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Mantle cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphomas (NHL) characterized in almost all cases by the chromosomal translocation t(11;14)(q13;q32) and nuclear cyclin D1 overexpression. Most patients present with advanced stage disease, often with extranodal dissemination, and typically pursue an aggressive clinical course. Recent improvement has been achieved by the successful introduction of monoclonal antibodies and dose-intensified approaches including autologous stem cell transplantation strategies. However, with the exception of allogeneic hematopoietic stem cell transplantation, current treatment approaches are not curative and the corresponding survival curve is characterized by a relatively steep and continuous decline, with a median survival of about 4 years and <15% long-term survivors. Despite its rarity, MCL is of particular clinical and scientific interest by providing a paradigm for neoplasms with dysregulated control of cell cycle machinery and impaired apoptotic pathways. Recently gained insights into underlying pathobiology unravel numerous promising molecular targeting strategies, however their introduction into clinical practice and current treatment algorithms remains a challenge. This article will provide relevant information for decision making in clinical practice and give a perspective on upcoming management strategies. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma is a rare yet well defined subtype of B-cell non-Hodgkin's lymphoma. The correct histological diagnosis of this lymphoma subtype is of the utmost importance; however, it is also a very difficult diagnosis. Clinical management is often complex, and despite the successful introduction of monoclonal antibodies and dose-intensified regimens. including autologous and allogeneic stem cell transplantation strategies, the prognosis remains particularly poor. Recently gained insights into the underlying biology and pathogenesis have unravelled numerous promising molecular targeting strategies; however, their introduction into clinical practice and current treatment algorithms remains a challenge. This article addresses these issues providing relevant in Formation for current state-of-the-art management of patients with mantle cell lymphoma and giving a perspective of upcoming treatment strategies. [ABSTRACT FROM AUTHOR]

Rituximab, gemcitabine and oxaliplatin (R-GemOx) has demonstrated to be effective and safe in lymphoma patients. We aimed to determine the maximum tolerated dose (MTD) of oxaliplatin in combination with rituximab and gemcitabine and to explore the efficacy and safety of R-GemOx in relapsed or refractory (r/r) indolent and mantle cell lymphoma (MCL). In this single-arm, phase I/II trial, we enrolled 55 patients with r/r indolent lymphoma and MCL not suitable for autologous stem-cell transplantation. Patients received 4 cycles of R-GemOx. In the dose escalation group, 70 mg/m2 of oxaliplatin was applied and interindividually increased by 10 mg/m2 until the MTD was reached together with fixed doses of rituximab and gemcitabine. At the oxaliplatin MTD, an extension cohort was opened. Primary aim was to detect an overall response rate (ORR) greater than 65% (α = 0.05). Oxaliplatin 70 mg/m2 (MTD) was chosen for the extension cohort after 3 of 6 patients experienced a DLT at 80 mg/m2. Among 46 patients evaluable for the efficacy analysis ORR was 72% (33/46), missing the primary aim of the study (p = 0.21). After a median follow-up of 7.9 years, median PFS and OS were 1.0 and 2.1 years. Most frequent grade ≥ 3 adverse events were cytopenias. R-GemOx induces decent response rates in r/r indolent lymphoma and MCL, though novel targeted therapies have largely replaced chemotherapy in the relapse setting. Particularly in MCL, R-GemOx might be an alternative option in late relapses or as bridging to CAR-T-cells. This study was registered with ClinicalTrials.gov on Aug 4th, 2009, number NCT00954005. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a distinct subtype of B-cell lymphoma and commonly used induction immunochemotherapies include the anti-CD20 antibody rituximab. However, efficacy data for rituximab regarding overall survival (OS) in first line MCL therapy remain conflicting. We report long-term outcomes of a pooled trials analysis comparing Cyclophosphamide, Doxorubicine, Vincristine, Prednisone (CHOP) to R-CHOP in MCL to confirm efficacy on failure free survival (FFS) and OS in relevant subgroups. Untreated, adult MCL patients of two prospective trials assigned to CHOP or R-CHOP were included. Primary endpoints were FFS and OS, secondary endpoints included duration of response (DOR), secondary malignancies and OS after relapse. Between 1996 and 2003, 385 MCL patients were assigned to CHOP (201) or R-CHOP (184). After a median follow-up of 13.4 years, the addition of Rituximab significantly improved FFS (1.36 vs. 2.07 years, HR 0.62 (0.50–0.77)), OS (4.84 vs. 5.81 years, HR 0.78 (0.61–0.99)) and DOR (1.48 vs. 2.08 years, HR 0.67 (0.53–0.86)). Furthermore, Rituximab improved survival across different MCL risk groups. In a post-hoc analysis of OS after relapse comparing patients receiving chemotherapy with / without rituximab, rituximab maintained efficacy with a median OS of 3.10 vs. 2.11 years (HR 0.70, 0.54–0.91). The rate of secondary malignancies was 0.5 and 3.9% for hematological and 7 and 8% for non-hematological malignancies for CHOP and R-CHOP patients, respectively. We present mature results of a pooled MCL cohort, demonstrating prolonged FFS, OS and DOR for the combined immuno-chemotherapy, confirming the standard of care in first line treatment. [ABSTRACT FROM AUTHOR]

The impact of a FLT3-intemal tandem duplication (FLT3ITD) on prognosis of patients with acute myeloid leukemia (AML) is dependent on the ratio of mutated to wild-type allele. In 648 normal karyotype (NK) AML patients, we found a significant independent effect of the quantitative FLT3ITD mRNA level--measured as {FLT3\TDIwtFLT3)l{FLT3\JDIwtFLT3 + 1) --on outcome. Moreover, this effect was clearly seen in 329 patients with a mutated NPM1 gene {NPM1+), but not in 319 patients without a NPM1 mutation (wtWPMJ). In a multivariate Cox regression model, the quantitative FLT3YTD mRNA level showed an independent prognostic impact on overall survival (OS) and relapse-free survival (RFS) only in the NPM1+ subgroup (OS: hazard ratio, 5.9; [95% confidence interval [CI]: 3.1-11.2]; RFS: hazard ratio, 7.5 [95% CI: 3.4-16.5]). The FLT3\JD mRNA level contributes to relapse risk stratification and might help to guide postremission therapy in WPMï-mutated AML [ABSTRACT FROM AUTHOR]

Background: The optimal treatment of early stage follicular Lymphoma is a matter of debate. Radiation therapy has frequently been applied with a curative approach beside watchful waiting. Involved field, extended field and total nodal radiation techniques are used in various protocols, but the optimal radiation field still has to be defined. Follicular lymphoma is characterized by stable expression of the CD20 antigen on the tumour cells surface. The anti CD20 antibody Rituximab (Mabthera®) has shown to be effective in systemic therapy of FL in primary treatment, relapse and maintenance therapy. Methods/design: The MIR (Mabthera® and Involved field Radiation) study is a prospective multicenter trial combining systemic treatment with the anti CD20 antibody Rituximab (Mabthera®) in combination with involved field radiotherapy (30 - 40 Gy). This trial aims at testing the combination's efficacy and safety with an accrual of 85 patients. Primary endpoint of the study is progression free survival. Secondary endpoints are response rate to Rituximab, complete remission rate at week 18, relapse rate, relapse pattern, relapse free survival, overall survival, toxicity and quality of life. Discussion: The trial evaluates the efficacy of Rituximab to prevent out-filed recurrences in early stage nodal follicular lymphoma and the safety of the combination of Rituximab and involved field radiotherapy. It also might show additional risk factors for a later recurrence (e.g. remission state after Rituximab only). Trial Registration: ClinicalTrials (NCT): NCT00509184 [ABSTRACT FROM AUTHOR]

Summary: Mantle cell lymphoma (MCL) is still considered incurable and the course of the disease is highly variable. Established risk factors include the Mantle Cell Lymphoma International Prognostic Index (MIPI) and the quantification of the proliferation rate of the tumour cells, e.g. by Ki‐67 immunohistochemistry. In this study, we aimed to validate the prognostic value of the gene expression‐based MCL35 proliferation assay in patient cohorts from randomized trials of the European Mantle Cell Lymphoma Network. Using this assay, we analysed the gene expression proliferation signature in routine diagnostic lymph node specimens from MCL Younger and MCL Elderly trial patients, and the calculated MCL35 score was used to assign MCL patients to low (61%), standard (27%) or high (12%) risk groups with significantly different outcomes. We confirm here in our prospective clinical trial cohort of MCL patients, that the MCL35 assay is strongly prognostic, providing additional information to the Ki‐67 index and the MIPI. Thus, this robust assay may assist in making treatment decisions or in devising risk‐adapted prospective clinical trials in the future. [ABSTRACT FROM AUTHOR]

Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant-eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age ≤ 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n = 16) or died (n = 2) during cytoreductive second-line treatment (considered “cytoreduction failure”); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P <  .0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P   =  .031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. Post-treatment surrogate end points, such as progression of disease within 24 months (POD24) are promising predictors for overall survival (OS) but are of limited clinical value, primarily because they cannot guide up-front treatment decisions. We used the clinical and molecular data from 2 independent cohorts of symptomatic patients in need of first-line immunochemotherapy (151 patients from a German Low-Grade Lymphoma Study Group [GLSG] trial and 107 patients from a population-based registry of the British Columbia Cancer Agency [BCCA]) to validate the predictive utility of POD24, and to evaluate the ability of pretreatment risk models to predict early treatment failure. POD24 occurred in 17% and 23% of evaluable GLSG and BCCA patients, with 5-year OS rates of 41% (vs 91% for those without POD24, P < .0001) and 26% (vs 86%, P < .0001), respectively. The m7-FL International Prognostic Index (m7-FLIPI), a prospective clinicogenetic risk model for failure-free survival, had the highest accuracy to predict POD24 (76% and 77%, respectively) with an odds ratio of 5.82 in GLSG (P = .00031) and 4.76 in BCCA patients (P = .0052). A clinicogenetic risk model specifically designed to predict POD24, the POD24-PI, had the highest sensitivity to predict POD24, but at the expense of a lower specificity. In conclusion, the m7-FLIPI prospectively identifies the smallest subgroup of patients (28% and 22%, respectively) at highest risk of early failure of first-line immunochemotherapy and death, including patients not fulfilling the POD24 criteria, and should be evaluated in prospective trials of precision medicine approaches in FL. [ABSTRACT FROM AUTHOR]

We revisited the prognostic value of frequently detected somatic gene copy number alterations (CNAs) in mantle cell lymphoma (MCL) patients treated first line with immunochemotherapy and autologous stem cell transplantation (ASCT), with or without high-dose cytarabine, in the randomized European MCL Younger trial. DNA extracted from tumor material of 135 patients (median age, 56 years) was analyzed by multiplex ligation-dependent probe amplification and/or quantitative multiplex polymerase chain reaction of short fluorescent fragments. As expected, MYC (18%) was the more frequently gained, whereas RB1 (26%), ATM (25%), CDKN2A (p16) (25%), and TP53 (22%) were the more frequently deleted. Whether adjusted for MCL International Prognostic Index (MIPI) or not, deletions of RB1, CDKN2A, TP53, and CDKN1B were associated with shorter overall survival (OS), similarly in both treatment arms, whereas CNAs in MYC,ATM, CDK2, CDK4, and MDM2 had no prognostic value. Additive effects were seen for CDKN2A (hazard ratio, 2.3; P = .007, MIPI-adjusted) and TP53 deletions (hazard ratio, 2.4; P = .007), reflected in a dismal outcome with simultaneous deletions (median OS, 1.8 years) compared with single deletions (median OS, 4.3 and 5.1 years) or without these deletions (median OS, 7 years), again similarly in both treatment arms. The additive prognostic effects of CDKN2A and TP53 deletions were independent of the Ki-67 index. Despite immunochemotherapy, high-dose cytarabine, and ASCT, younger MCL patients with deletions of CDKN2A (p16) and TP53 show an unfavorable prognosis and are candidates for alternative therapeutic strategies. This trial was registered at www.clinicaltrials.gov as #NCT00209222. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL displays an aggressive course, with a continuous relapse pattern and a median survival of only 3-7 years. However, a subset of up to 15% long-term survivors has recently been identified with a rather indolent clinical course. In general, conventional chemotherapy is only palliative and the median duration of remissions is only 1-2 years. In 2000, the European MCL Network () was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high dose cytosine arabinoside (Ara-C) to an R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated cell cycle machinery and impairment of several signaling transduction and apoptotic pathways. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Lisbon, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in constitutional overexpression of cyclin D1 and cell cycle dysregulation in virtually all cases. Clinically, MCL shows an aggressive clinical course with a continuous relapse pattern and a median survival of only 3-5 years. However, recently a subset of up to 15% long-term survivors has been identified with a rather indolent clinical course. Advanced stage disease is usually apparent already at first clinical manifestation; in general, conventional chemotherapy is only palliative and median duration of remissions is only 1-2 years. In 2000, the European MCL Network () was founded, which consists of 15 national lymphoma study groups supplemented by experts in hematopathology, cytogenetics and molecular genetics. During the last decade, the European consortium has successfully initiated the largest phase III trials in MCL worldwide. In the current study generation, the addition of high-dose Ara-C to a rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP)-like regimen followed by myeloablative consolidation achieved a significant improvement of progression-free survival. Similarly, in elderly patients, rituximab maintenance until progression led to a marked prolongation of remission duration. Emerging strategies include proteasome inhibitors, immune modulatory drugs (IMiDs), mammalian target of rapamycin (mTOR) inhibitors and others, all based on the dysregulated control of cell cycle machinery and impairment of several apoptotic pathways. Combination strategies are currently being investigated in numerous trials, but their introduction into clinical practice and current treatment algorithms remains a challenge. Future strategies will apply individualized approaches according to the molecular risk profile of the patient. At the annual conference in Warsaw, recent results of molecular pathogenesis, analyses of current clinical trials and new study concepts were discussed. [ABSTRACT FROM AUTHOR]

Jin M K, Hoster E, Dreyling M, Unterhalt M, Hiddemann W & Klapper W (2011) Histopathology , 586-592 Follicular dendritic cells (FDC) are specialized antigen-presenting cells found exclusively in the germinal centre (GC), which can be detected in B cell non-Hodgkin lymphomas (NHL) as reactive bystander cells. Recently, gene expression profiling has revealed that FDC networks might be associated with clinical outcome in follicular lymphoma. The aim was to characterize FDC in NHL and to evaluate a possible association with outcome in follicular lymphoma. The extent and immunophenotype of FDC was determined semi-quantitatively in reactive GC and NHL (follicular lymphoma, angioimmunoblastic T cell lymphoma, mantle cell lymphoma) using fluorescence double staining and digital image analysis. In all NHL tested CD23 and CD35 and CD54 were expressed at relatively low levels on FDC, comparable to FDC found in the dark zone of the GC. However, the extent of FDC networks did not correlate with the clinical outcome of 102 patients with follicular lymphomas treated within a prospectively randomized trial. FDC found in different types of NHL show quantitatively reduced expression of several proteins, suggesting that there are functional differences between FDC in normal GC and NHL. The extent of the FDC networks in follicular lymphoma is not useful as a prognostic marker. [ABSTRACT FROM AUTHOR]

On the basis of a preceding phase I study, the current trial explored bendamustine in combination with mitoxantrone and rituximab (BMR) in patients with stage III/IV relapsed or refractory indolent lymphomas and mantle cell lymphoma (MCL) with or without prior rituximab containing chemo-immunotherapy (R-chemo) treatment. Therapy consisted of bendamustine 90 mg/m2 days 1 + 2, mitoxantrone 10 mg/m2 day 1, rituximab 375 mg/m2 day 8. Treatment was repeated on day 29 for a total of four cycles. Between 3 April and 04 July, 57 patients were recruited from 24 participating institutions, 39% of whom had received prior R-chemo therapy. Median age was 66 years (40 - 83). Lymphoma subtypes were 29 follicular (FL), 18 MCL, and 10 other indolent lymphomas. The overall response rate (ORR) was 89% with 35% CR and 54% PR. ORR in R-chemo pretreated patients was 76% (38% CR, 38% PR). After a median observation time of 27 months (1 - 43), the estimated median progression free survival is 19 months. The 2 year overall survival is 60% for patients with FL and MCL. Treatment related toxicities of grade 3/4 comprised a reversible myelosuppression (10% anemia, 78% leukocytopenia, 46% granulocytopenia, 16% thrombocytopenia). However, unexpected hospitalisations were necessary after 4% of BMR-application only. BMR is a very effective new outpatient immuno-chemotherapy with low toxicity for patients with relapsed/refractory FL, MCL and other indolent lymphomas. [ABSTRACT FROM AUTHOR]

After decades of stagnation, the prognosis of patients with follicular lymphomas (FL) has changed substantially within the last few years due to new and effective therapeutic modalities. These include myeloablative therapy followed by autologous stem cell transplantation (ASCT) in younger patients in first remission, which showed a significant prolongation of remission duration in three prospective randomised trials while the impact on overall survival still needs to be determined. Adding the anti-CD 20 antibody Rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and, in two of four currently available prospective randomised studies, even in a longer overall survival. A prolongation of remission duration was also seen when Rituximab was given as maintenance after cytoreductive therapy including Rituximab. Radio-immunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies produced encouraging data in several phase II studies. New therapeutic perspectives have also emerged from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is a distinct lymphoma subtype with a particularly poor clinical outcome. The clinical relevance of the morphological characteristics of these tumours remains uncertain. The European MCL Network reviewed 304 cases of MCL to determine the prognostic significance of histopathological characteristics. Cytomorphological subtypes, growth pattern and markers of proliferation (mitotic and Ki-67 indices) were analysed. In addition to the known cytological subtypes, classical (87·5%), small cell (3·6%), pleomorphic (5·9%) and blastic (2·6%), we identified new pleomorphic subgroups with mixtures of cells ( classical + pleomorphic type; 1·6%) or transitions ( classical/ pleomorphic type; 1·6%), which, however, did not differ significantly in overall survival time. Exactly 80·5% of cases displayed a diffuse growth pattern, whereas 19·5% of cases had a nodular growth pattern, which was associated with a slightly more favourable prognosis. A high proliferation rate (mitotic or Ki-67 indices) was associated with shorter overall survival. Cut-off levels were defined that allowed three subgroups with different proliferation rates to be discriminated, which showed significantly different clinical outcomes ( P < 0·0001). Based on this large clinicopathological study of prospective clinical trials, multivariate analysis confirmed the central prognostic role of cell proliferation and its superiority to all other histomorphological and clinical criteria. [ABSTRACT FROM AUTHOR]

High-dose cytosine arabinoside (AraC)-containing regimens have shown the highest antileukaemic efficacy of all currently used regimens in the treatment of acute myeloid leukaemia (AML). This study aimed at increasing the antileukaemic potential of high-dose AraC by raising intracellular levels of AraC triphosphate (AraCTP), which is the mediator of cytotoxicity, via biochemical modulation by inhibitors of ribonucleotide reductase (RR) or haematopoietic growth factors (HGFs). Blasts from patients with de novo AML were analysed for their formation of AraCTP under high-dose AraC conditions (20 µm over 3 h) without prior modulation (n = 47) after a 2-h pre-exposure with fludarabine (50 µg/ml) (n = 40) or gemcitabine (30 ng/ml) (n = 40) and after a 48-h pre-exposure to granulocyte colony-stimulating-factor (G-CSF; 100 ng/ml) (n = 27) or granulocyte–macrophage colony-stimulating-factor (GM-CSF; 100 U/ml) (n = 28). Unmodulated formation of AraCTP (median 239·8 ng/107 cells) could not be increased via modulation by gemcitabine (232·4 ng/107 cells) or fludarabine (247·8 ng/107 cells). The lack of effect of RR inhibitors was also observed for all other known metabolites of AraC [Ara-cytosine monophosphate (CMP), Ara-cytosine diphosphate (CDP), AraCDP-choline, Ara-uridine monophosphate (UMP), Ara-uridine diphosphate (UDP) and Ara-uridine triphosphate (UTP)]. In contrast, pre-exposure to HGFs led to significant increases in AraCTP formation (G-CSF 556·0 ng/107 cells, 2·31-fold increase, P < 0·001; GM-CSF 447·9 ng/107 cells, 1·87-fold increase, P < 0·0001). To establish the mechanism responsible for these effects, the activity of the rate-limiting enzyme of AraC metabolism, deoxycytidine kinase (dCK), was investigated (n = 33). In vivo exposure to GM-CSF led to increases in dCK activity from unmodulated values at 0 h (29·8 pmol/min/mg protein) to 34·3 pmol/min/mg protein at 24 h (1·15-fold increase) and 54·5 pmol/min/mg protein at 48 h (1·83-fold increase). The raise in dCK activity over 48 h was significant (P < 0·013). [ABSTRACT FROM AUTHOR]