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C Varns - One of the best experts on this subject based on the ideXlab platform.
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extended rituximaB anti cd20 monoclonal antiBody therapy for relapsed or refractory low grade or <B>FollicularB> non hodgkin s lymphoma
Annals of Oncology, 1999Co-Authors: L D Piro, Antonio J Grillolopez, C Varns, Christine A White, Myron S Czuczman, Nalini Janakiraman, A Saven, T M Beck, S Shuey, J W LynchAbstract:Summary Background RituximaB is a chimeric monoclonal antiBody directed against the B-Cell CD20 antigen which has Been utilized for therapy of B-Cell non-Hodgkin's lymphoma (NHL). A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m2 of RituximaB in patients with relapsed or refractory low-grade or <B>FollicularB> B-Cell non-Hodgkin's lymphoma was well tolerated and had significant clinical activity. Patients and methods To assess the safety and efficacy of RituximaB treatment, an open-laBel, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m2 RituximaB in patients with low-grade or <B>FollicularB> B-Cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated. Results Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with suBsequent infusions. No patients developed a host antiBody response (HACA) to RituximaB. The mean serum immunogloBulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were Bcl-2 positive at Baseline in peripheral Blood Became Bcl-2 negative during treatment and remained negative at the time of B-Cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluaBle patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not Been reached after 19.4+ months and 13.4+ months, respectively. Conclusions The safety profile and efficacy achieved in this pilot study of extended treatment with RituximaB compares favoraBly with those seen with four weekly doses. Further studies are warranted to investigate whether this or other extended RituximaB schedules will result in increased efficacy in all or in certain suBgroups of patients with low-grade or <B>FollicularB> NHL.
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treatment of patients with low grade B Cell lymphoma with the comBination of chimeric anti cd20 monoclonal antiBody and chop chemotherapy
Journal of Clinical Oncology, 1999Co-Authors: Myron S Czuczman, Antonio J Grillolopez, Christine A White, Mansoor N Saleh, Leo I Gordon, Albert F Lobuglio, C Jonas, D Klippenstein, B K Dallaire, C VarnsAbstract:PURPOSE: To determine the safety and efficacy of the comBination of the chimeric anti-CD20 antiBody, Rituxan (RituximaB, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxoruBicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or <B>FollicularB> B-Cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in comBination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not Been reached after a median oBservation time of 29 + months. Twenty-eight of 38 assessaBle patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attriButaBle to CHOP were alopecia (38 pati...
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treatment of patients with low grade B Cell lymphoma with the comBination of chimeric anti cd20 monoclonal antiBody and chop chemotherapy
Journal of Clinical Oncology, 1999Co-Authors: Myron S Czuczman, Antonio J Grillolopez, Christine A White, Mansoor N Saleh, Leo I Gordon, Albert F Lobuglio, C Jonas, D Klippenstein, B K Dallaire, C VarnsAbstract:PURPOSE: To determine the safety and efficacy of the comBination of the chimeric anti-CD20 antiBody, Rituxan (RituximaB, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxoruBicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or <B>FollicularB> B-Cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in comBination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not Been reached after a median oBservation time of 29 + months. Twenty-eight of 38 assessaBle patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attriButaBle to CHOP were alopecia (38 pati...
Hongsheng Wang - One of the best experts on this subject based on the ideXlab platform.
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transcription factors irf8 and pu 1 are required for <B>FollicularB> B Cell development and Bcl6 driven germinal center responses
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Hongsheng Wang, Tomomi Sakai, Zohreh Naghashfar, Sadia Abbasi, Chen Feng Qi, Jangsuk Oh, Alexander L Kovalchuk, Peng Li, Shweta Jain, Silvia BollandAbstract:The IRF and Ets families of transcription factors regulate the expression of a range of genes involved in immune Cell development and function. However, the understanding of the molecular mechanisms of each family memBer has Been limited due to their redundancy and Broad effects on multiple lineages of Cells. Here, we report that douBle deletion of floxed Irf8 and Spi1 (encoding PU.1) By MB1-Cre (designated DKO mice) in the B Cell lineage resulted in severe defects in the development of <B>FollicularB> and germinal center (GC) B Cells. Class-switch recomBination and antiBody affinity maturation were also compromised in DKO mice. RNA-seq (sequencing) and ChIP-seq analyses revealed distinct IRF8 and PU.1 target genes in <B>FollicularB> and activated B Cells. DKO B Cells had diminished expression of target genes vital for maintaining <B>FollicularB> B Cell identity and GC development. Moreover, our findings reveal that expression of B-Cell lymphoma protein 6 (BCL6), which is critical for development of germinal center B Cells, is dependent on IRF8 and PU.1 in vivo, providing a mechanism for the critical role for IRF8 and PU.1 in the development of GC B Cells.
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an essential role of transcription factors pu 1 and irf8 in <B>FollicularB> B Cell development and the germinal center response
Journal of Immunology, 2018Co-Authors: Hongsheng Wang, Alexander L Kovalchuk, Shweta Jain, Herbert C. MorseAbstract:The transcription factors PU.1 and IRF8 regulate an unknown numBer of gene programs for differentiation of many hematopoietic Cells including B Cells, dendritic Cells and myeloid Cells. Their roles in B Cell development were previously studied using B Cell-specific conditional deletion mouse models, such as PU.1flox/flox-CD19Cre, IRF8flox/flox-CD19Cre, IRF8−/−PU.1flox/flox-CD19Cre, or IRF8flox/flox-PU.1flox/flox-CD19Cre mice. While PU.1-deficient B Cells are phenotypically normal, deletion of IRF8 in B Cells caused a moderate expansion of marginal zone B Cells. DouBle deletion of PU.1 and IRF8 caused moderate expansion of plasma Cells (PCs) in vitro. In this report, we investigated IRF8 and PU.1 douBle deletion mice using MB1-Cre - termed DKO mice. FACS analysis revealed normal levels of early stage B Cells in the Bone marrow and transitional B Cells in the spleens of DKO mice. However, <B>FollicularB> B Cells were markedly reduced and the MZ B Cell compartment was modestly expanded in DKO mice. The peritoneal CD5 + B-1a Cells, which are a major source of circulating IgM, were completely aBsent in DKO mice. Surprisingly, the serum levels of IgM were higher and the levels of IgG3 and IgA were slightly lower in DKO than control mice. While the levels of serum IgG1 were comparaBle Between DKO and control mice, DKO mice had no serum IgG2B or IgG2c antiBodies. More intriguingly, following immunization with NP-KLH/alum, although the DKO mice produced more IgM-secreting PCs early on, they failed to generate germinal centers and produced markedly reduced levels of NP-specific switched IgG antiBodies. Taken together, these data revealed a critical role of IRF8 and PU.1 in differentiation of <B>FollicularB> and germinal center B Cells.
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precocious interleukin 21 expression in naive mice identifies a natural helper Cell population in autoimmune disease
Cell Reports, 2017Co-Authors: Elisabeth Marnik, Hongsheng Wang, Shweta Jain, Xulong Wang, Thomas J Sproule, Giljun Park, Gregory J Christianson, Sarah Kate Lanereticker, Theodore Duffy, Gregory W CarterAbstract:Summary Interleukin 21 (IL-21) plays key roles in humoral immunity and autoimmune diseases. It is known to function in mature CD4 + T <B>FollicularB> B Cell helper (T FH ) Cells, But its potential involvement in early T Cell ontogeny is unclear. Here, we find that a significant population of newly activated thymic and peripheral CD4 + T Cells functionally expresses IL-21 soon after Birth. This naturally occurring population, termed natural (n)T H 21 Cells, exhiBits consideraBle similarity to mature T FH Cells. nT H 21 Cells originating and activated in the thymus are strictly dependent on autoimmune regulator (AIRE) and express high levels of NUR77, consistent with a Bias toward self-reactivity. Their activation/expansion in the periphery requires gut microBiota and is held in check By FoxP3 + T REG Cells. nT H 21 Cells are the major thymic and peripheral populations of IL-21 + Cells to expand in an IL-21-dependent humoral autoimmune disease. These studies link IL-21 to T Cell ontogeny, self-reactivity, and humoral autoimmunity.
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ifn regulatory factor 8 restricts the size of the marginal zone and <B>FollicularB> B Cell pools
Journal of Immunology, 2011Co-Authors: Jianxun Feng, Hongsheng Wang, Dongmi Shin, Marek Masiuk, Herbert C. MorseAbstract:Transcriptional control of marginal zone (MZ) and <B>FollicularB> (FO) B Cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B Cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B Cells. Mice with a conventional knockout of Irf8 (IRF8−/−) or a point mutation in the IRF association domain of IRF8 had increased numBers of MZ B Cells. To determine the B Cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numBers of MZ and FO B Cells compared with controls. The FO B Cells of CKO mice exhiBited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B Cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal AB responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B Cells But has little effect on B Cell function.
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irf8 regulates myeloid and B lymphoid lineage diversification
Immunologic Research, 2009Co-Authors: Hongsheng Wang, Herbert C. MorseAbstract:Interferon regulatory factor 8 (IRF8) is a memBer of the IRF family of transcription factors whose memBers play critical roles in interferon (IFN) signaling pathways governing the estaBlishment of innate immune responses By myeloid and dendritic Cells. IRF8 is also expressed in lymphoid Cells and recent studies have documented its involvement in B Cell lineage specification, immunogloBulin light chain gene rearrangement, the distriBution of mature B Cells into the marginal zone and <B>FollicularB> B Cell compartment, and the transcriptional regulation of critical elements of the germinal center reaction. Here we review the contriButions of IRF8 to B Cell development from hematopoietic stem Cells in the Bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B Cell fate.
Herbert C. Morse - One of the best experts on this subject based on the ideXlab platform.
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an essential role of transcription factors pu 1 and irf8 in <B>FollicularB> B Cell development and the germinal center response
Journal of Immunology, 2018Co-Authors: Hongsheng Wang, Alexander L Kovalchuk, Shweta Jain, Herbert C. MorseAbstract:The transcription factors PU.1 and IRF8 regulate an unknown numBer of gene programs for differentiation of many hematopoietic Cells including B Cells, dendritic Cells and myeloid Cells. Their roles in B Cell development were previously studied using B Cell-specific conditional deletion mouse models, such as PU.1flox/flox-CD19Cre, IRF8flox/flox-CD19Cre, IRF8−/−PU.1flox/flox-CD19Cre, or IRF8flox/flox-PU.1flox/flox-CD19Cre mice. While PU.1-deficient B Cells are phenotypically normal, deletion of IRF8 in B Cells caused a moderate expansion of marginal zone B Cells. DouBle deletion of PU.1 and IRF8 caused moderate expansion of plasma Cells (PCs) in vitro. In this report, we investigated IRF8 and PU.1 douBle deletion mice using MB1-Cre - termed DKO mice. FACS analysis revealed normal levels of early stage B Cells in the Bone marrow and transitional B Cells in the spleens of DKO mice. However, <B>FollicularB> B Cells were markedly reduced and the MZ B Cell compartment was modestly expanded in DKO mice. The peritoneal CD5 + B-1a Cells, which are a major source of circulating IgM, were completely aBsent in DKO mice. Surprisingly, the serum levels of IgM were higher and the levels of IgG3 and IgA were slightly lower in DKO than control mice. While the levels of serum IgG1 were comparaBle Between DKO and control mice, DKO mice had no serum IgG2B or IgG2c antiBodies. More intriguingly, following immunization with NP-KLH/alum, although the DKO mice produced more IgM-secreting PCs early on, they failed to generate germinal centers and produced markedly reduced levels of NP-specific switched IgG antiBodies. Taken together, these data revealed a critical role of IRF8 and PU.1 in differentiation of <B>FollicularB> and germinal center B Cells.
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ifn regulatory factor 8 restricts the size of the marginal zone and <B>FollicularB> B Cell pools
Journal of Immunology, 2011Co-Authors: Jianxun Feng, Hongsheng Wang, Dongmi Shin, Marek Masiuk, Herbert C. MorseAbstract:Transcriptional control of marginal zone (MZ) and <B>FollicularB> (FO) B Cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B Cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B Cells. Mice with a conventional knockout of Irf8 (IRF8−/−) or a point mutation in the IRF association domain of IRF8 had increased numBers of MZ B Cells. To determine the B Cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numBers of MZ and FO B Cells compared with controls. The FO B Cells of CKO mice exhiBited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B Cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal AB responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B Cells But has little effect on B Cell function.
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irf8 regulates myeloid and B lymphoid lineage diversification
Immunologic Research, 2009Co-Authors: Hongsheng Wang, Herbert C. MorseAbstract:Interferon regulatory factor 8 (IRF8) is a memBer of the IRF family of transcription factors whose memBers play critical roles in interferon (IFN) signaling pathways governing the estaBlishment of innate immune responses By myeloid and dendritic Cells. IRF8 is also expressed in lymphoid Cells and recent studies have documented its involvement in B Cell lineage specification, immunogloBulin light chain gene rearrangement, the distriBution of mature B Cells into the marginal zone and <B>FollicularB> B Cell compartment, and the transcriptional regulation of critical elements of the germinal center reaction. Here we review the contriButions of IRF8 to B Cell development from hematopoietic stem Cells in the Bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B Cell fate.
Ian W. Flinn - One of the best experts on this subject based on the ideXlab platform.
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long term follow up of a phase 1 study of idelalisiB zydelig in comBination with anti cd20 antiBodies rituximaB r or ofatumumaB o in patients with relapsed or refractory chronic lymphocytic leukemia cll
Blood, 2014Co-Authors: Richard R. Furman, Jacqueline C. Barrientos, Sven De Vos, Ian W. Flinn, Jeff P Sharman, John P. Leonard, Marshall T Schreeder, Thomas E Boyd, Nathan Fowler, Kanti R. RaiAbstract:Introduction: PI3Kδ signaling is critical for the proliferation, survival and homing/tissue retention of malignant B Cells. IdelalisiB is a first-in-class, highly selective, oral inhiBitor of PI3Kδ recently approved for the treatment of relapsed CLL in comBination with R. This report summarizes the long-term follow-up of the Phase 1 comBination experience of idelalisiB with anti-CD20 antiBodies. Methods: This Phase 1 study evaluated idelalisiB for relapsed/refractory CLL continuously given at 100 mg BID (4 of the pts receiving R) or 150 mg BID (all other pts) in comBination with a total of 8 infusions of rituximaB (R, 375 mg/m2 weekly x 8), or a total of 12 infusions of ofatumumaB (O, 300mg initial dose either on Day 1 or Day 2 relative to the first dose of idelalisiB, then 1,000 mg weekly x 7, then 1,000 mg every 4 wks x 4). Pts on treatment after 48 weeks were eligiBle to continue idelalisiB on an extension study. Clinical response was evaluated according to puBlished criteria (Hallek 2008; Cheson 2012). Results: 40 pts (12F/28M) with a median (range) age of 66 (43-87) years and a WHO performance status of 0 (24, 60%) or 1 (16, 40%) were enrolled. 19 pts received idelalisiB in comBination with R and 21 with O. Adverse disease characteristics (n, %) included Rai Stage III/IV (20, 50%), Bulky lymphadenopathy (23, 58%), refractory disease (15, 38%), multiple prior therapies (median 2, range: 1-9). Almost all pts (39, 98%) had at least 1 prior therapy containing R, and 3 of the 21 pts (14%) receiving idelalisiB + O had received prior O. 63% of the pts receiving idelalisiB + R, and 48% of the pts receiving idelalisiB + O were refractory to R. Prior therapies also included alkylating agents (31, 78%, [Bendamustine: 20, 50%]) and purine analogs (31, 78%, [fludaraBine: 28, 70%]). Data availaBle from 39 pts showed that 11 (28%) pts had evidence of del(17p) and/or TP53 mutations and 30 (75%) had unmutated IGHV. As of 7/15/2014, the median (range) treatment duration was 18 (0-44) months. 23 (58%) pts have completed the primary study and enrolled into the extension study. Primary reasons for study discontinuation (as reported By investigators) included disease progression (14, 35%), adverse events (AEs) (12, 30%), investigator request (3, 8%), withdrawal of consent (n=1), BMT (n=1). There were a total of 8 deaths on study: 2 deaths occurred after disease progression, and 6 pts died Because of AEs (all assessed as unrelated/unlikely related to idelalisiB By investigators). A total of 4 pts (10%) were continuing idelalisiB treatment on the extension study at time of analysis. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (55%/23%), cough (40%/3%), pyrexia (40%/3%), dyspnea (30%/3%), fatigue (25%/0%) nausea (25%/0%), rash (20%/0%), pneumonia (20%/18%), and pneumonitis (8%/5%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 30%/10%. Re-exposure to idelalisiB after resolution of TA elevation generally was successful; only 1 patient discontinued the study Because of (recurrent) TA elevation. Other AEs leading to study discontinuation and reported as possiBly/proBaBly related to idelalisiB included diarrhea/colitis (4, 10%), pyrexia (n=1), interstitial lung disease (n=1), pneumonia (n=1), rash (n=1), psoriasis (n=1). Secondary malignancies leading to discontinuation (all reported as unrelated) were Breast cancer (n=1), recurrent colon cancer (n=1), AML (n=1). There was no oBvious overall difference in the toxicity reported for pts receiving idelalisiB with rituximaB compared to those with ofatumumaB. The ORR (N=40) was 83% (33/40), with 2 CRs (5%) reported. Median PFS (N=40) and duration of response (DOR) (n=33) were 24 months. Median (range) time to response was 1.9 (range 1.7-16.9) months. Median overall survival (OS) has not Been reached with a KM estimate for OS of 80% at 24 months. For the 11 pts with del(17p) and/or TP53 mutations, the response rate was 73%, and the median PFS and DOR were 20 and 24 months, respectively. Conclusions: ComBinations of idelalisiB with anti-CD20 antiBodies such as R or O represent non-cytotoxic regimens with acceptaBle safety profiles and consideraBle activity resulting in duraBle tumor control in pts with relapsed/refractory CLL, including those with high risk factors such as del(17p) or TP53 mutations. A Phase 3 trial evaluating the efficacy of idelalisiB in comBination with ofatumumaB is ongoing ([NCT01659021][1]). Disclosures Furman: Gilead Sciences: Research Funding. Off LaBel Use: Zydelig is a kinase inhiBitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in comBination with rituximaB, in patients for whom rituximaB alone would Be considered appropriate therapy due to other co-morBidities; 2) Relapsed <B>FollicularB> B-Cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. de Vos: Gilead Sciences: Research Funding. Barrientos: Gilead Sciences: Research Funding. Schreeder: Gilead Sciences: Research Funding. Flinn: Gilead Sciences: Research Funding. Sharman: Gilead Sciences: Research Funding. Boyd: Gilead Sciences: Research Funding. Fowler: Gilead Sciences: Research Funding. Leonard: Gilead Sciences: Research Funding. Rai: Gilead Sciences: Research Funding. Kim: Gilead Sciences: Employment, Equity Ownership. Viggiano: Gilead Sciences: Employment, Equity Ownership. Jahn: Gilead Sciences: Employment, Equity Ownership. Coutre: Gilead Sciences: Research Funding. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01659021&atom=%2FBloodjournal%2F124%2F21%2F5653.atom
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long term follow up of a phase 1 trial of idelalisiB zydelig in comBination with Bendamustine B Bendamustine rituximaB Br fludaraBine f chloramBucil chl or chloramBucil rituximaB chlr in patients with relapsed or refractory chronic lymphocytic leukem
Blood, 2014Co-Authors: Jacqueline C. Barrientos, Steven Coutre, Sven De Vos, Ian W. Flinn, Jeff P Sharman, Kanti R. Rai, Nina D Wagnerjohnston, Marshall T Schreeder, Thomas E Boyd, John P. LeonardAbstract:BACKGROUND: PI3Kδ signaling is critical for the proliferation and survival as well as for homing and tissue retention of malignant B Cells. IdelalisiB is a first-in-class, targeted, highly selective, oral inhiBitor of PI3Kδ with consideraBle activity as monotherapy and in comBination with R in patients with relapsed/refractory CLL, and was recently approved for the treatment of relapsed CLL in comBination with R. This report summarizes the long-term follow-up of the Phase 1 comBination experience of idelalisiB with chemo- and immuno-chemotherapies. METHODS: 74 suBjects were sequentially enrolled into one of 5 regimens of idelalisiB comBined with either B (70 or 90 mg/m2 IV on D1,2 of cycles 1-6, N=18, enrolled Apr 2011-Nov 2011), BR (B: 70 mg/m2 IV on D1,2 of cycles 1-6; R: 375 mg/m2 IV on D1 of cycles 1-6, N=15, enrolled Apr 2011-Aug 2011), F (40 mg/m2 po D1-5 of cycles 1-6, N=12, enrolled Apr 2011-Aug 2011), Chl (10 mg/m2 po D1-7 x 3(min)-12(max) cycles, N=15, enrolled Mar 2012-Aug 2012), or ChlR (N=14, enrolled Mar 2012-Jul 2012). IdelalisiB was administered at 100 (4 of the pts receiving B) or 150 mg po BID (all other patients) continuously. Patients on treatment after 48 weeks were eligiBle to continue idelalisiB on an extension study. Clinical responses were evaluated according to puBlished criteria (Hallek 2008; Cheson 2012). RESULTS: Of 74 suBjects enrolled, 66% were male. Median age was 65 years, and median time since diagnosis was 8 years with a median of 3 (range 1-9) prior regimens. Overall, prior therapies included R (97%), F (78%), B (45%), and Chl (14%), and 55% of patients were refractory to last therapy. 65% of patients had Rai stage III/IV disease at enrollment. Adverse prognostic factors included del(17p) and/or TP53 mutation (30%), IGHV unmutated status (82%), NOTCH1 mutation (28%). As of 7/15/2014, the median idelalisiB exposure for patients of all cohorts was 12.8 (range 1-48) months. 41 (55%) of patients completed the 48 weeks of the primary study, and 20 suBjects (27%) were still on treatment on the extension study at the time of analysis. The most common reasons for discontinuation reported By investigators were adverse events (AEs) (15, 20%) or progressive disease (PD) (12, 16%). There were 13 deaths reported on study; 4 patients experienced PD Before death. Selected treatment-emergent AEs (any Grade/≥Gr 3, regardless of causality) included diarrhea/colitis (51%/18%), pyrexia (47%/5%), fatigue (35%/7%), cough (35%/0%), nausea (31%/1%), pneumonia (23%/14%), rash (22%/7%), dyspnea (19%/3%), and pneumonitis (3%/3%). Elevation of liver transaminases (TA, any Grade/≥Gr 3) was seen in 37%/14%. Of those, only 1 patient discontinued the study Because of (recurrent) TA elevation. Richter’s transformation as category of progressive disease was reported in 1 patient (3%). The ORR was 82% for all 74 patients with a CR rate of 10%. 4 of 74 patients (5%) were not evaluaBle Because of missing follow-up assessments. Among 69 suBjects with genetic data availaBle, the ORR in the 22 suBjects with either del(17p) and/or TP53 mutation was 68% vs. 87% among 47 suBjects with neither aBerration. The overall median PFS was not reached at the time of analysis (Figure 1); KM estimate of PFS was 57% [43-72%, 95% CI] at 24 months. Overall median time to response was 1.9 months, and overall median DOR was not yet reached. CONCLUSIONS: These preliminary results in patients with relapsed or refractory disease and multiple prior therapies suggest that idelalisiB can Be comBined with B, BR, F, Chl, and ChlR with acceptaBle safety and that these comBinations have suBstantial clinical activity. A Phase 3 study evaluating the comBination of idelalisiB with BR in relapsed CLL is ongoing (NCT01732926). Disclosures Barrientos:Gilead Sciences: Research Funding. Off LaBel Use: Zydelig is a kinase inhiBitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in comBination with rituximaB, in patients for whom rituximaB alone would Be considered appropriate therapy due to other co-morBidities; 2) Relapsed <B>FollicularB> B-Cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Coutre:Gilead Sciences: Research Funding. de Vos:Gilead Sciences: Research Funding. Wagner-Johnston:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Research Funding. Schreeder:Gilead Sciences: Research Funding. Boyd:Gilead Sciences: Research Funding. Rai:Gilead Sciences: Research Funding. Leonard:Gilead Sciences: Research Funding. Kim:Gilead Sciences: Employment, Equity Ownership. Viggiano:Gilead Sciences: Employment, Equity Ownership. Jahn:Gilead Sciences: Employment, Equity Ownership. Furman:Gilead Sciences: Research Funding.
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a phase 2 study of idelalisiB monotherapy in previously untreated patients 65 years with chronic lymphocytic leukemia cll or small lymphocytic lymphoma sll
Blood, 2014Co-Authors: Andrew D Zelenetz, Steven Coutre, Nicole Lamanna, Thomas J Kipps, Susan Obrien, Maria Aiello, Yoonjin Cho, Ronald L Dubowy, Ian W. FlinnAbstract:BACKGROUND: PI3K-delta (δ) is critical for activation, proliferation and survival of B Cells and plays a role in homing and retention in lymphoid tissues. PI3Kδ signaling is hyperactive in many B-Cell malignancies. IdelalisiB (Zydelig, IDELA,), a potent and selective orally administered inhiBitor of PI3Kδ, in comBination with rituximaB weekly x 8 has yielded an ORR of 97% in patients (pts) ≥65 years with previously untreated CLL or SLL (O’Brien, ASCO 2013). This report descriBes the preliminary experience in treating a similar cohort of pts with IDELA monotherapy. METHODS: Enrollment Began in NovemBer, 2013. Treatment-naive pts ≥65 yrs with CLL or SLL, requiring treatment per IWCLL 2008 criteria, and with measuraBle lymphadenopathy, were treated with IDELA 150 mg Bid continuously. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, using modified IWCLL guidelines (Hallek 2008, Cheson 2012). RESULTS: As of 21 July 2014, 37 pts were enrolled: 78% male; CLL/SLL in 92%/8%; median age 70 years; 73% Rai III or IV; WHO 0-1/2 in 97%/3%. 46% had ≥1 B-symptom. Hepatomegaly and splenomegaly were present in 14% and 57% respectively. Adverse prognostic factors: 14% del(17p) and/or TP53 mutated; 22% del(11q); 41% IGHV unmutated; β-2 microgloBulin median 4.35 mg/L (range: 2.1-12.4). The median idelalisiB exposure was 4.8 months (range 0.9-8.5). There has Been one discontinuation at 3 mo for respiratory distress, assessed as related to a prior condition. The median aBsolute lymphocyte count was 59.7 K/µl (range: 0.8-294) at Baseline peaking at 100 K/µl (range: 2-385) at week 4. 27 pts were evaluaBle for response, having reached the first evaluation time point of 8 weeks. Of these 27, the ORR was 81% with 9 (33%) PR and 13 (48%) PR with lymphocytosis. Splenomegaly has responded in 88% of 17 evaluaBle pts and hepatomegaly in 75% of 4 evaluaBle pts. The most frequent treatment emergent adverse events (TEAE) (% all Grade/% Grade ≥3) were rash (27/3), URI (16/0), constipation (14/0), cough (14/0), nausea (11/0), pyrexia (11/0), arthralgia (8/0), Back pain (8/0), diarrhea (8/3), and pneumonia (8/5). Pneumonitis was oBserved in 2 pts (5%), Gr ≥3 in 1(3%). Gr ≥3 treatment emergent laB aBnormalities included transaminase elevation (8%), anemia (5%), and neutropenia (20%); there was no Gr ≥3 thromBocytopenia. One pt had a TEAE leading to dose reduction. CONCLUSIONS: IDELA has suBstantial single agent activity in treatment-naive pts with CLL or SLL. Early lymphocytosis is oBserved with monotherapy in this population, as opposed to an attenuation of lymphocytosis seen in the earlier cohort treated with IDELA plus weekly rituximaB. IDELA was well tolerated and had a manageaBle safety profile in this preliminary analysis. Disclosures Zelenetz:Gilead Sciences: Research Funding. Off LaBel Use: Zydelig is a kinase inhiBitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in comBination with rituximaB, in patients for whom rituximaB alone would Be considered appropriate therapy due to other co-morBidities; 2) Relapsed <B>FollicularB> B-Cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna:Gilead Sciences: Research Funding. Kipps:Gilead Sciences: Research Funding. Coutre:Gilead Sciences: Research Funding. O9Brien:Gilead Sciences: Research Funding. Aiello:Gilead Sciences: Employment, Equity Ownership. Cho:Gilead Sciences: Employment, Equity Ownership. DuBowy:Gilead Sciences: Employment, Equity Ownership. Flinn:Gilead Sciences: Research Funding.
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update on a phase 2 study of idelalisiB in comBination with rituximaB in treatment naive patients 65 years with chronic lymphocytic leukemia cll or small lymphocytic lymphoma sll
Blood, 2014Co-Authors: Susan Obrien, Ian W. Flinn, Andrew D Zelenetz, Nicole Lamanna, Thomas J Kipps, Yoonjin Cho, Ronald L Dubowy, Jan A Burger, Leanne Holes, Steven CoutreAbstract:Background: The selectivePI3K-delta inhiBitor IdelalisiB (Zydelig®, IDELA), in comBination with rituximaB (R), has Been previously reported to yield a 97% ORR in treatment naive patients (pts) ≥65 years with CLL or SLL (O’Brien, ASCO 2013). This report is an update on that initial cohort of study pts. Methods: Treatment-naive pts ≥65 yrs with CLL or SLL were treated with R 375 mg/m 2 weekly x 8 and idelalisiB 150 mg Bid continuously for 48 weeks (primary study). Pts completing 48 weeks without progression could continue to receive idelalisiB on an extension study. Response assessment, at pre-determined time points, was investigator determined using either physical exam or CT scans per investigator discretion, Based on modified IWCLL guidelines (Hallek 2008, Cheson 2012). Results: 64 pts were enrolled, 59 CLL/5 SLL, median age 71 yrs (range: 65-90), 63% male, Rai stage III/IV 13/30 (%), nodes ≥5 cm in 11%, WHO 0/1/2 in 42/56/2 (%). Adverse risk factors: del(17p) and/or TP53 mutation in 14%, del(11q) in 16%, IGHV unmutated in 58%, median β2-microgloBulin 4.0 mg/L (range 1.9-15.8). Disposition: 43 pts completed the 48 wk primary study and 41 entered the extension study. 21 pts discontinued from the primary study (17 AE, 1 withdrawn consent, 3 deaths [pneumonitis; sepsis; metastatic melanoma with pneumonia]); an additional death occurred within 30 days of discontinuation due to pneumonitis. There were 17 discontinuations from the extension study (9 AE, 2 withdrawn consent, 1 investigator request, 4 PD, 1 death [myocardial infarction]), leaving 24 pts ongoing. The median IDELA exposure is 22.9 mos (range 0.8-45.3), with 13 (20%) pts treated for more than 36 months. The ORRis 97% (78% PR, 19% CR) with 3% nonevaluaBle; median time to response is 1.9 mos (range 1.6-5.7). The Kaplan-Meier (KM) estimated median PFS is not reached (NR), 95% CI (37.3 mo, --). The KM estimated DOR is NR, 95% CI (35.4,--). Of note, 9/9 pts with del(17p) and/or TP53 mutation responded (3 CR, 6 PR); 5 discontinued for AE (4) or investigator request (1) and 4 remain on treatment for 28, 34, 40 and 41 months. The most frequent Gr ≥3 AEs (%) were diarrhea/colitis (42), pneumonia (19), rash (13), dehydration (8), UTI (6), dyspnea (5) and respiratory failure (5). In addition, pneumonitis developed in 2 pts (3%), Both Gr 5, and one pt with diverticulitis developed Bowel perforation. The median time to onset of Gr ≥3 diarrhea/colitis was 9.5 mo, (range 3-29). Rechallenge was attempted in 21 of the 27 pts with Gr ≥3 diarrhea/colitis, and 12 pts were aBle to resume IDELA for ≥ 120 days. 15 (23%) pts developed Gr ≥3 ALT or AST elevation, all recovering, with successful resumption of IDELA, at a reduced dose, in 12. In total, 29 (45%) pts had one or more treatment-emergent AEs leading to IDELA dose reduction. Conclusions: IDELA + R is highly active, rapidly inducing responses in 97% of treatment-naive older pts with CLL and SLL. The responses are duraBle, including in those with del(17p)/TP53 mutation. Diarrhea/colitis was the most common Gr ≥3 AE, and IDELA was successfully reintroduced in 44% of the affected pts. Ongoing studies are further investigating the role of IDELA in the frontline setting. Disclosures O9Brien: Gilead Sciences: Research Funding. Off LaBel Use: Zydelig is a kinase inhiBitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in comBination with rituximaB, in patients for whom rituximaB alone would Be considered appropriate therapy due to other co-morBidities; 2) Relapsed <B>FollicularB> B-Cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Lamanna: Gilead Sciences: Research Funding. Kipps: Gilead Sciences: Research Funding. Flinn: Gilead Sciences: Research Funding. Zelenetz: Gilead Sciences: Research Funding. Burger: Gilead Sciences: Research Funding. Holes: Gilead Sciences: Employment, Equity Ownership. Cho: Gilead Sciences: Employment, Equity Ownership. DuBowy: Gilead Sciences: Employment, Equity Ownership. Coutre: Gilead Sciences: Research Funding.
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duraBle responses following treatment with the pi3k delta inhiBitor idelalisiB in comBination with rituximaB Bendamustine or Both in recurrent indolent non hodgkin lymphoma phase i ii results
Blood, 2014Co-Authors: Sven De Vos, Steven Coutre, Jacqueline C. Barrientos, Ian W. Flinn, Jeff P Sharman, Nina D Wagnerjohnston, Marshall T Schreeder, Nathan Fowler, Ralph V Boccia, Kanti R. RaiAbstract:Introduction: PI3K-delta signaling is critical for activation, proliferation and survival of B Cells, and is hyperactive in many B-Cell malignancies. IdelalisiB, a selective oral inhiBitor of PI3Kd, demonstrated consideraBle clinical activity as monotherapy in recurrent (Flinn, Blood 2014) or refractory iNHL suBjects (Gopal, NEJM 2014). FDA granted accelerated approval for IdelalisiB (ZYDELIG ® ) in patients who have received at least two prior systemic therapies with relapsed FL or SLL. This study evaluated IdelalisiB in comBination with rituximaB, Bendamustine, or Both. We now present mature safety and response data with up to 4 years of follow up. Methods : EligiBle patients had relapsed/refractory indolent NHL. IdelalisiB (Z) was administered continuously with rituximaB (R) (375 mg/m 2 given weekly for 8 doses) (R/Z regimen), with Bendamustine (B) (90 mg/m 2 given on Days 1 and 2, for 6 cycles) (B/Z regimen), or in comBination with R (375 mg/m 2 , on Day 1) and B (90 mg/m 2 given on Days 1 and 2 of each cycle, for 6 cycles (BR/Z regimen). Initial suBjects in the R/Z and B/Z groups (n=8 each), received IdelalisiB 100 mg/dose BID. Thereafter, all patients received an IdelalisiB dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Cheson 2007). The cutoff date for this analysis was June 2014, 26 months after the last patient enrolled. Results: Between April 2010 and May 2012, 79 suBjects with iNHL were enrolled (including 59 with FL, 15 with SLL, and 5 with MZL). Median [range] age was 61 [37-84] years. At Baseline patients had elevated Beta-2 microgloBulin (59%), stage IV disease (58%), Bulky adenopathy (> 5cm) (48%), anemia (HgB Frequent adverse events (all grade %/grade 3-4 %) included pyrexia (54/3), nausea (44/0), fatigue (43/4), diarrhea (39/15), rash (38/9), cough (35/0), pneumonia (22/19), pneumonitis (4/3), and feBrile neutropenia (3/3). LaBoratory aBnormalities included lymphopenia (75/62), neutropenia (56/41), anemia (47/10), thromBocytopenia (42/8), and serum transaminase elevations (56/17). Drug was temporarily held for Grade 3/4 ALT/AST elevations, and 8/13 pts (62%) were re-treated without recurrence of ALT/AST elevation. 27% of pts have discontinued therapy due to adverse events. Of the 79 suBjects enrolled, 64 had an oBjective response with an ORR of 81% (95% CI: 70.6-89.0). Complete responses were demonstrated in 26 patients (33%), and partial responses in 38 patients (48%). In addition, 7 patients had staBle disease (9%), and 4 patients had progressive disease (5%) as Best response on-study. Four patients were non-evaluaBle, as they did not have follow up CT scans. By treatment suBgroup, the ORR were (n=24/32) 75% (95% CI: 57-89) for R/Z, (n=29/33) 88% (95% CI: 72-97) for B/Z, and (n=11/14) 79% (95% CI: 49-95) BR/Z. The CR rates were 25% (n=8/32), 36% (n=12/33), and 43% (n=6/14) respectively; staBle disease was noted in 4/32 patients (13%), 3/33 patients (9%), and 0/14 patients in the three groups respectively. ORR/CR By iNHL suBtype is: FL (81%/39%), SLL (73%/13%), and MZL (100%/20%). The median progression-free survival is 32.8 months. Median PFS for R/Z group is 29.7 months, B/Z group 32.8 months, and BR/Z group 37.1 months. The PFS at 24 months was 55%, 64%, and 71% for the R/Z, B/Z, and BR/Z groups respectively. The median duration of response has not yet Been reached. Median DOR for the R/Z group is 28.6 months, for the B/Z, and BR/Z groups it is not yet reached. The DOR at 24 months was 65%, 67%, and 64% for the R/Z, B/Z, and BR/Z groups respectively. Figure 1: Median overall survival is not yet reached. Conclusions: IdelalisiB in comBination therapy was well tolerated, had an acceptaBle safety profile, and was highly effective in this recurrent iNHL population with an ORR of 81%, and CR rate of 33%. Responses are duraBle Beyond 2 years, supporting further evaluation of these comBination regimens. Phase 3 trials evaluating the efficacy of IdelalisiB in comBination with R or BR in iNHL are ongoing (NCT01732913, NCT01732929). Disclosures de Vos: Gilead Sciences: Research Funding. Off LaBel Use: Zydelig is a kinase inhiBitor indicated for the treatment of patients with: 1) Relapsed chronic lymphocytic leukemia (CLL), in comBination with rituximaB, in patients for whom rituximaB alone would Be considered appropriate therapy due to other co-morBidities; 2) Relapsed <B>FollicularB> B-Cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies; and 3) Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies.. Wagner-Johnston: Gilead Sciences: Research Funding. Coutre: Gilead Sciences: Research Funding. Flinn: Gilead Sciences: Research Funding. Schreeder: Gilead Sciences: Research Funding. Fowler: Gilead Sciences: Research Funding. Sharman: Gilead Sciences: Research Funding. Boccia: Gilead Sciences: Research Funding. Barrientos: Gilead Sciences: Research Funding. Rai: Gilead Sciences: Research Funding. Boyd: Gilead Sciences: Research Funding. Furman: Gilead Sciences: Research Funding. Holes: Gilead Sciences: Employment, Equity Ownership. Kim: Gilead Sciences: Employment, Equity Ownership. Godfrey: Gilead Sciences: Employment, Equity Ownership. Leonard: Gilead Sciences: Research Funding.
Myron S Czuczman - One of the best experts on this subject based on the ideXlab platform.
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extended rituximaB anti cd20 monoclonal antiBody therapy for relapsed or refractory low grade or <B>FollicularB> non hodgkin s lymphoma
Annals of Oncology, 1999Co-Authors: L D Piro, Antonio J Grillolopez, C Varns, Christine A White, Myron S Czuczman, Nalini Janakiraman, A Saven, T M Beck, S Shuey, J W LynchAbstract:Summary Background RituximaB is a chimeric monoclonal antiBody directed against the B-Cell CD20 antigen which has Been utilized for therapy of B-Cell non-Hodgkin's lymphoma (NHL). A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m2 of RituximaB in patients with relapsed or refractory low-grade or <B>FollicularB> B-Cell non-Hodgkin's lymphoma was well tolerated and had significant clinical activity. Patients and methods To assess the safety and efficacy of RituximaB treatment, an open-laBel, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m2 RituximaB in patients with low-grade or <B>FollicularB> B-Cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated. Results Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with suBsequent infusions. No patients developed a host antiBody response (HACA) to RituximaB. The mean serum immunogloBulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were Bcl-2 positive at Baseline in peripheral Blood Became Bcl-2 negative during treatment and remained negative at the time of B-Cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluaBle patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not Been reached after 19.4+ months and 13.4+ months, respectively. Conclusions The safety profile and efficacy achieved in this pilot study of extended treatment with RituximaB compares favoraBly with those seen with four weekly doses. Further studies are warranted to investigate whether this or other extended RituximaB schedules will result in increased efficacy in all or in certain suBgroups of patients with low-grade or <B>FollicularB> NHL.
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treatment of patients with low grade B Cell lymphoma with the comBination of chimeric anti cd20 monoclonal antiBody and chop chemotherapy
Journal of Clinical Oncology, 1999Co-Authors: Myron S Czuczman, Antonio J Grillolopez, Christine A White, Mansoor N Saleh, Leo I Gordon, Albert F Lobuglio, C Jonas, D Klippenstein, B K Dallaire, C VarnsAbstract:PURPOSE: To determine the safety and efficacy of the comBination of the chimeric anti-CD20 antiBody, Rituxan (RituximaB, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxoruBicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or <B>FollicularB> B-Cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in comBination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not Been reached after a median oBservation time of 29 + months. Twenty-eight of 38 assessaBle patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attriButaBle to CHOP were alopecia (38 pati...
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treatment of patients with low grade B Cell lymphoma with the comBination of chimeric anti cd20 monoclonal antiBody and chop chemotherapy
Journal of Clinical Oncology, 1999Co-Authors: Myron S Czuczman, Antonio J Grillolopez, Christine A White, Mansoor N Saleh, Leo I Gordon, Albert F Lobuglio, C Jonas, D Klippenstein, B K Dallaire, C VarnsAbstract:PURPOSE: To determine the safety and efficacy of the comBination of the chimeric anti-CD20 antiBody, Rituxan (RituximaB, IDEC-C2B8; IDEC Pharmaceuticals Corporation, San Diego, CA), and cyclophosphamide, doxoruBicin, vincristine, and prednisone (CHOP) chemotherapy. PATIENTS AND METHODS: Forty patients with low-grade or <B>FollicularB> B-Cell non–Hodgkin's lymphoma received six infusions of Rituxan (375 mg/m2 per dose) in comBination with six doses of CHOP chemotherapy. RESULTS: The overall response rate was 95% (38 of 40 patients). Twenty-two patients experienced a complete response (55%), 16 patients had a partial response (40%), and two patients, who received no treatment, were classified as nonresponders. Medians for duration of response and time to progression had not Been reached after a median oBservation time of 29 + months. Twenty-eight of 38 assessaBle patients (74%) continued in remission during this median follow-up period. The most frequent adverse events attriButaBle to CHOP were alopecia (38 pati...