phase i ii first in human trial with m7583 a bruton s tyrosine kinase inhibitor btki in patients with b cell malignancies

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Indolent lymphoma: the pathologist's viewpoint

Abstract Indolent lymphomas have recently been the object of numerous studies, which have focused on new aspects relevant both for the better comprehension of their histogenesis and the identification of new therapeutic strategies. As marginal-zone lymphoma (MZL) represents the category of indolent lymphomas that has obtained more benefit from such an approach, the authors focused on the most recent achievements and not yet solved controversies in this area. In spite of their postulated common derivation, the three categories of MZL of the WHO Classification appear dissimilar. In fact, they show significant molecular differences among them as well as a certain heterogeneity within each group. By no means, there is a cogent need of more refined tools to revise these neoplasms and to produce a more rational grouping. The recent identification of the IRTA gene family corresponding to IG-like receptors differentially expressed in B-cells might contribute to their better understanding

Controversies in the Treatment of Peripheral T-cell Lymphoma.

Peripheral T-cell lymphomas are a heterogeneous group of rare diseases with an aggressive behavior and dismal prognosis. Their classification is complex and still evolving, and several biomolecular markers now help refine the prognosis of specific disease entities, although still have limited impact in tailoring the treatment. First-line treatment strategies can cure only a minority of patients and relapsed-refractory disease still represents the major cause of failure. Frontline autologous transplantation may have an impact in the consolidation of response; however, its role is still questioned as far as complete responses obtained after induction chemotherapy are concerned. Newer drugs are now being evaluated in clinical trials, but effective salvage strategies for those who experience treatment failures are lacking. Here we review and discuss the most controversial aspects of diagnosis and treatment of peripheral T-cell lymphomas

Prognostic value of interim positron emission tomography in patients with peripheral T-cell lymphoma

The definition of the role of positron emission tomography (PET) in peripheral T-cell lymphomas (PTCLs) is still under investigation. The purpose of the present observational retrospective study was to assess the early prognostic value of PET after the first three cycles of therapy (PET+3), evaluating visual data in de novo PTCL patients treated in first line with standard chemotherapy and followed by both PET and computed tomography scan. Of 27 PET+3-negative patients, 19 also had a negative PET at the end of treatment (PET+6), whereas 8 of 27 had a positive final one; 6 of 7 PET+3-positive patients had a positive PET+6, whereas only 1 patient had a negative PET+6. Estimated overall survival plotted according to PET+3 results showed 78.6% for negative patients and 21.4% for positive patients at 88.7 months with a significant difference. Patients with negative PET+3 had superior progression-free survival of 72.6% compared with 16.7% of PET+3-positive patients. At the time of this analysis, 17 of 19 (89.5%) patients with negative PET+3 are in continuous complete response (CCR) and only 1 of 7 (14.2%) patients with positive PET+3 is still in CCR. In conclusion, our results indicate that positive PET+3 is predictive of a worse outcome in PTCL, and this significant statistical difference between the two curves could be clinically informative. Larger and prospective studies and harmonization of PET reading criteria are needed

Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma

Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity

Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma

The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (?H2AX), marker of DNA damage and genomic instability. Constitutive ?H2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL

An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma

Abstract Background Lenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL). Methods Patients received oral lenalidomide 25 mg on days 1–21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR). Results Two hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7–5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0–NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively. Conclusion Lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma

copanlisib monotherapy activity in relapsed or refractory indolent b cell lymphoma combined analysis from phase i and ii studies

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A phase II trial of CHOP chemotherapy followed by yttrium 90 ibritumomab tiuxetan (Zevalin) for previously untreated elderly diffuse large B-cell lymphoma patients

Background: A prospective, single-arm, open-label, nonrandomized phase II combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus radioimmunotherapy trial was conducted to evaluate the efficacy and safety in untreated elderly diffuse large B-cell lymphoma (DLBCL) patients. Patients and methods: From February 2005 to April 2006, in our institute we treated 20 eligible elderly (age 6560 years) patients with previously untreated DLBCL using a novel regimen consisting of six cycles of CHOP chemotherapy followed 6-10 weeks later by 90Y ibritumomab tiuxetan. Results: The overall response rate to the entire treatment regimen was 100%, including 95% complete remission (CR) and 5% partial remission. Four (80%) of the five patients who achieved less than a CR with CHOP improved their remission status after radioimmunotherapy. With a median follow-up of 15 months, the 2-year progression-free survival was estimated to be 75%, with a 2-year overall survival of 95%. The 90Y ibritumomab tiuxetan toxicity included grade 653 hematologic toxicity in 12 of 20 patients; the most common grade 653 toxic effects were neutropenia (12 patients) and thrombocytopenia (7 patients). Transfusions of red blood cells and/or platelets were given to one patient. Conclusion: This study has established the feasibility, tolerability, and efficacy of this regimen for elderly patients with DLBCL