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F Reyes - One of the best experts on this subject based on the ideXlab platform.
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european phase ii study of rituximab chimeric anti cd20 monoclonal antibody for patients with newly diagnosed mantle cell Lymphoma and previously treated mantle cell Lymphoma immunocytoma and small b cell Lymphocytic Lymphoma
Journal of Clinical Oncology, 2000Co-Authors: James M Foran, David Cunningham, B Coiffier, Philippe Solalceligny, Michele Ghielmini, Peter Johnson, C Gisselbrecht, Ama Z S Rohatiner, Razvan A Popescu, F ReyesAbstract:PURPOSE: Mantle-cell Lymphoma (MCL), immunocytoma (IMC), and small B-cell Lymphocytic Lymphoma (SLL) are B-cell malignancies that express CD20 and are incurable with standard therapy. A multicenter phase II study was conducted to assess the toxicity and the overall response rates (RR) and complete response (CR) rates to rituximab (chimeric anti-CD20 monoclonal antibody). PATIENTS AND METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and SLL (n = 29) received rituximab 375 mg/m2/wk for 4 weeks via intravenous infusion. Restaging studies were performed 1 and 2 months after treatment. An analysis of the duration of response was conducted in December 1998. RESULTS: Eleven patients were unassessable, including one who died of splenic rupture after the first infusion. The RR among the 120 assessable patients was 30% (36 of 120 patients). The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC, 28%; ...
Steven Coutre - One of the best experts on this subject based on the ideXlab platform.
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chronic Lymphocytic leukemia small Lymphocytic Lymphoma version 4 2020 nccn clinical practice guidelines in oncology
Journal of The National Comprehensive Cancer Network, 2020Co-Authors: William G Wierda, Jennifer R Brown, John C Byrd, Jeremy S Abramson, Syed Bilgrami, Greg Bociek, Danielle M Brander, Asher Chanankhan, Julio C Chavez, Steven CoutreAbstract:Chronic Lymphocytic leukemia (CLL) and small Lymphocytic Lymphoma (SLL) are characterized by a progressive accumulation of leukemic cells in the peripheral blood, bone marrow, and lymphoid tissues. Treatment of CLL/SLL has evolved significantly in recent years because of the improved understanding of the disease biology and the development of novel targeted therapies. In patients with indications for initiating treatment, the selection of treatment should be based on the disease stage, patient's age and overall fitness (performance status and comorbid conditions), and cytogenetic abnormalities. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.
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improvement in parameters of hematologic and immunologic function and patient well being in the phase iii resonate study of ibrutinib versus ofatumumab in patients with previously treated chronic Lymphocytic leukemia small Lymphocytic Lymphoma
Clinical Lymphoma Myeloma & Leukemia, 2018Co-Authors: Jacqueline C Barrientos, Christopher Pocock, Steven Coutre, Ulrich Jaeger, Susan Obrien, Nishitha Reddy, Stephen P. Mulligan, Jennifer R Brown, Stephen Devereux, Tadeusz RobakAbstract:Abstract Background Ibrutinib compared with ofatumumab significantly improves progression-free and overall survival in patients with previously treated chronic Lymphocytic leukemia/small Lymphocytic Lymphoma (CLL/SLL). Patients and Methods Measures of well-being were assessed in RESONATE, where previously treated patients with CLL/SLL were randomized to receive ibrutinib 420 mg/day (n = 195) or ofatumumab (n = 196) for up to 24 weeks. Endpoints included hematologic function, Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), disease-related symptoms, European Organization for Research and Treatment of Cancer Quality of Life Questionnaires Core 30 (EORTC QLQ-C30), and medical resource utilization. Results With up to 24 months' follow-up (median, 16.4 months), 79% of cytopenic patients showed sustained hematologic improvement (82% with improved platelet count, 69% with improved hemoglobin) on ibrutinib versus 43% on ofatumumab (P Conclusion Ibrutinib led to significant improvements in hematologic function and disease symptomatology versus ofatumumab, and can restore quality of life while prolonging survival in relapsed/refractory CLL/SLL.
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survival adjusting for crossover phase 3 study of ibrutinib vs chlorambucil in older patients with untreated chronic Lymphocytic leukemia small Lymphocytic Lymphoma
Haematologica, 2017Co-Authors: Steven Coutre, Tadeusz Robak, Alessandra Tedeschi, Paul M Barr, Carolyn Owen, Osnat Bairey, Jan A Burger, Cathy Zhou, Lori Styles, Danelle F JamesAbstract:Ibrutinib, a first-in-class, once-daily inhibitor of Bruton’s tyrosine kinase, is indicated by the US FDA for the treatment of patients with chronic Lymphocytic leukemia/small Lymphocytic Lymphoma (CLL/SLL) and allows for treatment without chemotherapy. This broad approval, including treatment-na
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ibrutinib as initial therapy for elderly patients with chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma an open label multicentre phase 1b 2 trial
Lancet Oncology, 2014Co-Authors: Susan Obrien, Steven Coutre, Richard R Furman, Jan A Burger, Jeff P Sharman, Kristie A Blum, Barbara Grant, Donald A Richards, Morton Coleman, William G WierdaAbstract:Summary Background Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic Lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic Lymphocytic leukaemia. Methods In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. Findings Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic Lymphocytic leukaemia and two patients with small Lymphocytic Lymphoma. Median age was 71 years (range 65–84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1–2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22·1 months (IQR 18·4–23·2), 22 (71%) of 31 patients achieved an objective response (95% CI 52·0–85·8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. Interpretation The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic Lymphocytic leukaemia, or small Lymphocytic Lymphoma is encouraging, and merits further investigation in phase 3 trials. Funding Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.
Nancy L Bartlett - One of the best experts on this subject based on the ideXlab platform.
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updated results from the phase 3 helios study of ibrutinib bendamustine and rituximab in relapsed chronic Lymphocytic leukemia small Lymphocytic Lymphoma
Leukemia, 2019Co-Authors: Graeme Fraser, Nancy L Bartlett, Sebastian Grosicki, Paula Cramer, Fatih Demirkan, Santucci R Silva, Alexander Pristupa, Ann Janssens, Jiři Mayer, Mariesarah DilhuydyAbstract:We report follow-up results from the randomized, placebo-controlled, phase 3 HELIOS trial of ibrutinib+bendamustine and rituximab (BR) for previously treated chronic Lymphocytic leukemia (CLL)/small Lymphocytic Lymphoma (SLL) without deletion 17p. Overall, 578 patients were randomized 1:1 to either ibrutinib (420 mg daily) or placebo, in combination with 6 cycles of BR, followed by ibrutinib or placebo alone. Median follow-up was 34.8 months (range: 0.1–45.8). Investigator-assessed median progression-free survival (PFS) was not reached for ibrutinib+BR, versus 14.3 months for placebo+BR (hazard ratio [HR] [95% CI], 0.206 [0.159–0.265]; P < 0.0001); 36-month PFS rates were 68.0% versus 13.9%, respectively. The results are consistent with the primary analysis findings (HR = 0.203, as assessed by independent review committee, with 17-month median follow-up). Median overall survival was not reached in either arm; HR (95% CI) for ibrutinib+BR versus placebo: 0.652 (0.454–0.935; P = 0.019). Minimal residual disease (MRD)-negative response rates were 26.3% for ibrutinib+BR and 6.2% for placebo+BR (P < 0.0001). Incidence of treatment-emergent adverse events (including grades 3–4) were generally consistent with the initial HELIOS report. These long-term data support improved survival outcomes and deepening responses with ibrutinib+BR compared with BR in relapsed CLL/SLL.
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ibrutinib combined with bendamustine and rituximab compared with placebo bendamustine and rituximab for previously treated chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma helios a randomised double blind phase 3 study
Lancet Oncology, 2016Co-Authors: Asher Chanankhan, Sebastian Grosicki, Graeme Fraser, Paula Cramer, Fatih Demirkan, Alexander Pristupa, Ann Janssens, Rodrigo Santucci Silva, Jiri Mayer, Nancy L BartlettAbstract:Summary Background Most patients with chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma. Methods The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (≥18 years of age) who had active chronic Lymphocytic leukaemia or small Lymphocytic Lymphoma with measurable lymph node disease (>1·5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m 2 intravenously on days 2–3 in cycle 1, and days 1–2 in cycles 2–6; rituximab: 375 mg/m 2 on day 1 of cycle 1, and 500 mg/m 2 on day 1 of cycles 2–6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Findings Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7–20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3–13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150–0·276; p vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Funding Janssen Research & Development.
Attilio Orazi - One of the best experts on this subject based on the ideXlab platform.
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transformation of chronic Lymphocytic leukemia small Lymphocytic Lymphoma to interdigitating dendritic cell sarcoma evidence for transdifferentiation of the Lymphoma clone
American Journal of Clinical Pathology, 2009Co-Authors: Cory R Fraser, Wei Wang, Mario Gomez, Taotao Zhang, Susan Mathew, Richard R Furman, Daniel M Knowles, Attilio OraziAbstract:Interdigitating dendritic cell sarcoma (IDCS) is a rare tumor derived from interdigitating dendritic cells. Three cases of IDCS associated with chronic Lymphocytic leukemia/small Lymphocytic Lymphoma (CLL/SLL) have been described, but no clonal relationship between the 2 neoplasms was demonstrated. We present a detailed case analysis of a CLL/SLL with metachronous IDCS and demonstrate that these 2 neoplasms are clonally related. The IDCS and CLL cells had trisomy 12 and identical monoclonal immunoglobulin heavy chain gene rearrangements. Analysis of transcription factors with a role in myeloid differentiation demonstrated PU.1 up-regulation and C/EBPα down-regulation in IDCS compared with CLL. High-density array comparative genomic hybridization also identified gains in part of chromosome 16q in IDCS. Our study demonstrates for the first time clonal transformation of CLL/SLL into IDCS. This phenomenon may be triggered by alterations in lineage-determining transcription programs, which result in transdifferentiation, coupled with additional oncogenic stimuli caused by chromosomal imbalances.
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chronic Lymphocytic leukemia small Lymphocytic Lymphoma with trisomy 12 and focal cyclin d1 expression a potential diagnostic pitfall
Archives of Pathology & Laboratory Medicine, 2005Co-Authors: Dennis P Omalley, Gail H Vance, Attilio OraziAbstract:Chronic Lymphocytic leukemia/small Lymphocytic Lymphoma (CLL/SLL) and mantle cell Lymphoma usually are distinctly different in regard to clinical presentation, morphology, immunophenotype, and molecular/genetic findings. In spite of this, select cases may show overlapping characteristics and represent a diagnostic challenge. Cyclin D1 immunohistochemical staining is usually envisioned as a definitive method for resolving this differential diagnosis, with positivity supporting a diagnosis of mantle cell Lymphoma. We report a case involving a 58-year-old man with a diagnosis of CLL/SLL for several years. A lymph node excision was performed after increased adenopathy was noted in the cervical region. The excised lymph node showed typical morphologic findings of CLL/SLL, including the presence of characteristic proliferation centers. Cyclin D1 staining, using 3 different antibodies, was present in scattered prolymphocytes and paraimmunoblasts, mostly within proliferation centers. Fluorescence in situ hybridization and conventional cytogenetics demonstrated trisomy 12 and an absence of t(11;14) in lymph node tissue. Focal cyclin D1 expression by immunohistochemistry in nodal CLL/SLL is quite unusual and is discussed as a potential diagnostic pitfall.
Bruce D Cheson - One of the best experts on this subject based on the ideXlab platform.
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ofatumumab and bendamustine in previously treated chronic Lymphocytic leukemia and small Lymphocytic Lymphoma
Leukemia & Lymphoma, 2015Co-Authors: Chaitra S Ujjani, Pari Ramzi, Edmund A Gehan, Hongkun Wang, Yiru Wang, Bruce D ChesonAbstract:Despite initial responses > 90% with fludarabine and rituximab-based regimens, patients with chronic Lymphocytic leukemia (CLL) invariably relapse and require further treatment. Ofatumumab and bendamustine have each shown efficacy in relapsed/refractory CLL with overall response rates (ORRs) of 58% and 76%, respectively. Given excellent data with bendamustine and rituximab in relapsed/refractory CLL/small Lymphocytic Lymphoma (SLL), this phase II study evaluated the combination of ofatumumab and bendamustine in previously treated patients. Patients received ofatumumab 300 mg intravenously (IV) day - 7, followed by ofatumumab 1000 mg IV day 1 and bendamustine 70 mg/m(2) days 1 and 2 of each 28-day cycle. Patients received 4-6 cycles depending on number of prior therapies, as long as well-tolerated or until progression. Of 10 patients enrolled, the ORR was 40% and complete response rate was 20%. The median progression-free and overall survivals were 8.1 months and 16.2 months. Three patients developed Richter transformation. The study was closed early due to unexpected adverse events including infusion-related reactions, infection and neurotoxicity.
