43 research outputs found
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
Intratumoral injection of BCNU in ethanol (DTI-015) results in enhanced delivery to tumor – a pharmacokinetic study
Solvent facilitated perfusion (SFP) has been proposed as a technique to increase the delivery of chemotherapeutic agents to tumors. SFP entails direct injection of the agent into the tumor in a water-miscible organic solvent, and because the solvent moves easily through both aqueous solutions and cellular membranes it drives the penetration of the solubilized anticancer agent throughout the tumor. To test this hypothesis, we compared the pharmacokinetics (PK) of 14 C-labeled 1,3-bis-chlorethyl-1-nitrosourea (BCNU) in intra-cerebral 9L rat gliomas after intravenous (IV) infusion in 90% saline –10% ethanol or direct intratumoral (IT) injection of 14 C-BCNU in 100% ethanol (DTI-015). Treatment with DTI-015 yielded a peak radioactive count (Cmax) for the 14 C label that was 100–1000 fold higher in the tumor than in all other tissues in addition to a concentration in the tumor that was 100-fold higher than that achieved following IV infusion of 14 C-BCNU. Pathologic and auto-radiographic analysis of tissue sections following IT injection of 14 C-BCNU in ethanol into either tumor or normal rat brain revealed both an enhanced local volume of distribution and an increased concentration of BCNU delivered to tumor compared to non-tumor bearing brain. To investigate the mechanism behind the SFP of BCNU to the tumor both dynamic contrast and perfusion MRI were performed on 9L tumors before and after treatment and demonstrated a decrease in tumor perfusion following IT injection of DTI-015. Finally, initial PK of patient blood samples following administration of DTI-015 into relapsed high-grade glioma indicated a 20-fold decrease in systemic exposure to BCNU compared to IV infusion of BCNU providing further evidence for the enhanced therapeutic ratio observed for DTI-015.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45396/1/11060_2004_Article_5675.pd
The restorative role of annexin A1 at the blood–brain barrier
Annexin A1 is a potent anti-inflammatory molecule that has been extensively studied in the peripheral immune
system, but has not as yet been exploited as a therapeutic target/agent. In the last decade, we have undertaken the
study of this molecule in the central nervous system (CNS), focusing particularly on the primary interface between the
peripheral body and CNS: the blood–brain barrier. In this review, we provide an overview of the role of this molecule
in the brain, with a particular emphasis on its functions in the endothelium of the blood–brain barrier, and the protective
actions the molecule may exert in neuroinflammatory, neurovascular and metabolic disease. We focus on the
possible new therapeutic avenues opened up by an increased understanding of the role of annexin A1 in the CNS
vasculature, and its potential for repairing blood–brain barrier damage in disease and aging
Single-agent lenalidomide is active in patients with relapsed or refractory aggressive non-Hodgkin lymphoma who received prior stem cell transplantation.
Patients with aggressive non-Hodgkin lymphoma (NHL) who relapse after autologous stem cell transplantation (ASCT) have a poor prognosis. Additional therapy is often poorly tolerated, and new treatment modalities are needed. This efficacy and safety study was a retrospective analysis of two phase II trials (NHL-002 and NHL-003) that studied single-agent lenalidomide in patients with relapsed/refractory aggressive NHL with prior (n = 87) compared with no prior ASCT (n = 179). The overall response rate in the ASCT group was 39% [14% complete response (CR)], including 29% in patients with diffuse large B-cell lymphoma, 63% in mantle cell lymphoma, and 60% in transformed lymphoma. The timing of transplant relative to receiving lenalidomide had no effect on outcomes. Median progression-free survival for the ASCT group was 3\ub77 months (16\ub79 months for patients in CR; 7\ub73 months for partial responders) at a median 12\ub75-month follow-up. Median response duration was 7\ub79 months. Regardless of prior ASCT, lenalidomide monotherapy was efficacious in heavily pretreated patients with aggressive, relapsed/refractory NHL, with a safety profile that was consistent with prior studies of single-agent lenalidomide
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Preliminary results from two phase II studies of lenalidomide monotherapy in relapsed/refractory non-Hodgkin’s Lymphoma
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Background: Lenalidomide is an immunomodulatory drug of the IMiD class that has activity in multiple myeloma, myelodysplastic syndromes and chronic lymphocytic leukemia. We report preliminary results of two Phase II studies assessing the safety and efficacy of lenalidomide monotherapy in subjects with relapsed/refractory indolent or aggressive non-Hodgkin’s lymphoma (NHL). Methods: Subjects with indolent (study NHL-001) or aggressive (study NHL-002) relapsed/refractory NHL following ≥ 1 prior treatment regimen with measurable disease are eligible. Subjects receive 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continue therapy for 52 weeks as tolerated until disease progression. Response and progression are evaluated using cross sectional imaging by the NCI criteria. Results: 10 subjects (2 indolent (I), 8 aggressive (A)) of a planned 80 (40 in each study) have enrolled thus far. Median age is 66 (45–80) and 7 subjects are female. Indolent histology is follicular center lymphoma grade 1, 2 (n = 2) and aggressive histology diffuse large cell lymphoma (n = 7) and follicular center lymphoma grade 3 (n = 1). Median time from diagnosis to lenalidomide monotherapy is 2.9 years (1.1–10) and median number of prior treatment regimens per subject is 3 (1–6). Median duration of follow-up is 2 months. Of eight subjects (2 I, 6 A) evaluable for response at two months, three demonstrated a decrease in their tumor burden by 72% (I), 68% (A) and 52% (A), two subjects (2 A) exhibited stable disease and three subjects (1 I, 2 A) had disease progression. Six of the ten subjects (2 I, 4 A) demonstrated no Grade 3 or 4 adverse events. Grade 3 or 4 hematological adverse events (neutropenia, thrombocytopenia) occurred in four subjects including one febrile neutropenia and one of these four subjects also exhibited Grade 3 cellulitis. No tumor flare or tumor lysis has been observed to date. Conclusions: Preliminary data of lenalidomide monotherapy in relapsed and refractory NHL are encouraging.
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Phase II trial of intratumoral BCNU injection and radiotherapy on untreated adult malignant glioma
The differential effect of lenalidomide monotherapy in patients with relapsed or refractory transformed non-Hodgkin lymphoma of distinct histological origin.
Transformed lymphoma (TL) represents a heterogeneous group of lymphomas with an aggressive course and poor prognosis. We assessed the clinical benefit of single-agent lenalidomide based on histological origin, including transformed follicular lymphoma (tFL) and transformed chronic lymphocytic leukaemia/small lymphocytic lymphoma (tCLL/SLL). Our analysis included 33 patients with TL. Patients received lenalidomide at a median dose of 25 mg/d. The overall response rate (ORR) was 46%, with a median response duration of 12·8 months after a median follow-up of 5·6 months. Median progression-free survival was 5·4 months. Among patients with tFL, ORR was 57%, with a median response duration of 12·8 months. None of the patients with tCLL/SLL responded to lenalidomide monotherapy. The most common grade 3/4 adverse events were reversible myelosuppression. Our results suggest that the original lymphoma histology (i.e. FL) in TL patients may potentially be associated with response to salvage lenalidomide monotherapy
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Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory aggressive non-Hodgkin lymphoma
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Background: Lenalidomide (Revlimid), an immunomodulatory drug of the IMiDs class, is approved in the US for treatment of relapsed/refractory multiple myeloma and myelodysplastic syndromes associated with a deletion 5q[31] cytogenetic abnormality. Lenalidomide also has activity in chronic lymphocytic leukemia and cutaneous T-cell lymphoma. This study was designed to assess the safety and efficacy of lenalidomide in patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). Methods: Patients with relapsed/refractory aggressive NHL with measurable disease after at least 1 prior treatment regimen were eligible. Patients received 25 mg lenalidomide orally once daily on Days 1–21 every 28 days and continued therapy for 52 weeks as tolerated or until disease progression. Response and progression were evaluated using the IWLRC methodology. Results: As of enrollment cut-off, 50 patients were enrolled and 49 received drug. Forty-one patients were evaluable for response. The median age was 65 (46–84) and 18 were female. Histology was diffuse large B-cell lymphoma [DLBCL] (n=21), follicular center lymphoma grade 3 [FL] (n=3), mantle cell lymphoma [MCL] (n=14) and transformed [TSF] (n=3). Median time from diagnosis to lenalidomide was 3.2 (0.4–32) years and median number of prior treatment regimens was 3 (1–7). Fourteen patients (34%) exhibited an objective response (5 complete responses unconfirmed (CRu) and 9 partial responses (PR)), 12 had stable disease (SD) for a tumor control rate (TCR) of 63% and 15 progressive disease (PD). Responses were seen in each of the aggressive histologic subtypes studied: DLBCL (5/21), MCL (6/14), FL (2/3), and TSF (1/3). Five of 11 patients (45%) with a prior stem cell transplant responded. Progression free survival although ongoing is currently > 239 (>191 - >373) days in patients experiencing CRu and > 160 (>54 - >251) days in patients with PR. Most common Grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%) while most common Grade 3 adverse events were neutropenia (22%), leukopenia (14%) and thrombocytopenia (12%). Conclusion: Lenalidomide oral monotherapy is active with manageable side effects in relapsed/refractory aggressive NHL.
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