scholarly journals Statins Potentiate the Cytotoxic Effect of ABT-199 in Diffuse Large B Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3969-3969
Author(s):  
David A. Fruman ◽  
Jong-Hoon Scott Lee ◽  
Thanh-Trang T Vo ◽  
Shruti Bhatt ◽  
Jonathan H. Schatz ◽  
...  
Keyword(s):  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Lymphoma Cells ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract BCL-2 is a key pro-survival protein that is highly expressed in many leukemias and lymphomas. ABT-199 (venetoclax) is a small molecule inhibitor of BCL-2 that has demonstrated impressive responses in chronic lymphocytic leukemia (CLL) leading to FDA approval for second line treatment of patients with 17p deletion. However, other hematologic malignancies are less responsive to ABT-199 as a single agent, suggesting that combinations of targeted therapies may be required to elicit more promising responses. We have investigated the potential of combining ABT-199 with HMG-CoA reductase (HMGCR) inhibitors (statins), which have known anti-cancer potential in hematologic malignancies. Using multiple chemically distinct statin compounds, we observed profound synergistic induction of apoptosis when combined with ABT-199 in both human diffuse large B cell lymphoma (DLBCL) as well as acute myeloid leukemia (AML) cell lines. This synergy was also seen in primary murine B lymphoma cells over-expressing MYC and BCL-2. Importantly, addition of exogenous mevalonate completely rescued cells from the combination, confirming on-target efficacy of HMGCR inhibition. Using BH3 profiling, we found that simvastatin significantly primed lymphoma cells for undergoing apoptosis (termed mitochondrial priming). Notably, the degree of priming correlated with its ability to synergize with ABT-199, suggesting that BH3 profiling may be used to predict patient responses. The combination did not synergize to kill normal human peripheral blood mononuclear cells from healthy donors, suggesting that statins may selectively prime cancer cells for apoptosis. Mechanistic studies support the hypothesis that statins synergize with ABT-199 by suppressing protein prenylation, particularly protein geranylgeranylation. In support, the addition of exogenous geranylgeranyl pyrophosphate (GGPP) completely rescued cells from the effects of simvastatin. Furthermore, selective inhibition of protein geranylgeranyl transferase (GGT) increased priming and was sufficient to recapitulate the effects of simvastatin in combination with ABT-199. Statins and GGT inhibitors increased the mitochondrial abundance of a subset of BH3-only pro-apoptotic proteins. Lastly, we have identified Rap1A de-prenylation as a marker of pharmacodynamic response to statins in vivo. Thus, this project highlights a novel combination for use in aggressive lymphomas, establishes its efficacy and tolerability using preclinical models, and provides proof-of-concept to warrant investigation of its clinical potential. Disclosures Letai: AbbVie: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Tetralogic: Consultancy, Research Funding.

scholarly journals Voruciclib Sensitizes High Risk Diffuse Large B Cell Lymphoma to BCL2 Inhibition Mediated Cell Death and Tumor Regression

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4167-4167
Author(s):  
Joyoti Dey ◽  
William Kerwin ◽  
Joseph Casalini ◽  
Angela Merrell ◽  
Marc Grenley ◽  
...  
Keyword(s):  
Cell Death ◽  
B Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Diffuse Large B Cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma in adults. Although upfront chemotherapy leads to favorable survival outcomes, relapsed or refractory patients continue to have poor prognosis with limited treatment options. In DLBCL, evasion of apoptosis - a key hallmark of cancer is mediated by functionally redundant BCL family members: BCL2, BCLxL and MCL-1. The BCL2 specific inhibitor venetoclax is approved for treating high-risk CLL, but responses in DLBCL have been limited, potentially due to compensatory upregulation of MCL-1. Currently a well-tolerated drug for inhibition of MCL-1, is unavailable in the lymphoma clinic. Voruciclib, is a novel clinical stage oral CDK inhibitor with potent activity (<10 nM) against CDKs 9, 4, 6 and 1. Multiple mechanisms for downregulation of MCL-1 activity have been described for CDK inhibitors. Arguably best characterized is transcriptional inhibition of MCL-1, a short half-life transcript, via inhibition of transcriptional regulator CDK9. We evaluated MCL-1 expression in the FFPE lymphatic tissues from 33 patients with DLBCL, and found that it was expressed in 52% of cases, of both GC (germinal center) and ABC (activated B-cell)-like type. We therefore investigated whether voruciclib could synergize with venetoclax in pre-clinical models of DLBCL via inhibition of MCL-1. In cell-based assays, exposure of DLBCL cells to voruciclib as a single agent resulted in apoptosis which was preceded by context-dependent downregulation of MCL-1. To further explore the impact of voruciclib on MCL-1 activity and DLBCL viability in vivo, we utilized Presage's CIVO tumor microinjection technology. CIVO enables investigation of multiple drugs and drug combinations simultaneously in a living tumor facilitating in vivo assessment of anti-tumor drug synergy (Klinghoffer et al. Sci. Transl Med. 2015; Dey et al. PLOS One 2016). Voruciclib was introduced as a single agent or in combination with venetoclax to DLBCL xenografts. Microinjection, resulting in localized tumor exposure to voruciclib, led to MCL-1 downregulation in vivo across multiple models of DLBCL. In contrast, tumor exposure to venetoclax led to MCL-1 upregulation. Co-exposure to voruciclib and venetoclax demonstrated that the ability of voruciclib to downregulate MCL-1 is dominant to the upregulation by venetoclax. Consistent with the hypothesis that MCL-1 compensates for loss of BCL2 function in DLBCL, synergistic cell death was observed when voruciclib was combined with venetoclax. Synergy between voruciclib and venetoclax was observed in vivo in models representing both ABC (RIVA: CI value 0.5) and GC subtypes (NUDHL1 and Toledo: CI values 0.4). Similar activity was noted when venetoclax was combined with A1210477, an investigational MCL-1 inhibitor thereby suggesting MCL-1 downregulation to play a role in the observed synergy between venetoclax and voruciclib. Consistent with these results, preliminary studies on xenografted mice have shown that systemic administration of a sub-efficacious dose of venetoclax in combination with voruciclib led to impediment of tumor growth which was greater than the effect observed with each single agent. Additional systemic studies are ongoing with venetoclax in combination with voruciclib in a panel of DLBCL models to further strengthen this observation. Based on the above findings, a Phase 1b clinical trial has been designed to evaluate the combination of voruciclib and venetoclax in patients with the goal of expediting future treatment options for relapsed/refractory DLBCL. We expect to initiate this trial at multiple centers in early 2017. Disclosures Dey: Presage Biosciences: Employment. Kerwin:Presage Biosciences: Employment. Casalini:Presage Biosciences: Employment. Merrell:Presage Biosciences: Employment. Grenley:Presage Biosciences: Employment. Ditzler:Presage Biosciences: Employment. Dixon:Presage Biosciences: Employment. Burns:Presage Biosciences: Employment. Danilov:ImmunoGen: Consultancy; GIlead Sciences: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Dava Oncology: Honoraria; Prime Oncology: Honoraria. Klinghoffer:Presage Biosciences: Employment.

scholarly journals A Phase I Trial of Brentuximab Vedotin in Combination with Lenalidomide in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3988-3988 ◽  
Author(s):  
Jeffrey P. Ward ◽  
Jessica Thein ◽  
Jingqin Luo ◽  
Nina D. Wagner-Johnston ◽  
Amanda F. Cashen ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
De Novo ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Background: The addition of rituximab to CHOP has improved the overall survival of patients with diffuse large B-cell lymphoma (DLBCL); however, approximately 30% of patients will relapse. Stem cell transplantation (SCT) provides a second chance at cure, but the prognosis for patients who are not candidates for SCT or who have refractory disease is poor, and new treatments with novel agents are needed. Brentuximab vedotin (BV), an antibody-drug conjugate that combines an anti-CD30 monoclonal antibody and the microtubule disrupting agent MMAE, has a single agent response rate (RR) of 44% (CR 17%) in CD30 (+) (Jacobsen, Blood 2015) and 27% (CR 3.7%) in CD30 (-) relapsed/refractory (rel/ref) DLBCL (Bartlett, ASH 2014). Lenalidomide (Len), an immunomodulator with multiple described mechanisms of action, has a single agent RR of 28% (CR 7%) in rel/ref DLBCL (Witzig, Ann Oncol 2011). Notably, the Len RR was 52.9% in the subset of patients with non-germinal center-like (non-GCB) DLBCL, compared to 8.7% in GCB DLBCL (Hernandez-Ilizaliturri, Cancer 2011). Given that both compounds have single agent activity in DLBCL and favorable, non-overlapping toxicity profiles, we hypothesized that the combination of BV and Len would be an effective and tolerable regimen in rel/ref DLBCL. Methods: This investigator initiated, phase I/dose expansion trial is ongoing to identify the safety and maximum tolerated dose (MTD) of the combination of BV and Len (Clinical Trials.gov NCT02086604). Eligible patients have rel/ref de novo or transformed DLBCL after at least one prior systemic therapy and have previously received or are ineligible for SCT. Response assessments are performed after cycles 2, 4, 6, 9 and then every six months for two years by PET/CT scan and response determined per the Revised International Working Group Response Criteria for Malignant Lymphoma 2007. The study is in two parts, a dose-escalation portion using a 3+3 design to determine the MTD, followed by a dose-expansion cohort enrolling patients with either CD30 (+) or CD30 (-) DLBCL assessed by visual assessment using routine IHC per local laboratory. BV is administered every 21 days and Len is dosed continuously for a maximum of 16 cycles until disease progression or unacceptable toxicity. Results: Eighteen patients have been enrolled to date. The median age is 61 years (range 51-79), with 83% having an ECOG performance status of 0-1. Median number of prior therapies is 2 (range 1-6), with 39% undergoing a previous autoSCT, and one patient a previous alloSCT. 72% of patients were refractory to their last regimen. 13 patients have CD30 (-) and 5 CD30 (+) DLBCL. Treatment-related adverse events (AEs) occurring in >20% of patients include anemia (50%), elevated ALT (28%), hypocalcemia (22%), peripheral neuropathy (22%), neutropenia (28%), thrombocytopenia (33%), and hypokalemia (28%). Anemia, febrile neutropenia, thrombocytopenia, and hypokalemia were the only grade 3/4 related AEs observed in >10% of patients. Growth factors were not given during cycle 1 but were administered in 11 patients with subsequent cycles. One patient came off study for thrombocytopenia after completing 8 cycles, while in a CR. 47% have required at least one dose reduction. The DLTs per dose cohort are summarized in the table. The MTD of the combination is 1.2 mg/kg of BV Q21d with 20 mg Len given continuously. At the time of this analysis, 17 patients (1 too early) have had restaging evaluations; 7 CR (41%), 2 PR, 3 SD, and 5 PD, for an overall RR of 53%. Five CRs occurred after C2, 1 after C6 and 1 after C8. All responses are ongoing with a range of 5 to 35 wks. Among the 7 CRs, 2 patients have CD30 (+) and 5 patients CD30 (-) DLBCL, 4 pts were GCB and 3 non-GCB. Of the four patients with CD30 (-) disease categorized as GCB, two achieved a CR. Conclusions: This Phase I study of BV plus Len identified the MTD of the combination at BV 1.2 mg/kg Q21d with Len 20 mg/d continuously. Dose expansion cohorts of 15 patients each for CD30 (-) and CD30(+) DLBCL are currently accruing. The predominant toxicity of the study regimen is related to cytopenias, consistent with prior experience. Although patient numbers are small, the high CR rate is intriguing. Updated results will be presented at the meeting. Table 1. # Patients Assigned BV Dose Assigned Len Dose # of DLT DLT Toxicity 9 1.2mg/kg 20mg 1 Neutropenia 6 1.2mg/kg 25mg 2 Neutropenia, DVT 3 1.8mg/kg 25mg 2 Fatigue, Neutropenia Disclosures Ward: Boehringer Ingelheim: Consultancy. Wagner-Johnston:Celgene: Research Funding; Gilead: Consultancy. Fehniger:Celgene: Research Funding. Bartlett:Gilead: Consultancy, Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Millennium: Research Funding; Colgene: Research Funding; Medimmune: Research Funding; Kite: Research Funding; Insight: Research Funding; Seattle Genetics: Consultancy, Research Funding; MERC: Research Funding; Dynavax: Research Funding; Idera: Research Funding; Portola: Research Funding; Bristol Meyers Squibb: Research Funding; Infinity: Research Funding; LAM Theapeutics: Research Funding.

scholarly journals IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J. Devin ◽  
T. Cañeque ◽  
Y.‐L. Lin ◽  
L. Mondoulet ◽  
J.‐L. Veyrune ◽  
...  
Keyword(s):  
B Cell ◽  
Iron Homeostasis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cellular Iron ◽  
Large B Cell Lymphoma ◽  
Cellular Iron Homeostasis ◽  
Large B Cell

scholarly journals Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 454-454 ◽  
Author(s):  
Yucai Wang ◽  
Umar Farooq ◽  
Brian K. Link ◽  
Mehrdad Hefazi ◽  
Cristine Allmer ◽  
...  
Keyword(s):  
B Cell ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Salvage Chemotherapy ◽  
Newly Diagnosed ◽  
Indolent Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

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