Potential Synergic Effect of Lenalidomide-Rituximab Combination: Durable Complete Remissions in Refractory Diffuse Large B Cell Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4989-4989
Author(s):  
Vadim Ivanov ◽  
Diane Coso ◽  
Therese Aurran-Schleinitz ◽  
Jean-Marc Schiano de Colella ◽  
Anne-Marie Stoppa ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Published Data ◽  
Significant Activity ◽  
Antitumor Effects ◽  
Histologic Subtype ◽  
Initial Results

Abstract Abstract 4989 Data emerging from initial clinical trials demonstrated that Lenalidomide has a significant activity against different subtypes of aggressive B-cell lymphoma. Clinical responses are histologic subtype-dependent and most prominent in mantle cell lymphoma. The results in DLBCL were less encouraging with ORR of 26%, CR of 9%, PFS of 2.7 mo. Concurrently targeting the tumor cell itself with monoclonal antibody and targeting the immune response and microenvironment with Lenalidomide may be a promising therapeutic strategy. By modulating the immune system through dendritic cells and NK cells, by changing the cytokine milieu, and by their anti-angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vitro and vivo antitumor effects against B-cell lymphoma. Recently the combination Lenalidomide-Rituximab (LR) was shown to be highly efficacious in follicular NHL. Encouraging by our initial results of LR combination in patient with refractory (R/R) DLBCL (Leuk Lymphoma 2010), Institutional Multidisciplinary Meeting proposed this combination for other 8 patients with R/R DLBCL. All patients were refractory to three or more previous lines of conventional immuno-chemotherapy. All except 3 primary-refractory pts were previously autografted. Patients received combination of Rituximab 375 mg/m2, day 1 or day 7; Lenalidomide (Revlimid), 15 mg/d for the first pt and 25 mg/d for other 8 pts, for 21 days. Dexamethasone 40mg, day 1–4 was given for first 6 pts. Initial decision on adding Dexamethasone was based on the extrapolation from the recommended regimen used in multiple myeloma, but it was abandoned in last 3 pts. Of 9 pts enrolled on study, 8 received > 2 cycles of LR and all of them were evaluable for response. Median age for evaluable pts was 52 (range: 19–73), 3 pts are female. Of 8 evaluable pts, 5 (63%) responded to LR, including 3 pts (38%) with CR and 2 (25%) patients with PR. These two PR pts were primary refractory to chemotherapy before LR and both were grafted (1 auto and 1 allo) after three courses of LR. One pt with clinical and PET-FDG scan improvement after 3 courses of LR was included into “auto-allo” tandem program and actually in CR after PBSCT. Two pts progressed on LR treatment and were switched to palliative regimens. As regards the follow-up, 3 pts in CR are evaluable for evaluation. Two pts received 6 and one pt 8 courses of RL treatment. One patient relapsed after 24 mo of CR and other 2 patients are in CR at +11 and +6 months. In relapsed/refractory DLBCL modest initial results of lenalidomide monotherapy emerge the use of new effective combinations. Recently several phase II studies of LR efficacy in indolent NHL were proposed. For instance, there is no published data of long-term safety and efficacy of this combination in DLBCL. Given the poor prognosis of refractory DLBCL, enrolment in already running prospective clinical trials with lenalidomide are underway and the investigation of the combination of Lenalidomide and Rituximab is further warranted. Disclosures: No relevant conflicts of interest to declare.

Pilot Study of Lenalidomide-Rituximab Combination in Relapsed/Refractory Diffuse Large B Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3695-3695
Author(s):  
Vadim Ivanov ◽  
Diane Coso ◽  
Thérèse Aurran ◽  
Jean Marc Schiano ◽  
Anne-Marie Stoppa ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Induction Phase ◽  
Significant Activity ◽  
Intention To Treat ◽  
Grade 3 ◽  
Initial Results

Abstract Abstract 3695 Despite recent immunochemotherapy advances approximately 50% of DLBCL patients relapse. Data emerging from initial clinical trials demonstrated that Lenalidomide has a significant activity against different subtypes of relapsed/refractory aggressive B-cell lymphoma. Clinical responses are histology subtype-dependent and most prominent in mantle cell lymphoma. The results in DLBCL were less encouraging with ORR of 26%, CR of 9%, PFS of 2.7 mo. Concurrently targeting the tumor cell itself with monoclonal antibody and targeting the immune response and microenvironment with Lenalidomide may be a promising therapeutic strategy. Encouraging by our initial results of Lenalidomide-Rituximab (LR) combination in patient with refractory (R/R) DLBCL (Ivanov V. et al., 2010), Institutional Multidisciplinary Meeting proposed this combination for 17 patients with R/R DLBCL. All pts were refractory to three or more (range: 2–5) previous lines of conventional immuno-chemotherapy. All eligible pts, except 4 primary-refractory, were previously autografted. Median age for the whole group was 62,5 years, (range: 43–79), 5 pts are female. 65% of patients were younger than 65 y. Patients received combination of Rituximab 375 mg/m2 on day 1 or day 7; Lenalidomide (Revlimid), 15 mg/d for the first pt and 25 mg/d for other 16 pts, for 21/28 days. Dexamethasone 40mg, day 1–4 was given for first 7 pts. Initial decision on adding Dexamethasone was based on the extrapolation from the recommended regimen used in multiple myeloma, but it was abandoned in last 10 pts. Initially the treatment duration was established for 6 months, but it was prolonged to 7–11 months for patients in CR. Of 17 pts enrolled on study, 3 patients stopped the treatment during the first course: 1 pt because of grade 3 toxicity and 2 pts because of explosive disease progression. Both patients were switched to palliative care. In 14 pts, received more than 1 course of treatment, 7 (50 %) responded to LR combination, including 6 pts (43%) with CR and 1 (7%) patient with PR. One pt with clinical and PET-FDG scan improvement after 3 courses of LR was included into “auto-allo” tandem program and actually in CR at +12 months after PBSCT. Six pts progressed on LR treatment and were switched to palliative regimens. In intention to treat analysis the CR rate for the whole group was 35%. As regards the follow-up, all 7 pts in PR and CR are evaluable for evaluation. The patient in PR progressed after 5 courses of LR. Six patients in CR group received an average of 8 (range: 7–11) courses of LR treatment. Two patients relapsed after 5 and 26 months of CR and other 4 patients are actually in CR at +7, +17, +18 and +24 months. Adverse events were manageable and the most common toxicity included thrombocytopenia and neutropenia. In relapsed/refractory DLBCL modest initial results of Lenalidomide monotherapy emerge the use of new effective combinations. Recently the combination Lenalidomide-Rituximab (LR) was shown to be highly efficacious in phase 2 study in elderly (>65 y.o.) patients with DLBCL (Zinzani et al., 2011). Into the group of 23 pts the ORR rate at the end of 6-months induction phase was 35%. Our data confirm results of Bologna group in the younger group of patients. Given the poor prognosis of refractory DLBCL, enrolment in already running prospective clinical trials with Lenalidomide are underway and the investigation of the combination of Lenalidomide and Rituximab is further warranted. Disclosures: No relevant conflicts of interest to declare.

Establishment of a New Mantle Cell Lymphoma Cell Line That Has Epigenetically Silenced CD20 As a Resistance Mechanism in Vivo

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4619-4619
Author(s):  
August Stuart ◽  
Kamal Sharma ◽  
Sara Shimko ◽  
Zainul Hasanali ◽  
Elliot M Epner
Keyword(s):  
B Cell ◽  
Mantle Cell Lymphoma ◽  
Cell Line ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Epigenetic Mechanism ◽  
Significant Activity ◽  
Antitumor Effects ◽  
Mantle Cell

Abstract Abstract 4619 Rituximab is an anti-CD20 monoclonal antibody that has significant activity in B cell lymphomas that express the cell surface protein CD20. The mechanism of its antitumor effects in vivo are not clear but include direct apoptotic effects, complement mediated cytotoxicity (CMC), and antibody dependent cellular cytotoxicity (ADCC). Previously we initiated a clinical trial of SAHA (vorinostat), cladribine, and rituximab (SCR) in patients with CD20+ B cell malignancies. In addition to its cytotoxic effects, recent evidence suggests that 2-CdA has hypomethylating properties. A 65 year old patient with newly diagnosed blastic,leukemic, mantle cell lymphoma (MCL) was initiated on the SCR trial. He responded promptly with normalization of his blood counts and resolution of his splenomegaly. A PET/CT scan performed prior to cycle 3 was consistent with a complete metabolic remission. He developed cytopenias prior to cycle 5 that met criteria for removal from the study. Imaging and blood studies were compatible with florid relapse of his MCL including CNS disease. At post mortem analysis, cells in the CNS were CD20 positive and cells in the blood, marrow, and lymph nodes were CD20 negative by immunohistochemistry and flow cytometry. CD20 mRNA analysis by qRT-PCR demonstrated marked reduction in CD20 mRNA. A cell line was derived from the patient's blood. The cells are cyclin D1 positive and expresses Sox 11 with ∼50 times less CD20 mRNA and appropriate sized protein. This 353 cell line has been grown in continuous culture for > 1 year and remains CD20 negative, CCND1 positive and contains the t(11;14). Analysis of the CD20 promoter and coding region demonstrated no evidence of a deletion or point mutation. Chromatin immunoprecipation (ChIP) assays were performed to access epigenetic changes at the CD20 promoter. First, we showed that the CD20 promoter in Granta MCL cells treated with cladribine contain decreased amounts of methylated histones H3K9 and K27, consistent with an epigenetic mechanism of action of cladribine involving histone methylation. Decreased DNA methylation at the CD20 promoter was also observed. ChIP analysis of the patient's cells before and after treatment with cladribine and vorinostat in vivo demonstrated decreases in CD20 promoter DNA and histone (H3 K9 and H3K27) methylation, consistent with the known epigenetic properties of these agents. The 353 cell line reported here will be of interest in studying epigenetic mechanisms of resistance to rituximab by silencing of CD20 gene expression. Experiments to overexpress exogenous CD20 to resensitize 353 cells to rituximab are in progress and will be reported. Future experiments will also aim at identifying a cDNA or drug that can overcome epigenetic resistance in vitro in 353 cells. These experiments could lead to improved treatments to overcome epigenetically mediated resistance to rituximab. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The biology behind B-cell lymphoma 2 as a target in chronic lymphocytic leukemia

2016 ◽  
Vol 7 (6) ◽  
pp. 321-329 ◽  
Author(s):  
Valentín Ortíz-Maldonado ◽  
Pablo Mozas ◽  
Julio Delgado
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Mitochondrial Pathway ◽  
Therapeutic Agents ◽  
Lymphocytic Leukemia ◽  
Hallmarks Of Cancer ◽  
Lymphoid Malignancies

B-cell lymphoma 2 (BCL2)-type proteins are key regulators of the intrinsic or mitochondrial pathway for apoptosis. Since escape from apoptosis is one the main ‘hallmarks of cancer’, BCL2 inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukemia (CLL). Multiple clinical trials have shown efficacy of these agents in patients with relapsed/refractory disease with a favorable toxicity profile. Moreover, some clinical trials indicate that combination with monoclonal antibodies and other novel agents may enhance their effect.

scholarly journals MicroRNA Signatures In B-Cell Lymphomas

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4155-4155
Author(s):  
Lorena Di Lisio ◽  
Margarita Sanchez-Beato ◽  
Gonzalo Gomez-Lopez ◽  
Maria E. E. Rodriguez ◽  
Santiago Montes-Moreno ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cell ◽  
Burkitt Lymphoma ◽  
Gene Expression Regulation ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoid Tissues ◽  
Molecular Features ◽  
Lymphoma Type

Abstract Abstract 4155 Beyond the conventional criteria of lymphoma classification (integrated clinical, morphological, immunophenotypic, and molecular features) additional markers are still required for a more precise differential diagnosis and a better understanding of lymphoma pathogenesis. MicroRNAs (miRNA) are non-coding small RNAs that play an important role in gene expression regulation, contributing to cell differentiation and tumorigenesis. Specifically, miRNAs have been already described to play a relevant role in B cell differentiation, and in some cases proposed to constitute lymphoma-type specific markers and possible therapeutic targets. We explore the potential diagnostic application of miRNA expression in a large series of 147 cases including all B-cell non-Hodgkin lymphomas (NHL) major types and appropriate controls. As an example of a practical application, data were also used to identify miRNAs differentially expressed when comparing Burkitt Lymphoma (BL) and Diffuse Large B-Cell Lymphoma (DLBCL) in paraffin-embedded samples. Each lymphoma type (BL, CLL, DLBCL, FL, MCL, MZL/MALT, NMZL and SMZL) was compared to the whole series of NHL by Significant Analysis of Microarray (SAM) method. The analysis identified a set of 128 characteristic miRNAs (FDR<0.01 and Fold change >1.5 log2). All lymphoma types were characterized by specific miRNA signatures, reflecting cell of origin and/or discrete oncogene alterations. Of interest is also the comparison with reactive lymphoid tissues, since it revealed a specific B-cell lymphoma miRNA profile, which includes a cluster of downregulated miRNAs, such as let7 family, miR-1 and miR-200 family. Burkitt Lymphoma was also directly compared to DLBCL, and 43 miRNA selected by SAM analysis were studied in a new series of 28 BL and 43 DLBCL samples using quantitative RT-PCRIn this second step, the differential expression of a set of 19 miRNAs was confirmed between BL and DLBCL. (FDR < 0.05 after t-test (limma)). These findings expand the potential diagnostic markers in lymphoma diagnosis and provide useful information on lymphoma pathogenesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Perceptions of Community Hematologists/Oncologists on Barriers to Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Diffuse Large B-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2198-2198
Author(s):  
Ajeet Gajra ◽  
Richard Sweat ◽  
Yolaine Jeune-Smith ◽  
Jonathan K. Kish ◽  
Bruce A Feinberg
Keyword(s):  
Clinical Trials ◽  
B Cell ◽  
Annual Meeting ◽  
Real World ◽  
Randomized Clinical Trials ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
The United States ◽  
Large B Cell Lymphoma ◽  
Car T

Introduction The ASH Annual Meeting is a venue for presentation of outcomes data from key clinical trials in hematologic malignancies and novel drug classes used to treat them. The approval of two CAR-T therapies, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel), in the treatment of large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL), has ushered in a new class of drugs, i.e. cellular therapy. At ASH 2018, Nastoupil et al. presented data from a retrospective analysis of the characteristics and outcomes of patients with relapsed/refractory LBCL, including DLBCL, treated with commercially available axi-cel CAR-T therapy at academic centers in the United States (Nastoupil LJ, et al. Blood. 2018;132[Suppl 1]:91). The authors found that early outcomes of real-world patients receiving axi-cel therapy were comparable to those observed in the clinical trial population, despite >40% of these patients failing to meet the clinical trial eligibility criteria. At a live meeting in February 2019, we sought the perceptions of community hematologists and oncologists (H/O) regarding their use of, referrals for and barriers to CAR-T therapy as well their perception of the value of the real-world evidence (RWE) presented. Methods A live meeting in February 2019 convened H/O with geographic representation from across the United States. The participants were shown data from selected oral and/or poster presentations from the 2018 ASH Annual Meeting and responded to questions regarding their perceptions of the data and its potential impact on current practice. Participants submitted their demographic responses via a web-based survey prior to the meeting and data impression responses via an audience response system at the live meeting. Results Among the 59 H/O who participated in this live market research program on February 22-23, 2019, 61% identified their primary specialty as hematology/oncology and 34% medical oncology. Only 27% of H/O had attended the 60th ASH Annual Meeting in December 2018. The participants were mostly community-based physicians, 50% in private community and 45% in community practices owned by a hospital or academic center. One-third have been in practice for over 20 years, one-third for 11-20 years and one-third for 10 or fewer years. This group sees an average of 20+ patients per day and reported B-cell non-Hodgkin lymphoma as one of the three most common hematologic malignancy they managed. 28% of H/O indicated that they have referred one patient and 24% have referred 2-5 patients for CAR-T therapy since the first approval on August 30, 2017. Of those H/O who had referred patients for CAR-T therapy, 45% indicated that none of their patients had yet received the infusion. The top two barriers to prescribing/recommending CAR-T therapy, as reported by the H/O, were the cumbersome logistics of administering therapy and following patients (52%), and the cost of the therapy (46%). Other concerns included high toxicity (24%) and lack of long-term survival data (19%), but not lack of knowledge of CAR-T therapy (2%). Furthermore, 87% of H/O agreed with the assertion that due to the limitations of randomized clinical trials, RWE is necessary to inform clinical practice. After review of the information presented on the real-world use of axi-cel, 73% of H/O indicated that this information is likely to cause them to recommend CAR-T therapy for more of their patients with DLBCL. Conclusions There is significant interest in adopting and using CAR-T therapies in LBCL amongst community H/O. This group does not perceive itself as lacking in knowledge regarding CAR-T therapy. The significant barriers of logistics and cost are potential deterrents to appropriate use. These results can inform stakeholders (manufacturers, payers, hospitals and practices) regarding the need to improve processes and develop payment models to address cost in order to facilitate access of these agents to the appropriate patients. RWE is viewed favorably by the vast majority of community H/O to inform clinical practice, due to the limitations of randomized clinical trials. Disclosures Gajra: Cardinal Health: Employment. Sweat:Cardinal Health: Employment. Jeune-Smith:Cardinal Health: Employment. Kish:Cardinal Health: Employment. Feinberg:Cardinal Health: Employment.

scholarly journals Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy

2019 ◽  
Vol 10 ◽  
pp. 204062071988282 ◽  
Author(s):  
Guillaume Richard-Carpentier ◽  
Courtney D. DiNardo
Keyword(s):  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Drug Administration ◽  
Myeloid Leukemia ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Intensive Chemotherapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a globally poor outcome, especially in patients ineligible for intensive chemotherapy. Until recently, therapeutic options for these patients included low-dose cytarabine (LDAC) or the hypomethylating agents (HMA) azacitidine and decitabine, which have historically provided only short-lived and modest benefits. The oral B-cell lymphoma 2 inhibitor, venetoclax, Venetoclax, an oral B-cell lymphoma 2 (BCL2) inhibitor, is now approved by the USA Food and Drug Administration (FDA) in combination with LDAC or HMA in older AML patients ineligible for intensive chemotherapy. Is now approved by the US Food and Drug Administration for this indication. In the pivotal clinical trials evaluating venetoclax either in combination with LDAC or with HMA, the rates of complete remission (CR) plus CR with incomplete hematological recovery were 54% and 67%, respectively and the median overall survival (OS) was 10.4 months and 17.5 months, respectively, comparing favorably with outcomes in clinical trials evaluating single-agent LDAC or HMA. The most common adverse events with venetoclax combinations are gastrointestinal symptoms, which are primarily low grade and easily manageable, and myelosuppression, which may require delays between cycles, granulocyte colony-stimulating factor (G-CSF) administration, or decreased duration of venetoclax administration per cycle. A bone marrow assessment after the first cycle of treatment is critical to determine dosing and timing of subsequent cycles, as most patients will achieve their best response after one cycle. Appropriate prophylactic measures can reduce the risk of venetoclax-induced tumor lysis syndrome. In this review, we present clinical data from the pivotal trials evaluating venetoclax-based combinations in older patients ineligible for intensive chemotherapy, and provide practical recommendations for the prevention and management of adverse events associated with venetoclax.

Abstract PO-28: Antitumor effects of cannabinoids against B-cell lymphoma

2020 ◽  
Author(s):  
Saba Omer ◽  
Dawn Boothe ◽  
Mohammedohammed Mansour ◽  
Muralikrishnan Dhanasekaran ◽  
Satyanarayana Pondugula
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Antitumor Effects
Sign in / Sign up

Export Citation Format

Share Document