or until disease progression (NHL-003 and MCL-001). All MCL patients received ≥1 prior treatment, including bortezomib in MCL-001. Efficacy data were examined by independent central review for MCL-001 and NHL-003 and by investigators for NHL-002. Results: 206 patients with relapsed/refractory MCL were studied. The median age was 67 y (range 33-84; 63% ≥65 y), 91% stage III/IV disease and 51% had received ≥4 prior regimens (76% prior bortezomib). Overall response rate (ORR) with lenalidomide was 32% (10% CR/CRu), with a median time to response of 2.1 months and median duration of response (DOR) of 16.6 months (not yet reached in patients with CR/CRu; Table). Kaplan-Meier estimates for median PFS and OS were 5.4 and 23.9 months, respectively. Mean daily dose of lenalidomide was 21 mg. Grade 3/4 AEs included neutropenia (44%), thrombocytopenia (29%), anemia (11%), and fatigue (7%). Other any-grade AEs included tumor flare reaction (7%), venous thromboembolic events (7%), and invasive second primary malignancies (3%). Conclusions: Lenalidomide produced rapid and durable responses in patients with relapsed/refractory MCL, and exhibited a predictable safety profile among 3 phase II studies of lenalidomide in heavily pretreated patients, including prior treatment with bortezomib. Clinical trial information: MCL-001: NCT00737529; NHL-002: NCT00179660; NHL-003: NCT00413036. [Table: see text]

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The Impact of Histological Subtypes on Outcome in Patients with Mantle Cell Lymphoma Treated with or without Autologous Stem Cell Transplant.

Blood ◽

10.1182/blood.v110.11.1904.1904 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1904-1904

Author(s):

Muhammad I. Zulfiqar ◽

Dennis D. Weisenburger ◽

Fausto R. Loberiza ◽

Julie M. Vose ◽

Philip J. Bierman ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Mantle Cell Lymphoma ◽

Stem Cell Transplant ◽

Cell Lymphoma ◽

Cell Transplant ◽

Histological Subtypes ◽

Mantle Cell ◽

Hodgkin's Lymphomas ◽

The Impact

Abstract Mantle cell lymphoma (MCL) accounts for 7% of all non-Hodgkin’s lymphomas, with median overall survival in most series of 3–4 years. MCL has been classified into three histological subtypes which include diffuse MCL, nodular MCL, and blastic MCL. A relatively small number of studies have examined the prognostic importance of histology in MCL. The aim of this study was to determine if the progression free survival (PFS) and overall survival (OS) rates in mantle cell lymphoma differ among histological subtypes. A total of 102 patients with MCL, treated by the Nebraska Lymphoma Study Group between January 1986 and June 2006, with a median age of 60 years (range 32–89 years) were available for study. Patients were treated with HyperCVAD or a CHOP like regimen with or without rituximab and autologous hematopoetic stem cell transplant (ASCT). All cases were confirmed using cyclin D1 staining. Regardless of treatment, our study failed to show a significant difference in PFS (p=0.26) or OS (P=0.06) among histological subtypes. There was a trend for better survival in patients with nodular MCL. However, in patients receiving ASCT, there was a significantly higher PFS (P=0.0001) and OS (p=0.0005) compared to patients not receiving ASCT. The 3 year PFS for patients receiving HyperCVAD followed by ASCT was 64% compared to the 3 year PFS for HyperCVAD alone of 0 (p=0.008). In conclusion, we failed to show association between histological subtypes of MCL with outcomes regardless of treatment. However, the use of ASCT improved survival.

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Gastrointestinal Mantle Cell Lymphoma: incidental finding on routine CT scan following pneumothorax.

Journal of Advances in Internal Medicine ◽

10.3126/jaim.v2i1.7635 ◽

2013 ◽

Vol 2 (1) ◽

pp. 24-26

Author(s):

Mingma Thsering Sherpa ◽

Damiano Rondelli ◽

Raksha Shrestha

Keyword(s):

Ct Scan ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Incidental Finding ◽

Signs And Symptoms ◽

Cell Transplant ◽

Rare Presentation ◽

Hematopoietic Stem ◽

Mantle Cell ◽

Hodgkin's Lymphomas

Gastric mantle cell lymphoma is a rare form of gastrointestinal tumor and represents 2.5–7% of all non-Hodgkin’s lymphomas. A 69-year-old maleadmitted with spontaneous pneumothorax was found to have a gastric masson CT scan. Results of histopathological,immunohistochemical and genetic analysis were consistent with mantle cell lymphoma(MCL).Patient responded well to intensive chemotherapy and subsequent allogeneic hematopoietic stem cell transplant and remains in complete remission.We would like to emphasize that a gastric mass, as in this case can occur as a rare presentation of MCL involving the gastrointestinal tract without any other overt signs and symptoms. Journal of Advances in Internal Medicine 2013;02(01):24-26 DOI: http://dx.doi.org/10.3126/jaim.v2i1.7635

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Combined Inhibition of CDK and PI3K/Akt Pathways Induces Apoptosis of Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.1384.1384 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1384-1384

Author(s):

Subhra Mohapatra ◽

Baoky Chu ◽

Xiuhua Zhao ◽

Jianguo Tao ◽

Eduardo Sotomayor ◽

...

Keyword(s):

B Cell ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Single Agent ◽

Tumor Formation ◽

Cdk Inhibitors ◽

Akt Inhibitor ◽

Mantle Cell ◽

Hodgkin's Lymphomas

Abstract Mantle cell lymphoma (MCL) arises from the neoplastic transformation of naïve B cells in the mantle zone of the B cell follicle. It is an aggressive and incurable B cell neoplasm. It accounts for 5% to 8% of non-Hodgkin’s lymphomas. Patients with MCL respond initially to chemotherapy but ultimately relapse. Mean survival time is only three to four years. Thus, the need for new treatments that effectively combat MCL is obvious and imperative. Defects in cell cycle regulation and apoptosis are primary events in MCL. It is characterized by the presence of a chromosomal translocation t (11:14)(q13:q32), which results in deregulated cyclin D1 expression. Cyclin D1 overexpression in MCL is thought to play a major role in lymphomagenesis, although the precise mechanisms by which tumor formation and progression occur are not fully understood. Constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis and survival of MCL. Activated AKT was found in cultured MCLs as well as in 100% of aggressive-blastoid variants of MCL tumors, compared to 30% of typical MCLs. Towards the search for novel therapies for MCLs, we examined the potential of roscovitine (rosc) or flavopiridol (flav), inhibitors of cyclin dependent kinase (CDK), as a single agent or in combination with LY294002 (LY), a PI3K/Akt inhibitor, in inducing apoptosis of various MCL lines as well as in MCL patient samples. CDK inhibitors modestly increased the percentage of apoptotic cells (∼30%), whereas LY had no effect. However, when added in combination, rosc/LY or flav/LY induced apoptosis in more than 70% of cells. In an effort to understand the mechanism of apoptosis, we identified three targets: cyclin D1, the anti-apoptotic proteins myeloid cell leukemia-1 (Mcl-1) and X-linked Inhibitor of Apoptosis (XIAP). CDK inhibitors eliminated Mcl-1 expression, slightly reduced XIAP abundance and had very little effect on abundance of cyclin D1. Conversely, LY reduced cyclin D1 expression and slightly reduced the abundance of Mcl-1 and XIAP. A larger decrease in XIAP abundance is seen in cultures treated with a combination of rosc/LY or flav/LY. On the basis of these findings, we suggest that agents that target Mcl-1, XIAP and cyclin D1 will be most effective in inducing apoptosis of human MCLs.

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A Phase II Study of Temsirolimus (CCI-779) in Combination with Rituximab in Patients with Relapsed or Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.1665.1665 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1665-1665 ◽

Cited By ~ 5

Author(s):

Stephen M Ansell ◽

Hui Tang ◽

Paul Kurtin ◽

Patricia Koenig ◽

David J Inwards ◽

...

Keyword(s):

Stem Cell ◽

Cyclin D1 ◽

Mantle Cell Lymphoma ◽

Response Rate ◽

Cell Lymphoma ◽

Single Agent ◽

Signal Transduction Pathway ◽

Antitumor Agent ◽

Cell Transplant ◽

Mantle Cell

Abstract Abstract 1665 Poster Board I-691 Mantle cell lymphoma (MCL) is an aggressive, incurable B-cell malignancy that represents approximately 6% of lymphoma cases. Patients with MCL who relapse after conventional therapy or stem cell transplantation have a poor prognosis and are candidates for treatment with novel agents. The characteristic feature of MCL is overexpression of cyclin D1. Cyclin D1 is under the control of the phosphatidylinositol-3 kinase signal-transduction pathway and is downstream of the mammalian target of rapamycin kinase (mTOR). We have previously shown that temsirolimus (CCI-779), a dihydroester of the selective mTOR inhibitor rapamycin, is an active antitumor agent in MCL. In previous phase 2 trials of temsirolimus as a single agent, we observed a 40% overall response rate (ORR) with a median duration of response (DR) of 6 months in patients with relapsed or refractory disease (J Clin Oncol 23:5347-56, 2005; Cancer 113:508-514, 2008). Due to the fact that rituximab has improved the response rate and overall outcome of lymphoma patients when combined with chemotherapy, we tested the efficacy and toxicity of temsirolimus in combination with rituximab in patients with MCL. Eligible patients with confirmed relapsed or refractory MCL based on morphologic and phenotypic features received temsirolimus 25 mg intravenously every week and four weekly doses of rituximab with the first cycle and then one dose of rituximab every other cycle. Patients with a tumor response after six cycles were eligible to continue treatment for a total of 12 cycles or two cycles after complete remission, and were then observed without maintenance. Seventy-one patients were enrolled between May 2005 and March 2009. The median age was 67 years (range, 44 to 86 years), with 51 males and 20 females enrolled. Patients had received a median of two prior therapies (range, 1-9), 31% had received a prior stem cell transplant and 28% were rituximab refractory. The ORR was 48% (34/71 patients) with 20% (14/71) complete responses and 28% (20/71) partial responses. The median DR was 9.5 months (95% CI, 4.5 to 11.3 months). The median DR in the rituximab sensitive patients was 9.5 months (CI: 4.5-11.6) and 7.15 months (CI: 4.1-11.3) in the rituximab refractory patients (p= 0.73). While the combination was generally well tolerated, 12 patients experienced grade 4 toxicity and 2 patients died while on therapy – both from progressive disease. Hematologic toxicities were the most common, with 5 patients having grade 4 thrombocytopenia and 3 having grade 4 neutropenia. This study demonstrates that temsirolimus in combination with rituximab is well tolerated and has substantial antitumor activity in relapsed MCL. Further comparative studies of this combination in MCL are therefore warranted. Disclosures Witzig: Wyeth: Patents & Royalties.

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