TGR-1202, a Novel Once Daily PI3Kδ Inhibitor, Demonstrates Clinical Activity with a Favorable Safety Profile, Lacking Hepatotoxicity, in Patients with Chronic Lymphocytic Leukemia and B-Cell Lymphoma

Abstract Background: TGR-1202 is a novel oral, next generation PI3Kδ inhibitor which notably lacks the hepatotoxicity associated with other PI3Kδ inhibitors. Preliminary data from an ongoing Ph I study of TGR-1202 demonstrated clinical activity in patients with advanced hematologic malignancies (ASCO 2014). Herein we present updated results from this Phase I, first in human study of TGR-1202 in patients with relapsed and/or refractory CLL and B-cell lymphoma. Methods: TGR-1202 is administered orally once daily following a 3+3 dose escalation design. Previously treated patients with an ECOG PS ≤ 2 and confirmed diagnosis of B-cell non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), or other lymphoproliferative disorders are eligible. Endpoints include safety, PK/PD, and efficacy. Results: 49 patients have been enrolled to date of various lymphoma subtypes including CLL, follicular lymphoma (FL), Hodgkin’s lymphoma (HL), DLBCL, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Demographics: 76% male, ECOG 0/1/2: 17/31/1, median age of 59 yrs (range: 22-85), median prior treatment regimens: 3 (range: 1-14), and 43% were refractory to prior treatment. 35 patients have been treated at doses ≥ 800 mg of a previous formulation where a threshold effect in activity was observed, and 6 have been treated with an improved micronized formulation (≥ 200 mg). TGR-1202 was well tolerated and no MTD has been reached to date. The only Gr≥3 AE occurring in >5% of patients was neutropenia (8%). AE’s of all grades occurring in >20% of patients were limited to diarrhea (24%), cough (22%), fatigue (20%), and nausea (20%). Notably, in comparison to other PI3Kδ inhibitors, no hepatotoxicity and no cases of colitis have been observed to date. Rates of infection and pneumonia have also been low (12% and 6%, respectively), and no cases of febrile neutropenia have been reported. Of the 41 patients treated at ≥ 800 mg of the previous formulation or with the micronized formulation, 32 are evaluable for efficacy (6 too early to evaluate, 2 non-compliant, 1 did not meet I/E criteria). Responses have been limited in patients with aggressive lymphoma and HL. Of the 9 evaluable CLL patients, 8 (89%) achieved a nodal PR (median nodal reduction of 71%), of which 5 achieved a PR per Hallek 2008 criteria with the remaining 4 having persistent lymphocytosis. The 1 CLL patient with SD had a >40% nodal reduction and remains on study. Of the 7 evaluable FL patients, all have shown clinical benefit with a reduction in tumor burden with 2 having achieved a PR, and the remaining 5 patients in SD. Additionally 2 MZL patients each achieved SD with >25% nodal reductions and remain on study. Notably, no patient with CLL or indolent lymphoma (FL & MZL) treated at ≥800 mg has progressed to date (median time on study of 20 weeks, range 6 – 73+), and no patient who achieved >50% reduction in tumor burden (including patients with CLL, FL, and HL) has progressed, with median time on study of 34 weeks (range 7 – 68+). Pharmacodynamic analysis in CLL patients indicates rapid suppression of pAKT at doses of 400 mg QD of the previous formulation. Conclusions: TGR-1202 is well tolerated in patients with relapsed and/or refractory hematologic malignancies with no reported hepatotoxicity or events of colitis and promising clinical activity. Enrollment continues in expansion cohorts and with the micronized formulation. Disclosures Brander: Celgene: Mentor received research funding Other. O'Connor:Celgene: Consultancy; Millennium Pharmaceuticals: Consultancy. Miskin:TG Therapeutics, Inc.: Employment, Equity Ownership. Sportelli:TG Therapeutics: Employment, Equity Ownership. Vakkalanka:Rhizen: Employment, Equity Ownership. Flinn:Infinity Pharmaceuticals: Consultancy.

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A Phase II Trial of Ofatumumab In Subjects with Waldenstrom's Macroglobulinemia.

Blood ◽

10.1182/blood.v116.21.1795.1795 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1795-1795 ◽

Cited By ~ 3

Author(s):

Richard R. Furman ◽

Herbert Eradat ◽

Julie C. Switzky ◽

Suzanne R. Hayman ◽

Craig C. Hofmeister ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Plasma Cells ◽

Cell Lymphoma ◽

International Workshop ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

Rapid Rise ◽

Grade 3

Abstract Abstract 1795 Background: Waldenstrom's macroglobulinemia (WM) is an indolent B-cell lymphoma characterized by a heterogeneous population of lymphocytes, plasmacytoid lymphocytes and plasma cells with variable CD20 expression. Rituximab (R) achieves an overall response rate (ORR) of 25–50% in relapsed/refractory WM and is associated with IgM flares, manifested by a rapid rise in IgM, potentially leading to complications of hyperviscosity. Ofatumumab (OFA) is a fully human monoclonal antibody that targets an epitope encompassing both the large and small extracellular loops of CD20 and effectively induces complement-dependent cytotoxicity of B-lymphoma cells. OFA is approved for the treatment of fludarabine- and alemtuzumab-refractory chronic lymphocytic leukemia (CLL) and has demonstrated clinical activity in non-Hodgkin's lymphoma. Given the efficacy of OFA in CLL, with its decreased CD20 antigen density, similar to WM where CD20 is down-regulated with differentiation of cells into plasma cells, a Phase II, open-label, single-arm trial of OFA in patients (pts) with WM was initiated to examine the safety and efficacy of OFA in this population. We report data from a planned interim analysis, which was performed to examine IgM flare, toxicity and response data. Methods: Pts (age ≥18 years) with WM requiring therapy by 2nd International Workshop on WM criteria were eligible. Pts received OFA 300 mg week 1 and 1000 mg weeks 2–4. Premedication included acetaminophen and antihistamine (all infusions) and glucocorticoid (infusions 1 and 2). Pts who experienced grade 3–4 infusion-related adverse events (AEs) during weeks 1 and 2 also received glucocorticoid during weeks 3 and 4. The primary endpoint was ORR assessed by 3rd International Workshop on WM criteria, and toxicity was assessed according to NCI-CTCAE, v3.0. Results: Fifteen pts were enrolled between March 2009 and January 2010. Median age was 59 years (range 43–85), and 9 pts were male. Pts had a median IgM level of 3.70 g/dL (range 1.21–6.62) and median hemoglobin (hgb) of 9.8 g/dL (range 5.3–11.7). Three pts were previously untreated; 12 pts had received a median of 3 therapies (range 2–5), including 11 pts who had received R, and 7 pts who had received a purine analog. Fourteen pts completed all 4 infusions of OFA. One pt withdrew from study after infusion 3 due to a drug-related serious AE (SAE). One pt had cryoglobulinemia, which interfered with IgM assessment. Of the 14 pts with evaluable IgM levels, 3 achieved partial response (PR), and 3 achieved minor response (ORR=43%) 8 weeks to 5 months after start of OFA therapy. One of 3 previously untreated pts and 5 of 12 relapsed pts responded. Four of 11 pts who had received prior R and 2 of 4 R-naïve pts responded. Five of 9 pts with IgM <4 g/dL and 1 of 5 pts with IgM >4 g/dL responded. Four pts with a median hgb of 8.0 g/dL (range 5.3–9.2) experienced ≥2.8 g/dL increase in hgb, including 3 pts who had >5 g/dL increase; median time to reach hgb ≥11.0 was 4 weeks. Infusion-related events occurred with dose 1 (300 mg) in 12 pts and with dose 2 (1000 mg) in 7 pts; all infusion events were grade 1–2 except 2 grade 3 events (rash, serum sickness). Nine pts developed 11 infections: 7 URI, 2 UTI, 1 sinusitis, 1 oral candidiasis (all grade 2). One pt developed grade 3 febrile neutropenia. Two pts developed SAEs possibly related to OFA. One pt developed grade 3 Coombs-negative hemolytic anemia after infusion 3 resulting in study withdrawal, and 1 pt with a baseline IgM level of 6.62 g/dL developed grade 3 renal insufficiency due to a rapid rise in IgM and cast nephropathy 6 weeks after starting OFA. One additional pt, with a baseline IgM level of 4.69 g/dL, developed a rapid rise in IgM and hyperviscosity symptoms. Both pts with a rapid rise in IgM underwent plasmapheresis with resolution of symptoms. No other OFA-related hematologic toxicity was observed. Conclusions: OFA has an acceptable toxicity profile, although a rapid rise in IgM requiring plasmapheresis was observed in 2 pts with high baseline IgM levels. OFA shows clinical activity in pts with WM, including those who relapse after R therapy, with rapid improvement in hgb and slower reduction of IgM levels. Based on the acceptable safety profile in this study and the dose of OFA approved for refractory CLL, the study was amended to increase the OFA dose to 2000 mg and allow a 2nd cycle of therapy for pts who do not attain PR after cycle 1. Accrual to the amended study is ongoing. Disclosures: Furman: GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Off Label Use: Ofatumumab is an investigational anti-CD20 monoclonal antibody, currently under development for the treatment of B-cell malignancies (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Waldenstroms macroglobulinemia and follicular lymphoma) as well as autoimmune diseases (rheumatoid arthritis and multiple sclerosis). Switzky:GlaxoSmithKline: Employment, Research Funding; Genmab: Employment, Research Funding. Leonard:GlaxoSmithKline: Consultancy. Liao:GSK: Employment. Shah:GlaxoSmithKline: Employment; Genmab: Research Funding. Brownell-Buttich:GlaxoSmithKline: Employment. Lisby:Genmab A/S: Employment. Lin:GlaxoSmithKline: Consultancy, Employment.

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The Bruton's Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies

Blood ◽

10.1182/blood.v116.21.57.57 ◽

2010 ◽

Vol 116 (21) ◽

pp. 57-57 ◽

Cited By ~ 13

Author(s):

Jan A. Burger ◽

Susan O'Brien ◽

Nathan Fowler ◽

Ranjana Advani ◽

Jeff Porte Sharman ◽

...

Keyword(s):

B Cell ◽

Phase 1 ◽

Study Drug ◽

Lymphocytic Leukemia ◽

Clinical Activity ◽

B Cell Malignancies ◽

Employment Equity ◽

Bcr Signaling ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 57 Introduction: Bruton's tyrosine kinase (Btk) is a downstream mediator of B-cell receptor (BCR) signaling and is not expressed in T-cells or NK-cells. As such, Btk represents an ideal therapeutic target for B-cell malignancies dependent upon BCR signaling. Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) has been reported to have constitutively active BCR signaling. PCI-32765 is a potent, selective, irreversible and orally bioavailable small molecule inhibitor of Btk that has pre-clinical activity in B-cell malignancies (Proc Natl Acad Sci 2010;107(29):13075-80). PCI-32765 was therefore moved forward to a Phase 1 study in B-cell malignancies including patients (pts) with CLL/SLL. A subsequent CLL/SLL-specific Phase 1b study was initiated to further explore safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of PCI-32765. This report includes a composite summary of the CLL/SLL experience in both of these studies. Pts and Methods: Pts with CLL/SLL who had relapsed or refractory disease after >1 prior treatment regimens were eligible for treatment in each of the studies whereas the second Phase 1b study also included a cohort of elderly pts (aged ≥ 65 years) with CLL/SLL who required treatment and were “treatment-naive”. Responses were assessed by the investigator using the International Working Group CLL criteria (Hallek et al, Blood 2008 for pts with CLL) and the International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas (Cheson et al, J Clin Oncol 2007 for pts with SLL). Results: To date, 30 CLL/SLL patients (including 4 treatment-naive) have been enrolled across the 2 studies. Eighty-four percent of subjects are men with an overall median age of 68 (range 44–82) years. Of the subjects with prior therapy for CLL/SLL the median number of prior therapies is 3 (range 1–4). Treatment has been well-tolerated; Grade ≥ 3 toxicities have been infrequent (10/30 pts; 33%). Two study-drug related serious adverse events have been reported: 1 case of viral adenitis (Grade 3) and 1 case of viral infection (Grade 2). Two adverse events have led to discontinuation of study drug: a small bowel obstruction (Grade 3) and exacerbation of chronic obstructive disease (Grade 3); both events were reported as unrelated to study drug. No study-drug related deaths have reported. There has been no change in either NK cell or T cell counts. Target inhibition as measured by a probe of Btk drug occupancy showed inhibition of Btk at PCI-32765 exposure levels of ≥ 245 ng•h/mL. Of the 14 patients currently evaluable for response using the pre-defined criteria, the overall response rate is 64% (1 complete remission [CR], 8 partial remissions [PR], and 4 SD). Both studies are ongoing and open to enrollment. An update on response rate, response duration, safety, and PD information will be presented on enrolled patients based on a November 2010 database cut-off. Conclusion: PCI-32765 is a novel oral and selective “first-in-human” inhibitor of Btk that induces objective partial and complete responses in a substantial proportion of pts with CLL/SLL and has a favorable safety profile. These data support further studies of both monotherapy and also combination treatment with PCI-32765 in CLL/SLL. Disclosures: O'Brien: Pharmacyclics, Inc: Honoraria, PI grant. Fowler:Pharmacyclics: Consultancy, Research Funding. Advani:Pharmacyclics, Inc: Honoraria, PI grant. Sharman:Pharmacyclics, Inc: Honoraria, PI grant. Furman:Pharmacyclics, Inc: PI grant. Izumi:Pharmacyclics, Inc: Employment. Buggy:Pharmacyclics, Inc: Employment, Equity Ownership. Loury:Pharmacyclics: Employment, Equity Ownership. Hamdy:Pharmacyclics, Inc: Employment, Equity Ownership.

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Comparison of Pharmacokinetics and Pharmacodynamics of Two Anti-CD20 Monoclonal Antibodies (Candidate Biosimilar DRL-Rituximab and Innovator Reference Product Rituximab (Mabthera®) in a Randomised, Multi-Centre, Double-Blind, Parallel Group Study of CHOP with Rituximab Chemotherapy in Patients with CD20-Positive Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.5391.5391 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5391-5391

Author(s):

Auro Viswabandya ◽

Asis Mukhopadhyay ◽

Sandip Shah ◽

Rajnish Vasant Nagarkar ◽

Sonica Sachdeva Batra ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Similarity Criterion ◽

B Cell Lymphoma ◽

Employment Equity ◽

Double Blind ◽

Large B Cell Lymphoma ◽

Parallel Group ◽

Equity Ownership ◽

Grade 3

Abstract Background: DRL-Rituximab (T) is a proposed biosimilar of rituximab. The similarity of DRL-Rituximab andtheinnovator reference products(USA: Rituxan®; European Union: Mabthera® [R]) has been demonstrated in physicochemical analyses and nonclinical studies. This study was undertaken to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of T with R sourced from the European Union. Methods: Multiple-center, randomized, double-blind, two-arm, parallel-group study conducted in patients of both genders, aged 18-60 with a centrally confirmed newly diagnosed CD20 positive diffuse large-B-cell lymphoma (DLBCL) in their first line of treatment. Patients were randomized to receive 6 cycles of 21 days either T or R at an initial dose of 375 mg/m2 along with chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone/prednisolone (CHOP). The primary objective of this study was to compare the PK of T and R. One of the secondary objectives was to establish the similarity of T and R in the pharmacodynamic parameters - as B-cell depletion and repletion in peripheral blood using counts of CD19+ positive cells determined by flow cytometry. The PK similarity criterion was that the 90% confidence intervals (CI) of the geometric mean ratios of AUC0-21days, and Cmax in Cycle 1 were within 80.00% - 125.00%. Cycle 1 PK, PD and summary safety results are reported here. Other PK parameters were evaluated as secondary endpoints. Results: A total of 151 patients were randomized to the study (76 to T, 75 to R). After exclusion of 2 patients with very low exposure (results confirmed to be outliers by a z-score higher than 3 and currently under further investigation), both products met the preset Cycle 1 PK similarity criterion (Table 1), with these 2 patients included the Cmax criterion was met, but for AUC the lower limit of the CI was 78.36% (Table 2). PK parameter values were generally comparable (Table 3). For PD both products appear comparable regarding both B-cell depletion and B-cell repletion, both in terms of proportion of patients as well as median time to depletion/repletion. (Table 4 & Figures 1A and 1B) Safety was also comparable between both products. Grade 3/4 Adverse Events (AEs) showed a similar trend in incidence across the two treatment arms [overall: 121 (80.1%); T: 57 (75.0%); R: 64 (85.3%)]. Neutropenia was the most frequently reported of the grade 3/4 AEs, followed by febrile neutropenia, leukopenia, and anaemia. The most commonly reported TEAEs related to the study drug were neutropenia [overall: 48 (31.8%); T: 29 (38.2%); R: 19 (25.3%)] and leukopenia [overall: 24 (15.9%); T: 16 (21.1%); R: 8 (10.7%)]. A total of 5 deaths are reported in the study amounting to 3.3% fatality rate. Conclusion: DRL-rituximab has equivalent PK profile to Mabthera in Cycle 1 when given in combination with standard CHOP chemotherapy for the treatment of CD20 positive DLBCL. PD and safety results are also similar. While awaiting results of further PK/PD data as well as outcomes from this trial, these results are highly encouraging and provide further impetus to development of DRL-rituximab as a candidate rituximab biosimilar. Acknowledgment: We thank all the Principal Investigators for their participation in conducting this study: Dr. Randeep Singh, Dr. Chiramana Haritha, Dr. Asis Mukhopadhyay, Dr. Anup Majumdar, Dr. Shailesh Bondarde, Dr. Rajnish Vasant Nagarkar, Dr. Vijay Ramanan, Dr. Chetan Dilip Deshmukh, Dr. MVT Krishna Mohan, Dr. SVSS Prasad, Dr. Nalini Kilara, Dr. Poonam Patil, Dr. Shekhar Patil, Dr. Neelesh Reddy, Dr. Suresh Sudalaiandi, Dr. Krishnan Srinivasan, Dr. Sundar Subramanian, Dr. VP Gangadharan, Dr. Auro Viswabandya, Dr. Alok Srivastava, Dr. Sharat Damodar, Dr. Rajesh Grover, Dr. Reena Nair, Dr. Bhausaheb Bagal, Dr. Kasi Viswanathan, Dr. Minish Jain, Dr. Jitendra Singh, Dr. Dipti Samanta, Dr. Sudha Sinha, Dr. Lakshmaiah Kuntegowdanahalli, Dr. Rajendersingh Arora, Dr. Sandip Shah, Dr. Shashikant Janardhan Apte, Dr. Mukul Goyal, and Dr. Prasanth Ganeshan. Disclosures Batra: Dr. Reddy's Labs: Employment, Equity Ownership. Lazaro:Dr. Reddy's Labs: Employment, Equity Ownership. Kankanwadi:Dr. Reddy's Labs: Employment, Equity Ownership.

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

Blood ◽

10.1182/blood.v128.22.3969.3969 ◽

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.

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Blinatumomab Monotherapy Shows Efficacy in Patients with Relapsed Diffuse Large B Cell Lymphoma

Blood ◽

10.1182/blood.v118.21.1637.1637 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1637-1637 ◽

Cited By ~ 8

Author(s):

Andreas Viardot ◽

Mariele Goebeler ◽

Richard Noppeney ◽

Stefan W. Krause ◽

Stefan Kallert ◽

...

Keyword(s):

Adverse Events ◽

B Cell ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Employment Equity ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Large B Cell

Abstract Abstract 1637 Blinatumomab (MT103) is a single-chain bispecific antibody construct with specificity for CD19 and CD3 belonging to the class of bispecific T cell engager (BiTE®). A phase I trial with indolent and mantle cell lymphoma patients established a maximal tolerable dose (MTD) at 60 μg/m2/d. The trial was subsequently amended to evaluate blinatumomab in patients with diffuse large B cell lymphoma (DLBCL). Patients were treated by 4–8-week continuous i.v. administration with the following dosing regimen: first week at 5 μg/m2/d, second week at 15 μg/m2/d and for the remaining treatment period at 60 μg/m2/d. Two cohorts each with 6 DLBCL patients were enrolled. The two cohorts solely differed by the dose and schedule of corticosteroid medication administered at the beginning of blinatumomab infusion for mitigation of adverse events. In the first cohort 100 mg prednisolone was applied 1 hour prior to start; and in the second cohort patients received dexamethasone on days 1, 2, and 3. Three sequential patients received dexamethasone also 6–12 hours prior to start of infusion. Out of the twelve patients, 5 were male and 7 female. The median age was 57 years (range from 26 to 78 years). Patients had received a median of 4 prior regimens (range from 2–6). All patients had been exposed to rituximab. Eight of the 12 patients had undergone autologous stem cell transplantation (ASCT). International prognostic index (IPI) at screening ranged from 1 to 3 with a median of 2. The most common clinical adverse events (AEs) regardless of causality (>30%) were pyrexia (81.8%), fatigue (54.5%), constipation (36.4%), headache (36.4%), tremor (36.4%) and weight increase (36.4%). The most frequent laboratory AEs regardless of causality (>30%) were hyperglycemia (63.6%), lymphopenia (54.5%), C-reactive protein increase (45.5%), gamma-glutamyltransferase increase (45.5%) and thrombocytopenia (36.4%). Most AEs occurred early and were reversible. Four of 12 patients discontinued infusion due to fully reversible CNS events, 2 of which qualified as dose limiting toxicities (DLTs). Although just one DLT (reversible CNS event grade 3) occurred in the prednisolone cohort, a further cohort applying prophylactic dexamethasone was opened to optimize management of CNS events. A further refinement of the dexamethasone schedule, starting longer time prior to start of blinatumomab, was introduced after one early patient in the cohort receiving dexamethasone had experienced a reversible CNS event leading to discontinuation. All three patients treated in this manner completed the first blinatumomab cycle without discontinuations. Only one showed a grade 1 tremor, and no other CNS AEs were reported in these three patients. Two of 12 patients were not exposed to 60 μg/m2/d due to early discontinuations and 1 patient is too early in treatment for response evaluation. Five out of the remaining 9 evaluable patients (56%) showed objective clinical responses (4 CR/CRu; 1 PR). Three out of the 5 patients with CR/CRu or PR had prior ASCT. Two patients achieved objective responses (1 CR, 1 PR) despite of discontinuation at 60 μg/m2/d. The median response duration is +182 days (longest current duration +428 days), with 4 out of 5 responses still ongoing. Further evaluation of the last cohort will refine the recommended phase II dose, and the intensity and timing of dexamethasone comedication. The observation of lasting CRs after blinatumomab monotherapy in DLBCL patients is promising and warrants further exploration in a phase II study. Disclosures: Krause: Micromet: Research Funding. Mackensen:Micromet Inc.: Research Funding. Topp:Micromet: Consultancy, Honoraria. Scheele:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Nagorsen:Micromet Inc.: Employment, Equity Ownership, Patents & Royalties. Zugmaier:Micromet: Employment. Degenhard:Micromet Inc: Employment. Schmidt:Micromet AG: Employment. Kufer:Micromet Inc: Employment, Equity Ownership. Libicher:Micromet Inc.: Consultancy, Honoraria. Bargou:Micromet: Consultancy, Honoraria.

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Differences In Treatment Patterns and Costs Among Diffuse Large B-Cell Lymphoma Patients Treated In The Clinic Vs. The Hospital Outpatient Setting

Blood ◽

10.1182/blood.v122.21.1751.1751 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1751-1751 ◽

Cited By ~ 1

Author(s):

Carolina Reyes ◽

Stacey Dacosta Byfield ◽

Laura K. Becker ◽

Art Small

Keyword(s):

Health Care ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Treatment Patterns ◽

Employment Equity ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Large B Cell

Abstract Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of Non-Hodgkin's Lymphoma (NHL) accounting for approximately 30% of newly diagnosed casesi. DLBCL is an aggressive form of NHL and without treatment, median survival estimates are <1 year.ii Rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is recommended first-line therapy for DLBCL patients and has been shown to improve overall survival compared with CHOP alone (previous standard therapy).iii In addition, published evidence suggests that receipt of granulocyte-colony stimulating factor (G-CSF) may improve outcomes among patients who initiate CHOP-based therapy.iv It is unclear whether differences in treatment and outcomes exist among cancer patients by site where care is delivered. This study examines differences in treatment patterns, health care resource use and costs among DLBCL patients receiving rituximab (R) or R+ chemotherapy in the office/clinic (OC) setting vs. the hospital outpatient (HOSP) setting. Methods This retrospective study used medical and pharmacy claims (1/2007 - 7/2012) from a national US commercial health plan to identify patients at least18 years old with ≥2claims for R. Patients were required to have evidence of DLBCL (≥1 claim with ICD-9-CM 200.78 or ≥2 claims with unique diagnosis codes from ICD-9-CM 200.70 to 200.77) and be enrolled in the health plan for ≥6 months before and after the index date (date of the first R claim). The follow-up period, that is, the episode of care (EOC), was the date of the first R infusion through 30 days after the last infusion prior to a gap in R administration of at least 7 months; those with less than 6 months of follow-up due to death were included. Patients with multiple cancers or receipt of R at both the OC and HOSP setting during the EOC were excluded. Differences in number of infusions, receipt G-CSF, healthcare utilization and per-patient per-month (PPPM) health care costs by cohort were examined. Results A total of 491 patients were identified, 65% OC (n=320) and 35% HOSP (n=171): by insurance type, 140 Medicare Advantage patients, 39% HOSP and 351 commercially insured patients, 33% HOSP. From 2007 to 2011/2012, the percentage of patients in HOSP increased from 32% to 43%. Descriptive results are shown in the Table. The cohorts had similar mean age, baseline Charlson comorbidity index scores and similar EOC lengths. However, compared to the OC cohort, the HOSP cohort had fewer infusions during the EOC and fewer infusions per month. In addition, fewer HOSP patients had evidence of combination therapy and receipt of any G-CSF during the EOC. HOSP patients also had significantly higher rates of emergency room visits, but not hospitalizations compared to OC patients. Total PPPM costs during the EOC as well as average costs of anti-cancer systemic therapy drugs plus administration costs incurred on days of rituximab infusions were significantly higher among the HOSP cohort compared to the OC cohort. Conclusions Increasing proportions of DLBCL patients receive infusions in the HOSP setting. HOSP patients had fewer infusions per month and incurred greater costs on the day of infusion compared to the OC cohort. There were fewer patients in HOSP with evidence of G-CSF during the EOC compared to OC patients. Overall, total PPPM costs were higher among the HOSP cohort compared to the OC cohort. Future research is warranted to assess the impact of these differences on clinical outcomes by site of care. [i] Armitage et al. JCO 1998;16(8):2780-95 [ii] Mey et al. Swiss Med Wkly 2012;140:w13511 [iii] NCCN Guidelines Version 1.2013 Diffuse Large B-cell Lymphoma [iv] Donnelly, et al, Leuk Lymphoma. 2000;39(1-2):67-75 Disclosures: Reyes: Genentech, inc: Employment, Equity Ownership. Dacosta Byfield:Genentech, Inc: Genentech contracted with OptumInsight to conducting the work described in the abstract. Stacey is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech., Genentech contracted with OptumInsight to conducting the work described in the abstract. Stacey is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech. Other; OptumInsight: Employment. Becker:Genentech, Inc: Genentech contracted with OptumInsight to conducting the work described in the abstract. Laura is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech., Genentech contracted with OptumInsight to conducting the work described in the abstract. Laura is employed at Optum but did not receive funds directly from Genentech and employment is not contingent on work with Genentech. Other; OptumInsight: Employment. Small:Genentech, Inc: Employment, Equity Ownership.

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Mutation Impact of Targeted Genes in Diffuse Large B-Cell Lymphoma Patients Treated with Ibrutinib

Blood ◽

10.1182/blood.v126.23.2642.2642 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2642-2642

Author(s):

Leo WK Cheung ◽

Karl J. Schweighofer ◽

Shiquan Wu ◽

Hsu-Ping Kuo ◽

Karl Eckert ◽

...

Keyword(s):

B Cell ◽

Clinical Response ◽

Cell Lymphoma ◽

Single Agent ◽

B Cell Lymphoma ◽

Good Clinical Response ◽

Employment Equity ◽

Mutation Impact ◽

Equity Ownership ◽

Tumor Biopsies

Abstract Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma, accounting for approximately 30% of newly diagnosed cases in the United States. DLBCL can progress quickly and advanced cases are inconsistently cured with current therapies. Ibrutinib, a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, is approved in the US and EU for patients with previously-treated mantle cell lymphoma and chronic lymphocytic leukemia (CLL) who have had one prior treatment, CLL with 17p deletion, and Waldenström macroglobulinemia. The activated B-cell (ABC) subtype of DLBCL is considered especially high risk and is characterized by chronic active B-cell receptor signaling, which is blocked by ibrutinib. Recent phase 2 trial results of ibrutinib as a single agent in DLBCL patients show an overall response rate of 41% in the ABC subtype (Wilson et al. ASH 2012; Wilson et al. Nat Med, 2015). Through targeted deep sequencing, we investigated the impact of baseline mutations of 317 targeted genes on clinical response of 51 DLBCL patients treated with ibrutinib. Based on our mutation impact analysis, we identified potential biomarkers for predicting DLBCL patient response to ibrutinib. In particular, we found sets of gene mutation patterns indicating poor (or good) clinical response across all subtypes (ABC, germinal-center B-cell-like [GCB], non-GCB) of DLBCL as well as uniquely within a subtype. Methods: H&E-stained slides from DLBCL patients enrolled in either PCYC-04753 (NCT00849654) or PCYC-1106 (NCT01325701) were reviewed to ensure sufficient nucleated cellularity and tumor content. DNA and RNA were extracted from unstained sections of FFPE DLBCL tumor biopsies. Sequencing was performed using the FoundationOne™ Heme panel following the validated NGS-based protocol to interrogate complete DNA coding sequences of 405 genes, as well as selected introns of 31 genes involved in rearrangements. RNA sequences of 265 commonly rearranged genes were analyzed to identify gene fusions. A subgroup of samples were analyzed on earlier versions of the FoundationOne™ panels where only DNA was extracted and sequenced. Sequence data was processed and analyzed for base substitutions, insertions, deletions, copy-number alterations, and selected gene fusions. Mutation impact indices (MII) of 317 genes were calculated and plotted for overall gene mutation pattern recognition. Chi-square association tests were performed on cases where sufficient sample sizes were available to determine statistical significance of mutation impact. DLBCL subtype classifications by gene expression profiling (GEP) and Hans' IHC were investigated and compared. For GEP, we used OmicSoft ArrayStudio's classification module to build linear discriminant analysis (LDA) model/classifier and neural networks with 5-fold cross validation procedure for model selection. The LDA was the best performing model and was selected for final GEP classification. Since only 29 (of 51) patients had central lab Hans' IHC classification information, we compared trends of the mutation impact results based on Hans' classification and GEP classification. Results: Single or multiple gene MII were generated from baseline tumor biopsies from DLBCL patients treated with single agent ibrutinib. The MII were generally consistent between GEP or Hans' IHC classification of tumor biopsies. We found novel baseline gene mutations associated with poor clinical response (SD or PD) to ibrutinib. These genes were involved in regulation of transcription (eg, mutations in EP300 in all DLBCL subtypes combined group [p=0.034], mutations in RB1 in ABC-DLBCL [p=0.031]), epigenetic modification (eg, mutations in MLL2 in ABC-DLBCL [p=0.053]), programmed cell death (mutations in BCL2 in all DLBCL subtypes [p=0.096]), and PI3K-AKT-mTOR pathway (eg, mutations in TSC2 in ABC-DLBCL [p=0.031]). Mutations identified as indicating good clinical response include mutations in CD79B (p=0.072) and MYD88 (p=0.024) in ABC-DLBCL. Co-existence of MYD88 and CD79B mutations (double-mutants) in ABC-DLBCL showed a stronger association to good clinical response (p=0.004) consistent with recent observations from Wilson et al. ASH 2012 & Nat Med, 2015. Conclusions: Our investigation reveals unique mutation patterns that underlie DLBCL subtypes and highlights the need for personalized medicine approaches to treating DLBCL patients. Disclosures Cheung: Pharmacyclics LLC, an AbbVie Company: Employment. Schweighofer:Pharmacyclics LLC, an AbbVie Company: Employment. Wu:Pharmacyclics LLC, an AbbVie Company: Employment. Kuo:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Balasubramanian:Pharmacyclics LLC, an AbbVie Company: Equity Ownership; Janssen: Employment, Equity Ownership. Ricci:Janssen: Employment, Equity Ownership, Patents & Royalties. Liang:Pharmacyclics LLC, an AbbVie Company: Employment. Beaupre:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment.

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Lenalidomide Efficacy in Activated B-Cell-Like Subtype Diffuse Large B-Cell Lymphoma Is Dependent Upon IRF4 and Cereblon Expression

Blood ◽

10.1182/blood.v120.21.3287.3287 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3287-3287

Author(s):

Ling-Hua Zhang ◽

Jolanta Kosek ◽

Maria Wang ◽

Carla Heise ◽

Peter H Schafer ◽

...

Keyword(s):

B Cell ◽

Cell Lines ◽

Molecular Mechanisms ◽

Cell Lymphoma ◽

Xenograft Model ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Employment Equity ◽

Large B Cell Lymphoma ◽

Equity Ownership

Abstract Abstract 3287 Background: Durable responses with lenalidomide monotherapy have been reported in patients with non-Hodgkin lymphoma. In relapsed/refractory diffuse large B-cell lymphoma (DLBCL), higher responses were observed in the activated B-cell-like (ABC) subtype than in the germinal centre B-cell (GCB)-like subtype (Czuczman, et al. British Journal of Haematology, 2011, 154, 477–481). Herein, the molecular mechanisms involved in the differential efficacy of lenalidomide in DLBCL subtypes were investigated. Methods: A panel of DLBCL cell lines, with 5 of ABC-subtype and 11 of non-ABC subtype, was collected and cell of origin subtype was confirmed based on literature, molecular and genetic analysis. The direct antiproliferative effect of lenalidomide on DLBCL cells was assessed using the 3H-thymidine incorporation assay and apoptosis analysis. The molecular mechanisms involved in the antiproliferative efficacy of lenalidomide in DLBCL subtypes were investigated by western blot, immunohistochemistry (IHC) and qRT-PCR analysis of key signaling events during B-cell receptor (BCR)-dependent NF-κB activation. The critical roles of interferon regulatory factor 4 (IRF4), and cereblon (CRBN) in lenalidomide efficacy were established by knock-in or knock-down of these proteins in sensitive ABC cells. Finally, a mouse xenograft model was used to confirm the antitumor effect of lenalidomide and the relevance of the molecular mechanism involved. Results: Using DLBCL cell lines, lenalidomide treatment was found to preferentially suppress proliferation of ABC-DLBCL cells in vitro at a concentration range of 0.01–100 μM (the median plasma concentration at Cmax for patients receiving 25 mg lenalidomide is 2.2 μM) and delay tumor growth in a human tumor xenograft model of OCI-Ly10 cells (lenalidomide 3–30 mg/kg, p.o. qdX28), with minimal effect on non-ABC-DLBCL cells. This tumoricidal effect of lenalidomide was associated with downregulation of IRF4, a survival factor in ABC-DLBCL cells. Treatment with lenalidomide for 1–3 days, similar to the inhibitors of PKCb and MALT1 (LY-333,531 and z-VRPR-fmk, respectively), was found to significantly (p<0.05) downregulate IRF4 protein levels in sensitive cell lines such as OCI-Ly10 and U2932. IRF4 inhibition by lenalidomide reduced CARD11-BCL-10-MALT1 complex activity of ABC-DLBCL cells (as measured by BCL-10 cleavage) and resulted in downregulation of B-cell receptor (BCR)-dependent NF-κB activity. An NF-κB-driven luciferase assay revealed that lenalidomide (1 μM) inhibited transcriptional activity of NF-κB up to 56% in the sensitive ABC-DLBCL cell lines OCI-Ly10 (p <0.05) and U2932 (p <0.01) after 2-day drug treatment. Lenalidomide also significantly (p <0.05) inhibited DNA binding by Rel A/p65, p50 and c-rel/p70 in 4 lines of ABC cells. While IRF4-specific siRNA mimicked the effects of lenalidomide reducing NF-κB activation, IRF4 overexpression conferred cell resistance to lenalidomide, indicating the crucial role of IRF4 inhibition in lenalidomide efficacy in ABC DLBCL. Furthermore, knockdown of CRBN in OCI-Ly10 (p <0.05) and U2932 (p <0.01) conferred resistance to lenalidomide as demonstrated by the abrogation of the inhibitory effects of lenalidomide on IRF4 expression, BCL-10 cleavage, NF-κB activity, and proliferation of these cells, whereas the activity of inhibitors to PKC β and IKKα/β (LY-333,531 and CC-415501, respectively) remained unaffected. These data indicate that antitumor effects of lenalidomide on ABC-DLBCL cells require the presence of cereblon. Conclusions: These data may provide a mechanism for the preferential efficacy of lenalidomide in ABC-DLBCL observed in clinical studies. These findings suggest that lenalidomide has direct antitumor activity against DLBCL cells, preferentially ABC-DLBCL cells, by blocking IRF4 expression and the BCR-NF-κB signaling pathway in a cereblon-dependent manner (also see Figure below). Disclosures: Zhang: Celgene Corp: Employment, Equity Ownership. Kosek:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Heise:Celgene Corporation: Employment, Equity Ownership. Schafer:Celgene: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership.

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Dual PI3Kδ/γ Inhibition By RP6530 Induces Apoptosis and Cytotoxicity In B-Lymphoma Cells

Blood ◽

10.1182/blood.v122.21.4411.4411 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4411-4411 ◽

Cited By ~ 4

Author(s):

Swaroop Vakkalanka ◽

Srikant Viswanadha ◽

Eugenio Gaudio ◽

Emanuele Zucca ◽

Francesco Bertoni ◽

...

Keyword(s):

B Cell ◽

Cell Lines ◽

Whole Blood ◽

Cell Lymphoma ◽

Annexin V ◽

B Cell Lymphoma ◽

Primary Cells ◽

Employment Equity ◽

Human Whole Blood ◽

Equity Ownership

Introduction Activation of the PI3K pathway triggers multiple events including cell growth, cell cycle entry, cell survival and motility. While α and β isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to cells of the hematopoietic system. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, dual targeting of PI3Kδ and γ represents a promising approach in the treatment of lymphomas. The objective of the experiments was to explore the therapeutic potential of RP6530, a novel, small molecule PI3Kδ/γ inhibitor, in B-cell lymphomas. Methods Activity and selectivity of RP6530 for PI3Kδ and γ isoforms and subsequent downstream activity was determined in enzyme and cell-based assays. Additionally, RP6530 was tested for potency in viability, apoptosis, and Akt phosphorylation assays using a range of immortalized B-cell lymphoma cell lines (Raji, TOLEDO, KG-1, JEKO, OCI-LY-1, OCI-LY-10, MAVER, and REC-1). Viability was assessed using the colorimetric MTT reagent after incubation of cells for 72 h. Inhibition of pAKT was estimated by Western Blotting and bands were quantified using ImageJ after normalization with Actin. Primary cells from lymphoid tumors [1 chronic lymphocytic leukemia (CLL), 2 diffuse large B-cell lymphomas (DLBCL), 2 mantle cell lymphoma (MCL), 1 splenic marginal zone lymphoma (SMZL), and 1 extranodal MZL (EMZL)] were isolated, incubated with 4 µM RP6530, and analyzed for apoptosis or cytotoxicity by Annexin V/PI staining. Results RP6530 demonstrated high potency against PI3Kδ (IC50=24.5 nM) and γ (IC50=33.2 nM) enzymes with selectivity over α (>300-fold) and β (>100-fold) isoforms. Cellular potency was confirmed in target-specific assays, namely anti-FcεR1-(EC50=37.8 nM) or fMLP (EC50=39.0 nM) induced CD63 expression in human whole blood basophils, LPS induced CD19+ cell proliferation in human whole blood (EC50=250 nM), and LPS induced CD45R+ cell proliferation in mouse whole blood (EC50=101 nM). RP6530 caused a dose-dependent inhibition (>50% @ 2-7 μM) in growth of immortalized (Raji, TOLEDO, KG-1, JEKO, REC-1) B-cell lymphoma cells. Effect was more pronounced in the DLBCL cell lines, OCI-LY-1 and OCI-LY-10 (>50% inhibition @ 0.1-0.7 μM), and the reduction in viability was accompanied by corresponding inhibition of pAKT with EC50 of 6 & 70 nM respectively. Treatment of patient-derived primary cells with 4 µM RP6530 caused an increase in cell death. Fold-increase in cytotoxicity as evident from PI+ staining was 1.6 for CLL, 1.1 for DLBCL, 1.2 for MCL, 2.2 for SMZL, and 2.3 for EMZL. Cells in early apotosis (Annexin V+/PI-) were not different between the DMSO blank and RP6530 samples. Conclusions RP6530 is a potent and selective dual PI3Kδ/γ inhibitor that inhibited growth of B-cell lymphoma cell lines with a concomitant reduction in the downstream biomarker, pAKT. Additionally, the compound showed cytotoxicity in a panel of lymphoma primary cells. Findings provide a rationale for future clinical trials in B-cell malignancies. Disclosures: Vakkalanka: Rhizen Pharmaceuticals, S.A.: Employment, Equity Ownership; Incozen Therapeutics Pvt. Ltd.: Employment, Equity Ownership. Viswanadha:Incozen Therapeutics Pvt. Ltd.: Employment. Bertoni:Rhizen Pharmaceuticals SA: Research Funding.

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Selective Inhibitor Of Nuclear Exports (SINE) KPT-330 In Combination With The Novel Proteasome Inhibitor Carfilzomib As a Novel Therapeutic Regimen For Treating Aggressive B-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.5147.5147 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5147-5147

Author(s):

Elyse R Lopez ◽

Erin M Dominici ◽

Muychi T Vang ◽

Archito T. Tamayo ◽

Zhishuo Ou ◽

...

Keyword(s):

B Cell ◽

Cell Lines ◽

Nuclear Export ◽

Proteasome Inhibitor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Selective Inhibitor ◽

The Novel ◽

Employment Equity ◽

Equity Ownership

Abstract Aggressive non-Hodgkin lymphomas (NHL), such as Diffuse Large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), are one of a small number of important human cancers increasing in incidence in the US over the last four decades. Although these lymphomas are now potentially curable, almost half the treated patients still develop relapsed/refractory disease with poor survival outcomes, indicating an urgent need for better therapeutic approaches with improved efficacy. Double–hit lymphomas (DHL) constitute a particularly aggressive subtype of DLBCL and are characterized by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, usually a t(14;18)(q32;q21) involving BCL2. Prognosis for DHL is extremely poor, indicating a need for new treatment options as well. Multi-drug combination therapies are expected to potentiate therapeutic responses and delay disease recurrence by blocking adaptive resistance responses. Carfilzomib (CFZ), a novel second-generation proteasome inhibitor, and the novel Selective Inhibitor of Nuclear Exports (SINE) KPT-330 are effective treatments for refractory lymphomas. We hypothesized that combining the two would be even more successful because the drugs target different cellular pathways and processes in malignant B-cells. CFZ inhibits chymotrypsin-like, protein-degrading activity in the ubiquitin-proteasome pathway while KPT-330 irreversibly inhibits the major nuclear export receptor, chromosome region maintenance 1, CRM1, also termed XPO1. This study investigates whether the effects of CFZ and KPT-330 in combination are synergistic and thus more effective, reducing side effects and chemoresistance. Two DLBCL cell lines, DOHH-2 and OCI-Ly10, two DH-DLBCL cell lines, CJ and U-2973, and two MCL cell lines, Mino and Jeko-1, were used. Working with these cell lines, we identified and analyzed the increase in the efficacy of the combination over single agents alone through MTS proliferation and Annexin-V binding apoptosis assays. Growth inhibitory combination indexes for each cell line were calculated, and the Chou-Talalay Method was used to quantify additive effects (CI=1), synergistic effects (CI<1), or antagonistic affects (CI>1). Results indicated strong synergistic behavior of the combinatorial therapy, with many of the dose combinations indexes falling below 1. Apoptosis assays also showed a high degree of synergy when combining CFZ with KPT-330. The efficacy of CFZ and KPT-330 in combination signifies the combination’s potential as a foundation for future studies, treatments, and clinical trials. Disclosures: Kirk: Onyx Pharmaceuticals: Employment, Equity Ownership. Kauffman:Karyopharm Therapeutics Inc.: Employment. Shacham:Karyopharm : Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

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