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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]

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]

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]

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]

The article discusses a study regarding the improvement of survival for advanced stage mantle cell lymphoma. It notes on the continuous rise of malignant lymphoma incidence while being considered to be incurable by conventional chemotherapy. Within the past three decades as of 2009, median overall survival (OS) of advanced-stage cell lymphoma patients increased from 2.7 years to 4.8 years. Moreover, improvement in OS could be the use of anthracycline-containing treatment regimens and antilymphoma antibodies paired with advances in general supportive care, new diagnostic tools and life span improvement.

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]

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]

Recent retrospective analyses indicate prolonged survival for patients with follicular lymphoma over the past 25 years, attributed most likely to improved supportive care and sequential application of effective therapies. Encouraging results were obtained from several randomized trials evaluating myeloablative therapy followed by autologous stem cell transplantation (ASCT) as consolidation therapy applied to patients with advanced-stage follicular lymphoma either in first remission or as salvage therapy. However, because of the successful introduction of rituximab to the standard therapeutic repertoire, with its long-term beneficial clinical impact, ASCT must be reevaluated in prospective clinical trials, especially taking into account the potential short- and long-term toxicity associated with high-dose therapy. The concept of in vivo purging before or after ASCT and the introduction of radioimmunotherapy as part of the myeloablative regimen may further improve treatment results, reduce toxicity, and increase applicability. Combination of these novel strategies into a multimodal approach justifies hope that the treatment outcome of patients suffering from follicular lymphoma will be further improved. [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]

Patients with refractory acute leukemias after intensive induction and salvage attempts have a particularly poor prognosis and therapeutic options are limited. In the current study, the pharmacologically based FIS-HAM regimen was applied, which included fludarabine 15 mg/m2 q 12 h (days 1, 2, 8, and 9), cytosine arabinoside as a 45-min infusion every 3 h at 750 mg/m2 per single application (days 1, 2, 8, and 9), and mitoxantrone 10 mg/m2 (days 3, 4, 10, 11). Twenty-six intensively pretreated patients [median age: 38 years; range: 22-65; 16 cases of acute myeloid leukemia (AML) and 10 of acute lymphoblastic leukemia (ALL)] were included. Of 16 patients with AML, 5 achieved a complete remission (CR, 31%), 1 a partial remission (PR, 6%), 2 were nonresponders (13%), and 8 succumbed to early death (ED, 50%). Of 10 patients with ALL, 5 achieved a CR, 1 a PR, 1 was a nonresponder, and 3 died early. Overall, the CR rate was 38%. The median disease-free survival time was 50 days and median survival 90 days. Two patients underwent allogeneic bone marrow transplantation and are alive after 27 and 28 months. Neutropenia amounted to a median of 46 days. Toxicity WHO III/IV included infection (61%), diarrhea (48%), nausea/vomiting (43%), impairment of heart function (30%), and mucositis (26%). The current data indicate a significant activity of FIS-HAM chemotherapy in advanced acute leukemias. However, due to its pronounced toxicity, this regimen should be restricted to third-line therapy for patients expecting a suitable donor for allogeneic transplantation, and supportive treatment should be optimized. [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]

Purpose: To detect possible interactions between (-)-formyl-tetrahydrofolic acid (leucovorin, (-)-fTHF) and (+)-formyl-tetrahydrofolic acid ((+)-fTHF) on the plasma and intracellular pharmacokinetics following their simultaneous administration. Methods: Plasma levels of (-)-fTHF, (-)-methyl-THF, and (+)-fTHF were determined in samples from four volunteers following the administration of both (-)-fTHF and (±)-fTHF and in seven patients during a 5-fluorouracil (5-FU)/fTHF combination chemotherapy. In addition, the intracellular uptake of 14C-(-)-mTHF in the presence of (+)-mTHF at increasing concentrations was measured in vitro. Analyses were performed using a highly specific high-performance liquid chromatography procedure. Results: The pharmacokinetic parameters obtained for (-)-fTHF following the administration of (-)-fTHF only were: terminal half-life, 1.2 h; area under the curve, 10 μg · h/ml; maximum concentration, 12 μg/ml; clearance, 305 ml/min; volume of distribution, 19 l. The parameters did not differ significantly as compared with those obtained following the administration of (±)-fTHF to both volunteers and patients. There were no differences in the pharmacokinetics of (-)-mTHF or in the protein binding of both substances with the different forms of administration. The intracellular uptake of 14C-(-)-mTHF did not depend on the presence of (+)-mTHF at either concentration. Conclusions: These data suggest that (-)-fTHF is not therapeutically superior to (±)-fTHF and that the latter is appropriate during combination chemotherapy with 5-FU/fTHF in patients with colorectal cancers. [ABSTRACT FROM AUTHOR]