Survival In Mantle Cell Lymphoma Research Articles

Gene knockdown studies revealed CCDC50 as a candidate gene in mantle cell lymphoma and chronic lymphocytic leukemia

The two B-cell non-Hodgkin's lymphoma entities, chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), show recurrent chromosomal gains of 3q25-q29, 12q13-q14 and 18q21-q22. The pathomechanisms affected by these aberrations are not understood. The aim of this study was to identify genes, located within these gained regions, which control cell death and cell survival of MCL and CLL cancer cells. Blood samples collected from 18 patients with CLL and 6 patients with MCL, as well as 6 cell lines representing both malignancies were analyzed by gene expression profiling. By a comparison of genomic DNA and gene expression, 72 candidate genes were identified. We performed a limited RNA interference screening with these candidates to identify genes affecting cell survival. CCDC50 (coiled coil domain containing protein 50), SERPINI2 and SMARCC2 mediated a reduction of cell viability in primary CLL cells as well as in cell lines. Gene knockdown and a nuclear factor kappa B (NFkappaB) reporter gene assay revealed that CCDC50 is required for survival in MCL and CLL cells and controls NFkappaB signaling.

Mature results of the M. D. Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma

AbstractIn this study, we analyzed the long-term outcome of a risk-adapted transplantation strategy for mantle cell lymphoma in 121 patients enrolled in sequential transplantation protocols. Notable developments over the 17-year study period were the addition of rituximab to chemotherapy and preparative regimens and the advent of nonmyeloablative allogeneic stem cell transplantation (NST). In the autologous transplantation group (n = 86), rituximab resulted in a marked improvement in progression-free survival for patients who received a transplant in their first remission (where a plateau emerged at 3-8 years) but did not change the outcomes for patients who received a transplant beyond their first remission. In the NST group, composed entirely of patients who received a transplant beyond their first remission, durable remissions also emerged in progression-free survival at 5 to 9 years. The major determinants of disease control after NST were the use of a peripheral blood stem cell graft and donor chimerism of at least 95%, whereas the major determinant of death was immunosuppression for chronic graft-versus-host disease. Our results show that long-term disease-free survival in mantle cell lymphoma is possible after rituximab-containing autologous transplantation for patients in first remission and after NST for patients with relapsed or refractory disease.

Patterns of Chemotherapy/Immunotherapy and Survival in Mantle Cell Lymphoma: Evidence from SEER-Medicare

Introduction: Mantle cell lymphoma (MCL) is a relatively rare form of non-Hodgkin's lymphoma (NHL) comprising approximately 6% of all new NHL cases.Methods: Using the National Cancer Institute's SEER registry linked to Medicare claims, we identified 503 patients with MCL (histology code 9673) as their first malignancy between January 1, 1999 and December 31, 2002. Patients were followed until the development of a second primary cancer, transition to an HMO, the end of their claims history (December 31, 2005), or death. Medicare claims were used to identify and classify chemotherapy and/or immunotherapy (C/I) regimens as well as to identify radiation therapy. The initial C/I treatment approach (no treatment, chemotherapy only, and immunotherapy with or without chemotherapy) was based on the first 90 days after diagnosis. The specific regimen was identified using the 30 day period after the initial C/I administration. Multivariate Cox proportional hazards analyses were performed to identify patient socio-demographic and clinical factors associated both with time to treatment initiation and with survival. Potential risk factors in the models included age, gender, race, stage, comorbidity burden*, year of diagnosis, education, rural/urban status, poverty indicators, nodal involvement, anemia*, neutropenia*, and thrombocytopenia* (*=based on diagnosis codes).Results: Median age was 76 years, 65% were male, 11% were non-white, and 57% were diagnosed with Stage IV disease. Overall, 81% (n=405) received C/I of whom 30% (n=123) received radiation at any time during follow up. The median time to first C/I was 51 (95% CI 46–56) days. Among patients receiving C/I, 138 received rituximab with or without CHOP or CVP, 101 received either CHOP or CVP alone, 96 could not be clearly classified into these groups, and 70 did not have identifiable C/I agents in the data (only administration codes were present). In multivariate analysis of time to initiating C/I, patients age ≥ 80 years were 46% less likely to initiate C/I (compared to age 66–70), those with advanced disease (Stage III or IV) were 41% (Stage III) or 59% (Stage IV) more likely to initiate C/I (compared to Stage I), and those with anemia were 49% more likely to initiate C/I (p<0.05 for all). Unadjusted median survival for the cohort was 29 (95% CI 26–31) months. Unadjusted median survival was 20 (95% CI 12–30) months in patients untreated with either chemo- or immunotherapy, 28 (95% CI 24–31) months in patients treated with chemotherapy only, and 33 (95% CI 28–39) months in patients treated with immunotherapy (with or without chemotherapy). In multivariate survival analysis, compared to no C/I treatment, immunotherapy with or without chemotherapy was associated with 44% lower risk of death (95% CI 23% to 60%), while chemotherapy alone was not significantly different. Other factors significantly associated with mortality included increasing age, increasing stage, and diagnosis of anemia.Conclusion: Findings indicate the majority of patients in this elderly population received C/I within the first 2 months following diagnosis. Immunotherapy, but not chemotherapy alone, was associated with improved survival. However, because these are observational data, even with extensive adjustment, the possibility of residual confounding should be kept in mind.

Indolent Mantle Cell Lymphoma (MCL): A Retrospective Detailed Clinical and Morphological Analysis of 21 Patients, with Histological, Cytological, Cytogenetic, Interphase Genetic, Immunoglobulin Gene, and Gene Expression Profiling Analysis.

MCL is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 and with a genetic hallmark, the t(11;14) (q13;q32) translocation leading to the overexpression of cyclin D1, considered as the initial oncogenic event. However this entity may show a spectrum of morphological features broader than initially described. Clinically most of the patients have a poor prognosis with a rapid acquisition of chemoresistance. It has been recently described that some patients may follow an indolent clinical evolution, with the possibility of confusion in diagnosis because of overlapping morphological features with other small B cell lymphomas such as marginal zone lymphoma (MZL) and small lymphocytic lymphoma (SLL). The aim of our study was to analyze patients treated for a B cell lymphoma bearing the t(11;14)(q13;q32) who had a good outcome with a long survival. We retrospectively selected 21 patients (pts) with a t(11;14) B cell lymphoma and who followed an indolent outcome defined by an overall survival of more than 5 years after no more than 1 therapeutic regimen. Feature review included morphologic aspect, immunophenotype, cytogenetics, immunoglobulin (Ig) variable heavy chain (VH) gene usage and mutation patterns. Expression of CD5, CD10, CD23, and CD43, were evaluated on CD19+ cells by FCM. Cytogenetic analysis consisted in conventional cytogenetics on fresh tissue samples completed by a FISH analysis against 11q, 12p, 17p, and 18p realized on fresh frozen material. We further analysed the gene expression profiling of available samples using quantitative real-time PCR using microfluidic cards designed with selected genes of 3 independent signatures (Rosenwald A, et al. Cancer Cell 2003 - Ruiz-Ballesteros E, et al. Blood 2005 - Thieblemont C, et al. Blood 2004). Clinical characteristics showed that median age was 61 (range 45–81). All pts had a good PS and presented with a disseminated disease: bone marrow and blood involvement in 19 (90%) and 11/17 (65%) pts, respectively; peripheral and profound nodes involvement in 15 (71%); and splenomegaly in 13 (62%). LDH and b2-microglobulin levels were elevated in 4 pts. None of the pts had a monoclonal component. IPI score was low in 18 (86%) pts. Splenectomy alone or with chemotherapy (chlorambucil or fludarabine in 4; CHOP in 1) was proposed in 7 pts; monochemotherapy (chlorambucil or fludarabine) in 4 pts, CHOP +/− rituximab (R) in 2 pts, CHOP +/− R followed by autotransplant in 8. One pt did not receive any treatment. With a median follow-up at 6.44 years, median overall survival was 9.18 years. Morphologic review distinguished 2 groups of cases: true MCL cases (MCL, n = 8) and BorderLine Cases (BLC, n=13). Among the 8 MCL and 13 BCL, 7 and 12 were CD5+, 1 and 4 CD5/CD23+, 4 and 5 CD43+, respectively. All cases exhibited a t(11;14), associated with a complex caryotype in 5/8 (62%) MCL and in 9/13 (69%) BLC. Chromosome 7q deletion (n=1) and trisomy chr3/3q (n=3) were present only in BLC cases. IgVH gene was unmutated in 10 cases (3 MCL, 7 BLC) and mutated in 4 (2 MCL, 2 BLC). The most common VH families were VH1 (n=4), VH 3 (n=8) and VH4 (n=3). From the gene expression profiling studies we selected 70 genes specific of the diagnosis of MCL, MZL and SLL. A set of 5 MCL, 5 SLL, and 5 MZL control samples allowed us to validate 25 out of these 70 genes. These 25 genes were further used to analyse MCL and BLC samples. All these samples exhibited a more heterogeneous profile than control samples. Three MCL were more similar to MCL samples, whereas two were closer to MZL samples. All the BLC exhibited a profile close to that of MZL. We further analysed these samples with the 18 gene-signature predicting MCL survival. This signature could not discriminate survival of these MCL and BCL pts. In conclusion, pts with B cell lymphoma bearing the translocation t(11;14)(q13;q32) and with an indolent outcome can be distinguished in at least 2 groups with different characteristics in terms of morphology, immunophenotype, caryotype, and molecular profiles. Using a 25 gene-signature, we found profiles similar to either MCL or MZL for MCL samples, and similar to MZL for BCL samples. The signature discriminating the survival of MCL could not discriminate these indolent MCL. These findings will be validated on a larger series.

Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group

AbstractMantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

Five-Gene Model to Predict Survival in Mantle-Cell Lymphoma Using Frozen or Formalin-Fixed, Paraffin-Embedded Tissue

Despite the common underlying translocation t(11;14) involving cyclin D1 that is present in nearly all cases of mantle-cell lymphoma (MCL), the clinical course of the disease is highly variable. The aim of the present study was to develop a quantitative gene expression-based model to predict survival in newly diagnosed patients with MCL that involves a minimum number of genes and is applicable to fresh-frozen and formalin-fixed, paraffin-embedded (FFPE) tumor samples. The expression of 33 genes with potential prognostic and pathogenetic impact in MCL was analyzed using quantitative reverse-transcription polymerase chain reactions (qRT-PCR) in a low-density array format in frozen tumor samples from 73 patients with MCL. Multivariate Cox methods and stepwise algorithms were applied to build gene expression-based survival predictors. An optimized five-gene model was subsequently applied to FFPE tumor samples from 13 patients with MCL from the initial series and to 42 independent MCL samples. The optimized survival predictor was composed of the five genes RAN, MYC, TNFRSF10B, POLE2, and SLC29A2 and was validated for application in FFPE tissue samples. It allowed the survival prediction of patients with MCL with widely disparate clinical outcome and was superior to the immunohistochemical marker Ki-67, an established prognostic factor in MCL. We here present a validated qRT-PCR-based test for survival prediction in patients with MCL that is applicable to fresh frozen as well as to FFPE tissue specimens. This test may prove useful to guide individualized treatment approaches for patients with MCL.

PIK3CA as a molecular target in mantle cell lymphoma

8612 Background: We sought to determine the contribution of PIK3CA gene alterations to the pathogenesis of mantle cell lymphoma (MCL). PIK3CA is known to be involved in the PI 3-kinase/AKT signaling pathway, which is activated in MCL. Methods: We analysed 35 primary MCL cases (14 frozen and 21 paraffin-embedded specimens) and 2 MCL cell lines (Granta, REC1). To search for PIK3CA mutations, we isolated genomic DNA from primary MCL cases and MCL cell lines and performed direct sequencing of the exons 9 and 20 of PIK3CA. We used real-time quantitative PCR to investigate genomic amplification of the PIK3CA gene. We also analyzed PTEN and phoshorylated Akt protein levels in primary cases and cell lines using western blotting and immunohistochemistry (IHC). Flow cytometry analysis was used to assess apoptosis after treatment of MCL cell lines and the Raji Burkitt lymphoma cell line with LY294002, a specific inhibitor of PI3KCA. Results: We found that 14 of 23 (58%) primary MCL cases with amplifiable β- globin and two of two cell lines harboured a gain (>3) of PIK3CA gene copy number. PIK3CA gene mutations were not identified. In addition, amplification of PIK3CA correlated with the status of Akt phosphorylation in 7 of 12 (58%) primary MCL cases and the two MCL cell lines. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by western blotting whereas five of 33 (15%) cases tested by IHC had loss of PTEN protein expression. Only one of the 5 MCL cases with loss of PTEN expression harboured gain of PIK3CA gene copy number. Therefore, PI3KCA gene amplification and PTEN loss were nearly mutually exclusive. Conclusions: We conclude that PIK3CA is an oncogene in MCL and PIK3CA amplification may be linked to pathogenesis and survival in MCL. No significant financial relationships to disclose.

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

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.

Host Genetic Variation in the Cell Cycle and NF-κB Pathways and Overall Survival in Mantle Cell Lymphoma.

Background: Mantle cell lymphoma (MCL) is an incurable non-Hodgkin lymphoma. MCL is characterized by the chromosomal translocation t(11;14) leading to overexpression of cyclin D1 (CCND1), a regulator of the cell cycle. NF-κB plays a central role in key cellular processes, including cell cycle regulation and apoptosis, and it has been shown to be constitutively activated in MCL cell lines and in patient biopsy samples and to play a key role in the growth and survival of MCL cells. In an exploratory study, we evaluated the hypothesis that germline variation in candidate genes from the cell cycle and NF-κB pathways predict overall survival in MCL.Methods: We genotyped 235 SNPs from 29 cell cycle genes and 447 SNPs from 55 NF-κB genes in 39 MCL patients aged 38–64 years who participated in a population-based study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles county. Tagging single nucleotide polymorphisms (SNPs) were selected from HapMap. Stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site. To assess the statistical significance of a gene, we first used principal components analysis to capture the genetic variation of the SNPs within a gene. Cox proportional hazards analysis was then used to assess the association between the top principal components from a gene with overall survival.Results: Through early 2005, there were 22 deaths in 39 patients (56%). The median follow-up of the 17 surviving patients was 56 months (range 36–70). Eleven of the 55 genes (TNFSF14 p=0.0007, NF-κBIA p=0.003, IL1R2 p=0.01, TNFRSF25 p=0.02, TNFSF13B p=0.02, FAS p=0.03, TLR2 p=0.04, TNFSF10D p=0.04, TNFSF10 p=0.06, MAP3K2 p=0.06) in the NF-κB pathway were associated with overall survival. In the cell cycle pathway, only 3 of the 29 genes (CASP5 p=0.06, CASP9 p=0.09, BCL2 p=0.09) were associated with overall survival, and a previously reported SNP in CCND1 (rs603965) showed no association (p=0.5). Permutation p-values for observing at least this number of associated tests in each pathway due to chance (from multiple testing) was p=0.8 for the cell cycle pathway and p=0.03 for NF-κB pathway. The small sample size precluded multi-gene modeling.Conclusion: In a population series of MCL patients, we found suggestive evidence that host genetic variation in candidate NF-κB pathway genes affects overall survival. These results complement tumor expression data implicating this pathway in the pathogenesis of MCL. In addition, such findings further support the value of developing therapeutic targets from this pathway.

P150 Expression of ZAP-70, RAF-1 and C-MYC in B-cell lymphomas and chronic leukaemia. Overexpression of ZAP70 predicts poor survival in mantle cell lymphoma

P150 Expression of ZAP-70, RAF-1 and C-MYC in B-cell lymphomas and chronic leukaemia. Overexpression of ZAP70 predicts poor survival in mantle cell lymphoma

Increased MDM2 expression is associated with inferior survival in mantle cell lymphoma, but not related to the MDM2 SNP309

We here show that increased expression of MDM2, a negative regulator of p53, correlates with inferior survival in a series of 43 mantle cell lymphomas. MDM2 overexpression is associated with copy number gains of the MDM2 locus in single tumors, but not with the recently reported MDM2 promoter SNP309.

Activation of Mammalian Target of Rapamycin Signaling Promotes Cell Cycle Progression and Protects Cells from Apoptosis in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

Frontline High Dose Sequential Chemotherapy with Rituximab (R-HDS) and Autologous Stem Cell Transplantation Induces High Rates of Complete Response and Prolongs Survival in Mantle Cell Lymphoma (MCL).

We showed recently that the dismal outcome of MCL might be improved in 28 young patients (pts) (<61 years) by an up-front Rituximab supplemented high-dose sequential chemotherapy (R-HDS) supported by stem cell autograft (ASCT) (A.M. Gianni et al, Blood, 2003). Following this encouraging experience we treated other 26 pts aged<61 years with standard R-HDS and 19 aged >60 years with an age-adapted R-HDS. We report the outcome of 54 young pts (group 1), including the first 28 cases and that of 19 elderly pts (group 2). The majority of both groups had an advanced stage and bone marrow infiltration, while in elderly pts prevail B symptoms and > 1 extranodal site. One third of cases had >2 adverse prognostic features according to IPI. After 2–3 cycles of either doxorubicin- or cisplatin-containing chemotherapy, group 1 received standard R-HDS including: HD-cyclophosphamide (CTX) 7 gr/sqm and HD-Ara-C (2 g/sqm every 12 hours for 6 days). Following HDS chemotherapy a conditioning program with HD-melphalan (180 mg/sqm) and/or HD-mitoxantrone plus melphalan (60 and 180 mg/sqm) with ASCT was planned. Rituximab (375 mg /sqm) was given for a total of 6 doses, twice after HD-CTX and HD-Ara-C, as in vivo purging before CD34+ cells harvest and twice after ASCT. Elderly patients received an age-adapted R-HDS: HD-CTX (3–4 gr/sqm) and HD-Ara-C (1–1.5 g/sqm every 12 hours for 3–5 days), followed by HD-melphalan (120 mg/sqm) and HD-mitoxantrone plus melphalan (40 and 120 mg/sqm). 35 pts (65%) in group 1 and 9 (47%) in group 2 completed the planned program and a median number of 7.6 and 6.8 x 10^6 cells CD34+/kg were transplanted. After ASCT the CR rate was 88% in young and 95% in elderly patients. One young pt (2%) died during treatment, 1 developed sMDS and 5 died of late toxicity including a case of lung carcinoma. Among elderly pts only one died tardily because of cardiac disease. With a median follow-up of 48 months (range 8–101) in group 1 and 25 months (range 9–68) in group 2, the 5-year estimated OS, EFS and DFS were 77%, 60% and 71%, in group 1 and 55%, 53% and not yet achieved in group 2. The Cox multivariate analysis failed to identify within potential prognostic markers factors predictive for OS and EFS. We conclude that R-HDS is an effective regimen for the induction of complete remissions in pts with newly diagnosed MCL. The manageable toxicity of the program in elderly pts proved that an age-adjusted R-HDS regimen can be safely applied to this age subgroup still producing long-term remissions.

Improvement of Overall Survival in Mantle Cell Lymphoma during the Last Decades.

Purpose: Mantle cell lymphomas (MCL) represent a lymphoma subtype with an especially poor long term prognosis. Although various therapy strategies have been applied within the last 30 years, MCL is still considered incurable by conventional chemotherapy.Patients and methods: To determine whether patient outcome has improved during the last decades, we compared data from the “Kiel lymphoma group” (KLG) collected in the years 1975–1986 with data from the “German lymphoma study group” (GLSG) of the years 1996–2004. To minimize potential heterogeneity of risk profiles of the two patient populations, frequency matching was pursued. Additionally, the effects of other potential prognostic parameters were adjusted by a Cox proportional hazard model.Results: A total of 520 patients were evaluable for analysis. The median overall survival significantly increased from 2.7 years up to 4.8 years (p<0.0001; hazard ratio (HR) 0.44) and 5-year-survival of advanced MCL more than doubled from 22% [95% CI, 13% to 31%] to 47% [95% CI, 38% to 55%]. Multivariate analysis identified a poor performance status (HR 2.26), a high LDH level (HR 1.75), and age (HR 1.38) as additional prognostic variables.Conclusion: Patients with advanced MCL benefit from the progress of medical treatment resulting in almost doubling of overall survival during the last 3 decades, even though relapses are regularly observed.

Constitutive activation of Akt contributes to the pathogenesis and survival of mantle cell lymphoma

To determine whether the PI3K/Akt signaling pathway is involved in the pathogenesis of mantle cell lymphoma (MCL), we investigated the phosphorylation status of Akt and multiple downstream targets in primary MCL cases and cell lines. Akt was phosphorylated in 12 of 12 aggressive blastoid MCL variants and in 4 of 4 MCL cell lines. In contrast, phosphorylated Akt was present in only 5 of 16 typical MCL, 3 at comparable levels to the blastoid cases, and 2 at low levels. The presence of p-Akt was accompanied by the phosphorylation of p27(kip1), FRKHL-1, MDM2, Bad, mTOR, and p70S6K. Inhibition of the PI3K/Akt pathway in the MCL cell lines abrogated or reduced the phosphorylation of Akt, p27(kip1), FRKHL-1, MDM2, Bad, mTOR, GSK-3beta, IkappaB, and led to cell-cycle arrest and apoptosis. Six MCL cases (5 with activated Akt and 1 with inactive Akt) and 3 of 4 cell lines showed loss of PTEN expression. PIK3CA mutations were not detected. We conclude that constitutive activation of the PI3K/Akt pathway contributes to the pathogenesis of MCL and preferentially occurs in blastoid variants. One possible mechanism of activation is loss of PTEN expression. These data suggest that PI3K/Akt inhibitors may be effective in the treatment of Akt-activated MCL.

Early lymphocyte recovery after autologous stem cell transplantation predicts superior survival in mantle-cell lymphoma

Autologous stem cell transplantation (ASCT) is an effective treatment strategy for mantle-cell lymphoma (MCL) demonstrating significantly prolonged progression-free survival (PFS) when compared to interferon-alpha maintenance therapy of patients in first remission. The study of absolute lymphocyte count at day 15 (ALC-15) after ASCT as a prognostic factor in non-Hodgkin lymphoma (NHL) included different lymphoma subtypes. The relationship of ALC-15 after ASCT in MCL has not been specifically addressed. We evaluated the impact of ALC-15 recovery on survival of MCL patients undergoing ASCT. We studied 42 consecutive MCL patients who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. ALC-15 threshold was set at 500 cells/microl. The median follow-up after ASCT was 25 months (range, 2-106 months). The median overall survival (OS) and PFS times were significantly better for the 24 patients who achieved an ALC-15 >or=500 cells/microl compared with 18 patients with ALC-15 <500 cells/microl (not reached vs 30 months, P<0.01 and not reached vs 16 months, P<0.0006, respectively). Multivariate analysis demonstrated ALC-15 to be an independent prognostic factor for OS and PFS. The ALC-15 >or=500 cells/microl is associated with a significantly improved clinical outcome following ASCT in MCL.

Maintenance rituximab following induction chemoimmunotherapy may prolong progression-free survival in mantle cell lymphoma: a pilot study from the Wisconsin Oncology Network

There is no standard first line treatment for mantle cell lymphoma. This was a multicenter phase II pilot study of rituximab and modified hyper-fractionated cyclophosphamide, vincristine doxorubicin, dexamethasone (modified R-hyperCVAD) administered every 28 days for four to six cycles followed by rituximab maintenance therapy consisting of four weekly doses every 6 months for 2 years. Unlike traditional hyperCVAD regimens, no methotrexate or cytarabine was administered. Of 22 patients, the overall response rate was 77% and the complete response rate was 64%. With a median follow-up time of 37 months in surviving patients, the median PFS was 37 months and the median OS was not reached. The achievement of a molecular remission did not correlate with improved outcome. The major toxicity was expected myelosuppression. Two patients died during induction treatment. There were no major adverse effects during maintenance therapy. In a multicenter trial, modified R-hyperCVAD was tolerable and effective induction therapy for untreated MCL. Maintenance rituximab appeared to prolong PFS without increasing toxicity.

Caspase 3 Expression in Mantle Cell Lymphoma: An Immunohistochemical Study of 84 Patients.

Mantle cell lymphoma (MCL) is a malignant lymphoma associated with a relatively aggressive clinical course and a median overall survival time of 3–4 years. We investigated immunohistochemically the expression of the apoptotic marker caspase 3 in relation to the clinical course. Biopsy specimen from 84 untreated patients enrolled in two multicenter prospective trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, Caspase3. The Caspase3 expression was analyzed in three groups: less than 1 positive cell per high power field (HPF), more than 1 positive cell per HPF and more than 2 positive cells per HPF. The expression was compared with the overall survival data analysed according to Kaplan and Meier. In 75 cases the caspase 3 staining could be analyzed. The caspase 3 expression had a range of 0.1–4.7 positive cells per HPF (median value:1.1, mean:1.3). Patients with mantle cell lymphoma that had less than 1 caspase 3 positive cell per HPF (33 cases) had a median overall survival time of 48 months compared to 27 months for patients with more than 1 positive cell per HPF (24 cases) and 15 months for more than 2 positive cells per HPF (18). The Kaplan-Meier analysis showed a significant difference in the overall survival time between these groups (p<0.0001). The immunohistochemical detection of caspase 3 in mantle cell lymphoma is a predictor for survival in MCL.

Early Lymphocyte Recovery after Autologous Stem Cell Transplantation Predicts Superior Survival in Mantle Cell Lymphoma.

Mantle-cell lymphoma (MCL) is characterized by an aggressive clinical course and poor prognosis with a median survival of only 3 to 4 years. High dose chemotherapy followed by autologous stem cell transplantation (ASCT) is an effective treatment strategy for MCL demonstrating significantly prolongs progression free survival (PFS) when compared to IFNa maintenance therapy of patients in first remission. We have previously shown that absolute lymphocyte count at day 15 (ALC-15) after ASCT is an independent prognostic factor for survival in hematologic malignancies (non-Hodgkin's lymphoma (NHL), Hodgkin's disease, multiple myeloma, primary amyloidosis, acute myelogenous leukemia) and breast cancer. The study of ALC-15 after ASCT as a prognosis factor in NHL included different subtypes of lymphomas. The relationship of ALC-15 after ASCT in patients with MCL has not been specifically addressed. Herein we present data evaluating the impact of early lymphocyte recovery (ALC-15) in patients undergoing ASCT for MCL. We retrospectively reviewed the medical records of 42 consecutive patients (9 females and 33 males) with MCL who underwent ASCT at the Mayo Clinic in Rochester from 1993 to 2005. Based on our previous studies, the ALC-15 threshold was set at 500 cells/μL. The median patient age at transplant was 57 years (range, 37–71) and the median follow-up after ASCT was 25 months (range, 2–106 months). The median overall (OS) and PFS times were significantly better for the 24 patients that achieved an ALC-15 ≥ 500 cells/mL compared with 18 patients with ALC-15 < 500 cells/μL (not reached versus 30 months, P < 0.01 and not reached versus 16 months, P < 0.0006, respectively). Multivariate analysis adjusting for other prognostic factors suggests that ALC-15 is an independent prognostic factor for OS and PFS. ALC-15 ≥ 500 cells/mL is associated with significantly improved clinical outcomes following ASCT in patients with MCL.

Minichromosome maintenance protein 6, a proliferation marker superior to Ki-67 and independent predictor of survival in patients with mantle cell lymphoma

Minichromosome maintenance protein 6 (MCM6) is one of six proteins of the MCM family which are involved in the initiation of DNA replication and thus represent a marker of proliferating cells. Since the level of cell proliferation is the most valuable predictor of survival in mantle cell lymphoma (MCL), we investigated lymph node biopsy specimens from 70 patients immunohistochemically with a monoclonal antibody against MCM6. The percentage of MCM6 expressing lymphoma cells ranged from 12.0 to 95.6%, with a mean of 61.0%, and was significantly higher than the percentage of Ki-67-positive cells (P<0.0001). Surprisingly, the ratio of MCM6-positive cells to Ki-67-positive cells was higher than in normal stimulated peripheral blood mononuclear cells, indicating a cell early G1-phase arrest in MCL. A high MCM6 expression level of more than 75% positive cells was associated with a significantly shorter overall survival time (16 months) compared to MCL with a low MCM6 expression level of less than 25% (no median reached, P<0.0001). Multivariate analysis revealed MCM6 to be an independent predictor of survival that is superior to the international prognostic factor and the Ki-67 index. Therefore, aside from gene expression profiling, immunohistochemical detection of MCM6 seems to be the most promising marker for predicting the outcome in MCL.