SciCombinator

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Concept: Mantle cell lymphoma

166

BackgroundRituximab-hyper-CVAD alternating with rituximab-high-dose methotrexate and cytarabine is a commonly utilized regimen in the United States for mantle cell lymphoma (MCL) based on phase II single institutional data. To confirm the clinical efficacy of this regimen and determine its feasibility in a multicenter study that includes both academic and community-based practices, a phase II study of this regimen was conducted by SWOG.Patients and methodsForty-nine patients with advanced stage, previously untreated MCL were eligible. The median age was 57.4 years (35-69.8 years).ResultsNineteen patients (39%) did not complete the full scheduled course of treatment due to toxicity. There was one treatment-related death and two cases of secondary myelodysplastic syndrome (MDS). There were 10 episodes of grade 3 febrile neutropenia, 19 episodes of grade 3 and 1 episode of grade 4 infection. With a median follow-up of 4.8 years, the median progression-free survival was 4.8 years (5.5 years for those ≤65 years) and the median overall survival (OS) was 6.8 years.ConclusionsAlthough this regimen is toxic, it is active for patients ≤65 years of age and can be given both at academic centers and in experienced community centers.

Concepts: Clinical trial, United States, Chemotherapy, Acute myeloid leukemia, Chemotherapy regimens, Fever, Mantle cell lymphoma, Myelodysplastic syndrome

165

Mantle cell lymphoma (MCL) is an uncommon type of non-Hodgkin lymphoma with poor overall prognosis, requiring the development of new therapies. Lenalidomide is an immunomodulatory agent demonstrating antitumor and antiproliferative effects in MCL. We report results from a long-term subset analysis of 57 patients with relapsed/refractory MCL from the NHL-003 phase II multicenter study of single-agent lenalidomide in patients with aggressive lymphoma DESIGN: Lenalidomide was administered orally 25 mg daily on days 1-21 every 28 days until progressive disease (PD) or intolerability. The primary end point was overall response rate (ORR).

Concepts: Cancer, Medical terms, Chemotherapy, Lymphoma, Mantle cell lymphoma

165

JNJ-26854165 (serdemetan) has previously been reported to inhibit the function of the E3 ligase human double minute-2, and we initially sought to characterize its activity in models of mantle cell lymphoma (MCL) and multiple myeloma (MM). Serdemetan induced a dose dependent inhibition of proliferation in both wild-type (wt) and mutant (mut) p53 cell lines, with IC50’s from 0.25 μ/L to 3 μ/L, in association with an S phase cell cycle arrest. Caspase-3 activation was primarily seen in wtp53 bearing cells, but also occurred in mutp53 bearing cells, albeit to a lesser extent. 293T cells treated with JNJ-26854165, and serdemetan-resistant fibroblasts displayed accumulation of cholesterol within endosomes, a phenotype reminiscent of that seen in the ATP-binding cassette sub-family A member-1 (ABCA1) cholesterol transport disorder, Tangiers disease. MM and MCL cells had decreased cholesterol efflux and electron microscopy demonstrated the accumulation of lipid whorls, confirming the lysosomal storage disease phenotype. JNJ-26854165 induced induction of cholesterol regulatory genes sterol regulatory element-binding transcription factor-1 and -2, liver X receptors α and β, along with increased expression of Niemann-Pick disease type-C1 and -C2. However, JNJ-26854165 induced enhanced ABCA1 turnover despite enhancing transcription. Finally, ABCA1 depletion resulted in enhanced sensitivity to JNJ-26854165. Overall, these findings support the hypothesis that serdemetan functions in part by inhibiting cholesterol transport, and that this pathway is a potential new target for the treatment of MCL and MM.

Concepts: DNA, Protein, Gene, Golgi apparatus, Chromosome, Cell cycle, Proteasome, Mantle cell lymphoma

165

BackgroundCentral nervous system (CNS) involvement in mantle cell lymphoma (MCL) is uncommon, and the manifestations and natural history are not well described.Patients and methodsWe present the data on 57 patients with MCL who developed CNS involvement, from a database of 1396 consecutively treated patients at 14 institutions.ResultsThe crude incidence of CNS involvement was 4.1%, with 0.9% having CNS involvement at diagnosis. Blastoid histology, B-symptoms, elevated lactate dehydrogenase, Eastern Cooperative Group performance status ≥2 and a high Mantle Cell Lymphoma International Prognostic Index score were enriched in the cohort with CNS involvement, and the presence of ≥1 of these features defined a high-risk subset (an actuarial risk of CNS involvement 15% at 5 years) in a single-institution subset. The median time to CNS relapse was 15.2 months, and the median survival from time of CNS diagnosis was 3.7 months. The white blood cell count at diagnosis <10.9 × 10(9)/l, treatment of CNS involvement with high-dose anti-metabolites, consolidation with stem cell transplant and achievement of complete response were all associated with improved survival.ConclusionsIn MCL, CNS involvement is uncommon, although some features may predict risk. Once manifest outlook is poor; however, some patients who receive intensive therapy survive longer than 12 months.

Concepts: Central nervous system, Nervous system, Brain, Lactate dehydrogenase, Mantle cell lymphoma

164

The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue appearing. In this trial we evaluated the feasibility, safety and efficacy of R-Hyper-CVAD alternating with R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan. Patients received 6 cycles followed by a single dose of 90Y-Ibritumomab-Tiuxetan. Thirty patients were enrolled. Median age was 59 years. Twenty four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60-93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation. In the intent- to- treat population, failure free, progression free and overall survival at 4 years were 40 % (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure free and overall survival were 55% (95% confidence interval 31.48&-78.52) and 87% (95% confidence interval 70-100), respectively. Hematological toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with median duration of 5 and 12 weeks, respectively. Six (20%) patients died, 3 due to secondary malignancies (myelodisplastic syndrome and bladder and rectum carcinomas). In conclusion, our experience with R-Hyper-CVAD/R-MtxAraC followed by consolidation with 90Y-Ibritumomab-Tiuxetan is efficacious although less feasible than expected. The unacceptable toxicity observed, specially secondary malignancies, advise against the indication of this strategy. Trial registration: clinical.gov identifier: NCT2005-004400-37.

Concepts: Cancer, Lung cancer, Chemotherapy, Types of cancer, Interval finite element, Normal distribution, Hematological malignancy, Mantle cell lymphoma

161

The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model.

Concepts: Immune system, Protein, Cancer, Signal transduction, Lymph node, Types of cancer, Sarcoma, Mantle cell lymphoma

158

Although ibrutinib is highly effective in patients with relapsed/refractory mantle cell lymphoma (MCL), a substantial proportion of patients have resistant disease. The subsequent outcomes of such patients are unknown.

Concepts: Cancer, Chemotherapy, Lymphoma, Mantle cell lymphoma, Mantle zone

151

Non-Hodgkin lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with widely varying biologic, histologic and clinical features. For the B-cell NHLs, great progress has been made due to the addition of monoclonal antibodies and, more recently, other novel agents such as B-cell receptor signaling inhibitors, immunomodulatory agents, and proteasome inhibitors. Autologous hematopoietic cell transplantation (auto-HCT) offers the promise of cure or prolonged remission in some NHL patients. For some patients, however, auto-HCT may never be a viable option, while in others their disease may progress despite auto-HCT. In those settings, allogeneic HCT (allo-HCT) offers the potential for cure. Over the past 10-15 years, considerable progress has been made in the implementation of allo-HCT, such that this approach now is a highly effective therapy for patients up to (and even beyond) age 75. Recent advances in conventional lymphoma therapy, peri-transplant supportive care, patient selection, and donor selection (including the use of alternative hematopoietic cell donors), has allowed broader application of allo-HCT to NHL patients. As a result, an ever-increasing number of NHL patients over age 60-65 years stand to benefit from allo-HCT. In this review, we present data in support of the use of allo-HCT for patients with diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. These histologies account for a large majority of allo-HCT performed for patients over 60 in the U.S. Where possible, we highlight available data in older patients. This body of literature strongly supports the concept that allo-HCT should be offered to fit patients well beyond age 65 and, accordingly, that this treatment should therefore be covered by their insurance carriers.

Concepts: Lymphocyte, Types of cancer, Lymphoma, Hematopoietic stem cell transplantation, Follicular lymphoma, Lymphoproliferative disorders, Mantle cell lymphoma, T-cell lymphoma

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Advanced follicular lymphoma (FL) and mantle cell lymphoma (MCL) are incurable diseases with conventional treatment. The high dose treatment (HDT) with autologous stem cell transplantation (ASCT), however, offers a certain proportion of these patients the prospect of a prolonged disease-free and overall survival. The aim of this study was to investigate the event free survival (EFS) and overall survival (OS) in patients with FL and MCL treated with ASCT.

Concepts: Cancer, Disease, Cure, Chemotherapy, Types of cancer, Lymphoma, Follicular lymphoma, Mantle cell lymphoma

29

Interactions between the Bruton tyrosine kinase (BTK) inhibitor PCI-32765 and the proteasome inhibitor (bortezomib) were examined in diffuse large-B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) cells, including those highly resistant to bortezomib. Co-administration of PCI-32765/bortezomib synergistically increased mitochondrial injury and apoptosis in germinal centre- or activated B-cell-like-DLBCL cells and in MCL cells. These events were accompanied by marked AKT and nuclear factor (NF)-κB (NFKB1) inactivation, down-regulation of Mcl-1 (MCL1), Bcl-xL (BCL2L1), and XIAP, and enhanced DNA damage (e.g., γH2A.X formation) and endoplasmic reticulum (ER) stress. Similar interactions were observed in highly bortezomib-resistant DLBCL and MCL cells, and in primary DLBCL cells. In contrast, PCI-32765/bortezomib regimens displayed minimal toxicity toward normal CD34(+) bone marrow cells. Transfection of DLBCL cells with a constitutively active AKT construct attenuated AKT inactivation and significantly diminished cell death, whereas expression of an NF-κB “super-repressor” (IκBα(ser34/36) ) increased both PCI-32765 and bortezomib lethality. Moreover, cells in which the ER stress response was disabled by a dominant-negative eIF2α construct were resistant to this regimen. Finally, combined exposure to PCI-32765 and bortezomib resulted in more pronounced and sustained reactive oxygen species (ROS) generation, and ROS scavengers significantly diminished lethality. Given promising early clinical results for PCI-32765 in DLBCL and MCL, a strategy combining BTK/proteasome inhibitor warrants attention in these malignancies.

Concepts: DNA, Cancer, Adenosine triphosphate, Mitochondrion, Bone marrow, Endoplasmic reticulum, Reactive oxygen species, Mantle cell lymphoma