Mantle cell lymphoma: correlation of clinical outcome and biologic features with three histologic variants.

PURPOSE Clinical data and histologic material were retrospectively analyzed in 46 cases of previously untreated mantle cell lymphoma (MCL) to more fully characterize the clinical response pattern of these lymphomas and to determine whether growth pattern significantly affected clinical outcome. MATERIALS AND METHODS The histologic pattern was classified as diffuse (61%), nodular (13%), and mantle zone (26%) in accordance with stated criteria. RESULTS Bone marrow infiltration was detected in 69% of cases; the frequency of involvement correlated with histologic pattern, being most common in diffuse variants and least common in mantle zone variants. Other sites of extranodal involvement were observed in 50% of cases. Cyclin-D1 staining revealed nuclear positivity in 23 of 25 patients (92%) and no difference was observed between the various histologic patterns. Rearrangement at the bcl-1 major translocation cluster (MTC) was detected in seven of 21 cases, without regard for histologic pattern. Complete response rates to doxorubicin-based regimens showed a striking correlation with histologic pattern. Seventy-three percent of patients with a mantle zone pattern attained a complete response compared with only 25% of patients with a nodular pattern and 19% with a diffuse pattern. Three-year survival rates were 100%, 50%, and 55% for patients with mantle zone, nodular, and diffuse histologic patterns, respectively. CONCLUSION We conclude that (1) diffuse and nodular MCL are associated with a poor treatment response and a poor overall survival rate; (2) the mantle zone variant exhibits the clinical attributes of a low-grade lymphoma; and (3) the poor survival rates of patients with nodular and diffuse MCL suggest that these variants be classified as intermediate-grade lymphomas. However, the trend of the time to treatment failure curve does not indicate that current regimens can cure MCL.

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Rituximab maintenance improves progression-free and overall survival rates after combined immuno-chemotherapy (R-FCM) in patients with relapsed follicular and mantle cell lymphoma: Final results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7502 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7502-7502 ◽

Cited By ~ 15

Author(s):

M. Dreyling ◽

R. Forstpointner ◽

M. Gramatzki ◽

H. Böck ◽

M. Hänel ◽

...

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Survival Rates ◽

Progression Free Survival ◽

Remission Induction ◽

Low Grade ◽

Free Survival ◽

Mantle Cell ◽

The Impact

7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]

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Mantle Cell Lymphoma in the Thyroid: A Rare Presentation

Case Reports in Pathology ◽

10.1155/2017/6749801 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 1

Author(s):

Uzma Mohammad Siddiqui ◽

Sarika N. Rao ◽

Pallavi Kanwar Galera ◽

Nahida Islam ◽

Mira S. Torres

Keyword(s):

Flow Cytometry ◽

Mantle Cell Lymphoma ◽

Growth Pattern ◽

Cell Lymphoma ◽

Case Series ◽

Low Grade ◽

Mantle Zone ◽

Ki 67 ◽

Mantle Cell ◽

Zone Growth

Background. While 2% of all extranodal Non-Hodgkin Lymphomas present in the thyroid, there exists insufficient data to describe the incidence of mantle cell lymphoma in the thyroid. A case series of 1400 patients revealed that <1% of thyroid lymphomas may be MCL; hence better understanding of the disease course is essential.Patient Findings. A 65-year-old female was referred for a multinodular goiter. Multiple fine needle aspirations from the dominant right nodule were consistent with Hashimoto’s thyroiditis and flow cytometry was negative. Due to progressing dysphagia, she underwent total thyroidectomy.Summary. Pathology revealed MCL with mantle zone growth pattern in the right thyroid. Flow cytometry showed monoclonal B cells comprising 9% of total cells. The Ki-67 index was 10%. She was diagnosed as having stage IIE MCL and offered conservative management by medical oncology, given that she had no B symptoms.Conclusion. Though chemotherapy is the treatment of choice in MCL, a subset of patients with low-grade disease may be observed. As in our patient, mantle zone growth pattern and a Ki-67 index < 10% suggest a favorable prognosis. A diagnosis of primary MCL in the thyroid remains rare and staging modalities as well as treatment options continue to evolve.

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High ZAP-70 expression correlates with worse clinical outcome in mantle cell lymphoma

Leukemia ◽

10.1038/sj.leu.2404362 ◽

2006 ◽

Vol 20 (10) ◽

pp. 1905-1908 ◽

Cited By ~ 1

Author(s):

D Hui ◽

L Dabbagh ◽

J Hanson ◽

H M Amin ◽

R Lai

Keyword(s):

Clinical Outcome ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Mantle Cell

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Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma

Blood ◽

10.1182/blood.v95.2.619 ◽

2000 ◽

Vol 95 (2) ◽

pp. 619-626 ◽

Cited By ~ 156

Author(s):

Roberto Chiarle ◽

Leo M. Budel ◽

Jeffrey Skolnik ◽

Glauco Frizzera ◽

Marco Chilosi ◽

...

Keyword(s):

Overall Survival ◽

Protein Degradation ◽

Mantle Cell Lymphoma ◽

Molecular Mechanisms ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Low Grade ◽

High Grade ◽

Ki 67 ◽

Mantle Cell

Mantle cell lymphoma (MCL) is an aggressive neoplasm characterized by the deregulated expression of cyclin D1 by t(11;14). The molecular mechanisms responsible for MCL's clinical behavior remain unclear. The authors have investigated the expression of p53, E2F-1, and the CDK inhibitors p27 and p21 in 110 MCLs, relating their expression to proliferative activity (Ki-67). For comparison, they have similarly analyzed low-grade (12 MALT, 16 CLL/SLL) and high-grade (19 DLCL) lymphomas. p53 was detected more frequently in large-cell MCL (l-MCL; 5 of 7) than in classical MCL (s-MCL; 13 of 103) and DLCL (8 of 19). In MCL and DLCL, the percentage of E2F-1+ nuclei was high, correlating with high Ki-67 expression. Most MCLs (91 of 112) and DLCLs (12 of 19) showed a loss of p27; MALT and CLL/SLL, however, were p27 positive. Reverse transcription–polymerase chain reaction and in vitro protein degradation assays demonstrated that MCLs have normal p27 mRNA expression but increased p27 protein degradation activity via the proteasome pathway. Correlation of MCL p53 and p27 expression with clinical data showed an association between reduced overall survival rates and the overexpression of p53 (P = .001), the loss of p27 (P = .002), or both. Loss of p27 identified patients with a worse clinical outcome among p53 negative cases (P = .002). These findings demonstrated that MCL has a distinct cell cycle protein expression similar to that of high-grade lymphoma. The loss of p27 and the overexpression of p53 in MCL are prognostic markers that identify patients at high risk. The demonstration that low levels of p27 in MCL result from enhanced proteasome-mediated degradation should encourage additional clinical trials. (Blood. 2000;95:619-626)

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Abnormal serum free light chain ratio predicts poor overall survival in mantle cell lymphoma

British Journal of Haematology ◽

10.1111/bjh.12094 ◽

2012 ◽

Vol 160 (1) ◽

pp. 63-69 ◽

Cited By ~ 9

Author(s):

Michelle Furtado ◽

Nimish Shah ◽

Alison Levoguer ◽

Stephen Harding ◽

Simon Rule

Keyword(s):

Overall Survival ◽

Mantle Cell Lymphoma ◽

Light Chain ◽

Cell Lymphoma ◽

Free Light Chain ◽

Poor Overall Survival ◽

Serum Free ◽

Serum Free Light Chain ◽

Mantle Cell

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Activity of Bendamustine (TREANDA™) in Chronic Lymphocytic Leukemia and Mantle Cell Lymphoma Cells with Alterations in DNA Damage Response Pathway.

Blood ◽

10.1182/blood.v108.11.2510.2510 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2510-2510

Author(s):

Gaël Roué ◽

Mónica López-Guerra ◽

Pierre Milpied ◽

Patricia Pérez-Galán ◽

Neus Villamor ◽

...

Keyword(s):

Cell Death ◽

Chronic Lymphocytic Leukemia ◽

Mantle Cell Lymphoma ◽

Tumor Cells ◽

Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Low Grade ◽

Mantle Cell ◽

P53 Status

Abstract Mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) are two different types of mature B-cell non-Hodgkin’s lymphoma (NHL). CLL has an indolent natural history and patients are very responsive to frontline chemotherapy. Unfortunately, multiple relapses are inevitable, and ultimately, no regimen or treatment strategy offers a distinct survival benefit over another. In contrast, patients with MCL generally experience a more aggressive course, with rapid disease progression and also without specific therapeutic options. Bendamustine hydrochloride (Treanda™) is a multifunctional, alkylating agent that exhibits single-agent activity in multiple hematologic and solid tumors. Recently, the combination of bendamustine with rituximab has demonstrated to be a highly active regimen in the treatment of low-grade lymphomas and MCL. However, very little is known about its mode of action. The ability of bendamustine to induce apoptosis in vitro in MCL and CLL cells and the mechanisms implicated in bendamustine-evoked cell death signaling were investigated. Bendamustine exerted cytostatic and cytotoxic effects in 11 MCL cell lines and primary tumor cells from 7 MCL patients and 10 CLL patients independent of their p53 status, and other gene alterations. In vitro treatment of cells with bendamustine induced activation of both p53-dependent and -independent signaling pathways that converged in all cases to the activation of the pro-apoptotic protein Noxa, conformational changes of Bax and Bak, and mitochondrial depolarization. These events led to cytosolic release of the mitochondrial apoptogenic factors cytochrome c, Smac/DIABLO and AIF, and activation of both caspase -dependent and -independent cell death. Genotoxic stress and caspase-independent cell death are often associated with the generation of reactive oxygen species (ROS). We observed that ROS production was a key step in the induction of apoptosis by bendamustine, since pre-incubation of tumor cells with ROS scavengers reverted all the typical hallmarks of apoptosis. Furthermore, bendamustine exerted a cytotoxic effect in p53 deleted CLL cases that were resistant to fludarabine treatment. These findings support the use of bendamustine as a therapeutic agent in MCL and CLL cells and also establish the basis for the use of bendamustine in lymphoid malignancies that show resistance to classic genotoxic agents that depend on cellular p53 status.

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High Complete Response Rates with Dose Dense/Dose Intense Chemotherapy Plus Radioimmunotherapy in High Risk Diffuse Large B Cell and Mantle Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.2681.2681 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2681-2681 ◽

Cited By ~ 1

Author(s):

Anne W Beaven ◽

David A. Rizzieri ◽

Zachary Powell ◽

Zhiguo Li ◽

Peggy Alton ◽

...

Keyword(s):

High Risk ◽

B Cell ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Complete Response ◽

Mantle Cell ◽

Dose Dense ◽

Large B Cell

Abstract Abstract 2681 Background: Despite recent advances, the 5 year overall survival for patients with high risk diffuse large B cell lymphoma (DLBCL) is approximately 50% and there is still no known cure for patients with mantle cell lymphoma (MCL). This phase II study of multimodal dose dense therapy evaluated 2 courses of dose intense chemotherapy followed by radioimmunotherapy (RIT) consolidation in patients with previously untreated, mantle cell or high/high intermediate (int) risk aggressive B cell lymphoma. Aim: To evaluate the efficacy and safety of dose intense/dose dense, multimodal chemo-immunotherapy combined with RIT. Methods: Patients with untreated MCL or high int/high risk DLBCL were enrolled. Treatment regimen involved 3 phases of therapy: induction 1, induction 2 and consolidation with RIT (Table 1). Induction 2 occurred approximately 5 weeks after induction 1 and RIT was given 12–24 weeks after rituximab was completed. Patients were evaluated after each treatment phase and those with stable disease (SD) or better and blood count recovery could proceed to the next phase of therapy. Results: Thirty nine patients (pts) with high/high int risk DLBCL (n=25) or MCL (n=14) were enrolled. The median age was 60 years (range 21–80). Toxicity: Common, anticipated toxicities in the induction phases were thrombocytopenia, neutropenia, nausea, fatigue, and anemia. During Ind1 (n=39), grade (gr) III mucositis occurred in 13 pts (33%) and febrile neutropenia (FN) in 31 (79%). Three pts did not proceed to Ind2 due to death (1 candidemia, 1 septic knee prosthesis, 1 from complications of colectomy for prolonged diverticulitis after count recovery) and 2 withdrew to pursue less intense chemotherapy. During Ind2 (n=34) gr III mucositis occurred in 12pts (35%) and FN in 24 (67%). Two pts had gr III/IV cerebellar toxicity that was disabling in 1 pt. Of the 34 pts who received the Ind2, 9 did not receive RIT due to progressive disease (PD) (4), prolonged cytopenias (4), or diagnosis of pancreatic cancer (1). Twenty five pts received RIT and 3 (12%) had FN, 20 (80%) had gr III/IV neutropenia, 23 (92%) had gr III/IV thrombocytopenia, 1 pt died from bacteremia. Two pts developed myelodysplasia 21 and 48 months after starting therapy. Response: Pts were evaluated for response after Ind1, Ind2 and RIT. 38/39 pts were evaluable for response, with 1 pt withdrawing prior to assessment. The pts who died prior to response evaluation were counted as non-responders. The best overall response rate (ORR) was 95% (36/38) with a complete response rate (CR) of 84% (32/38). See tables 2 and 3 for more detailed response data by phase of treatment and disease type. After a median follow up of 17.2 months, 30 pts (77%) are alive (see figure). The median overall survival for MCL has not been reached and is 36.5 months for DLBCL. Deaths were from Hodgkin lymphoma (1), infection (3), DLBCL (2), complications of surgery (1), MCL (2). The median progression free survival is 36.5 months with 11/14 (79%) MCL and 14/25 (56%) DLBCL pts alive and in continued CR. Conclusion: The combination of dose dense, dose intense chemotherapy, monoclonal antibody, and RIT demonstrates considerable efficacy, despite expected toxicity, in high risk DLBCL and MCL pts. The response rates seen in this study are higher than expected from standard R-CHOP in this pt population. Further follow up to determine impact on OS and long term complications will be required to confirm these promising outcomes. Disclosures: Beaven: Glaxo Smith Kline: Family Member Employed by GSK. Off Label Use: Tositumomab is approved for use in relapsed/refractory low grade CD20 positive NHL. It is not FDA approved for first line use in diffuse large B cell lymphoma or mantle cell lymphoma. Neither cytarabine nor etoposide are approved for use in non-Hodgkin lymphoma. Rizzieri:Glaxo Smith Kline: Speakers Bureau. Moore:Glaxo Smith Kline: Speakers Bureau.

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The clinical outcome of 65 cases of mantle cell lymphoma initially treated with non-intensive therapy by the British National Lymphoma Investigation Group

British Journal of Haematology ◽

10.1046/j.1365-2141.1997.4693273.x ◽

1997 ◽

Vol 99 (4) ◽

pp. 842-847 ◽

Cited By ~ 51

Author(s):

E. Vandenberghe ◽

C. De Wolf-Peeters ◽

G. Vaughan Hudson ◽

B. Vaughan Hudson ◽

S. Pittaluga ◽

...

Keyword(s):

Clinical Outcome ◽

Mantle Cell Lymphoma ◽

Cell Lymphoma ◽

Intensive Therapy ◽

Mantle Cell

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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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