Therapeutics Inc Research Articles

Development of CD38 CAR Engineered Human Placental Hematopoietic Stem Cell Derived Natural Killer Cells (PNK-CAR38) As Allogeneic Cancer Immunotherapy

Background: Natural killer (NK) cells exhibit innate anti-tumor activity owing to the expression of a multitude of activating receptors. Celularity has developed a GMP process for generating off-the-shelf and allogeneic human Placental Hematopoietic Stem Cell derived Natural Killer (PNK-007) cells. To develop a tumor targeted approach, we have engineered PNK cells to express Chimeric Antigen Receptor (CAR) against tumor antigen CD38. PNK cells expressing CD38 CAR (PNK-CAR38) have enhanced anti-tumor function against CD38+ lymphoma and multiple myeloma (MM) cell lines in pre-clinical studies and do not exhibit on-target off-tumor cytotoxicity against healthy CD38+ cells. Here we report the development of a CD38 CAR specific NK cell therapy. Methods: PNK-CAR38 cells were generated through transduction of human placental CD34+ cells with a retroviral vector carrying second generation anti-CD38 chimeric antigen receptor (CAR2-anti-CD38 A2; CD38scFv-CD28CD3ζ) followed by expansion and differentiation of transduced CD34+ cells into NK cells in presence of cytokines including thrombopoietin, SCF, Flt3 ligand, IL-7, IL-15 and IL-2. The anti-tumor activity of untransduced PNK and PNK-CAR38 cells was assessed against Lymphoma (Daudi and Raji) and Multiple Myeloma (Molp8, LP1 and OPM2) cell lines at various effector to target (E:T) ratios. PNK-CAR38 in vivo anti-tumor activity was assessed in a disseminated lymphoma xenograft model in NSG mice. Briefly, luciferase-expressing Daudi cells (3×106) were intravenously (IV) injected at Day0, followed by IV injection of PNK-CAR38 cells (20×106) at Day1 and Day3. Tumor burden was assessed weekly by Bioluminescence Imaging (BLI). Differences between the groups were calculated using two-tailed Student t-test. Results: Placental CD34+ cells were efficiently gene-modified using a retroviral vector and achieved a median of 64% (range 38% to 87%; n=11 donors) CD38 CAR expression in PNK cells at the end of 35-day culture. The median PNK-CAR38 cell yield achieved was 29,000-fold (range 7,800-48,000 fold; n=8) with NK purity >90% measured by CD3-CD56+ population. In vitro an overall improvement in anti-tumor response by PNK-CAR38 over PNK cells was observed. In a NK resistant lymphoma cell line model Daudi, PNK-CAR38 cells from various donors (n=8) elicited 72%±10% lysis versus 6%±3.5% lysis by PNK alone (p<0.01) at 10:1 E:T ratio. PNK-CAR38 elicited significant cytotoxicity 27%±9% versus 13%±5% by PNK cells (p<0.01) against Raji cells depending on NK cell donor. Using MM lines, at 10:1 E:T ratio, PNK-CAR38 cells elicited 33%±16% lysis versus 21%±12% by PNK (p<0.01) against LP1; 44%±6% versus 28%±3% by PNK (p<0.01) against OPM2; and 32%±6% versus 2%±0.5% by PNK (p<0.01) against MOLP8. Since CD38 is also expressed on normal immune and progenitor cells, PNK-CAR38 cells were co-cultured with healthy donor-derived activated T cells and CD34+CD38+ progenitor cells. No on-target off-tumor cytotoxicity against these cells was observed. In the disseminated Daudi xenograft NSG model, PNK-CAR38 significantly reduced tumor burden (approximately 50% BLI reduction) compared to vehicle control 10 days post treatment. Conclusions: The novel PNK-CAR38 demonstrated enhanced in vitro cytotoxic potential against lymphoma and MM lines and showed no on-target off-tumor cytotoxicity against healthy donor-derived cells in vitro. In vivo anti-tumor activity of PNK-CAR38 was shown in a lymphoma disseminated NSG model. Further development of PNK-CAR38 for hematological malignancies is warranted. Disclosures Somanchi: Celularity Inc: Employment. Guo:Celularity, Inc.: Employment. He:Celularity Inc: Employment. Mathur:Celularity Inc: Employment. Difiglia:Celularity Inc: Employment. Rana:Celularity Inc: Employment. Ling:Celularity Inc: Employment. Edinger:Celularity Inc: Employment. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zeldis:Sorrento Therapeutics Inc: Employment, Equity Ownership. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hariri:Celularity Inc: Employment. Zhang:Celularity Inc: Employment.

Phase 3, Multi-Center, International, Randomized, Double-Blind, Placebo Controlled Study of Oral Rigosertib + Injectable Azacitidine (AZA) Versus Injectable Azacitidine in Treatment-Naive Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS)

Background The only approved medications for treatment of first line HR-MDS are HMAs (AZA & decitabine (DEC) in US, AZA only in EU). It is estimated that progression to Acute Myeloid Leukemia (AML) as well as median OS for these pts is <1-3 yrs (Greenberg 2012). Although AZA monotherapy demonstrated improvement in OS in HR-MDS, clinically meaningful & durable responses continue to be limited to a subset of pts (Silverman 2006). One obvious strategy is to identify a novel drug that can be administered effectively in combo with AZA & has minimal overlapping toxicity with AZA. Based on this current approach & favorable results of the Ph2 study (Navada EHA 2019) the 1st pivotal Ph3 randomized study of oral rigosertib in combo with AZA has been developed as part of an effort to increase overall responses as well as reduce risk of transformation to AML for pts with treatment-naive HR-MDS. Studies have demonstrated that rigosertib binds directly to the Ras-Binding Domains (RBD) found in Ras effector proteins, such as the Raf kinases & PI3K & inhibits the RAS-RAF-MEK & the PI3Ks pathways (Athuluri-Divakar 2016 Cell 2016). In vitro, the combo of rigosertib with AZA synergistically inhibits growth & induces apoptosis of leukemic cells in a sequence-dependent fashion. Sequential exposure with rigosertib followed by AZA achieved maximum synergy with clinically achievable concentrations (Skiddan AACR 2006, Silverman EHA 2019). In a ph2 study (09-08) oral rigosertib at doses ≥ 840 mg/d administered in combo with AZA demonstrated efficacy in HMA-naive MDS pts with an ORR of 90% & a CR rate of 34%. The combo administered in repetitive cycles for more than 2 yrs was well tolerated & the observed GU toxicity was mitigated using specific management guidelines. Based on the efficacy data & favorable safety profile, the pivotal Ph3 trial presented here in treatment-naive HR-MDS population has been developed. (Navada EHA 2019). Study Design & Methods Ph3, multi-center, international, randomized, double-blind, placebo-controlled study to be conducted in treatment-naive pts with HR-MDS who will receive oral rigosertib 1120mg/d (560 mg morning & 560 mg afternoon) or placebo in combo with AZA 75mg/m2 daily (SC or IV). Pts will take rigosertib/placebo on days 1-21 of a 28-day cycle & starting on Day 8, AZA will be administered by SC injection or IV infusion at a 75 mg/m2 daily dose for 7 days of a 28-day cycle according to the approved label. 400 pts are anticipated for enrollment. Major inclusion criteria are shown in Figure 1. Major exclusion criteria are prior treatment with rigosertib or HMA; chronic myelomonocytic leukemia; & prior BMT. Treatment will continue until disease progression as defined by IWG 2006, or unacceptable toxicity. Treatment will continue until PD as defined by IWG 2006 or unacceptable toxicity, after which pts will be followed for survival every 2 mos until death or 3 yrs, whichever occurs first. The primary analysis of all efficacy endpoints will be in the intention-to-treat population. The safety population will include all pts classified according to the protocol treatment they received, regardless of random assignment. Randomized pts who receive no treatment will be excluded. Management guidelines for treatment emergent adverse events requiring dose adjustments, either dose delay or dose modification at time of AE, is provided in protocol. The final analysis of response rate will be conducted using IWG 2006. Endpoints All endpoints for the study are provided in Table 1. Conclusion This pivotal Phase 3 trial in treatment-naive HR-MDS population has been developed based on efficacy data & favorable safety profile from 09-08. The Intergroup randomized ph2 combo study in pts with HR-MDS treated with AZA + lenalidomide (ORR 49%), or AZA + vorinostat (ORR 27%) had a similar ORR to pts treated with AZA monotherapy (ORR 38%) (Sekeres 2017). In contrast, the ph2 study of oral rigosertib in combo with AZA had an ORR of 90% & a CR rate of 34% (Navada EHA 2019). This proposed study is the 1st ph3 combo study of oral rigosertib with AZA & may provide a potential new treatment for first line in a pt population with poor prognosis & limited therapeutic options. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Navada:Onconova Therapeutics Inc: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Adesanya:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Silverman:Medimmune: Research Funding; Celgene: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.

Maintenance of Health-Related Quality of Life in the Phase 4 BYOND Study of Bosutinib for Pretreated Chronic Phase Chronic Myeloid Leukemia

Maintenance of Health-Related Quality of Life in the Phase 4 BYOND Study of Bosutinib for Pretreated Chronic Phase Chronic Myeloid Leukemia

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

Influence of Cytogenetics in Patients with Relapsed Refractory Multiple Myeloma Treated with Oral Selinexor and Dexamethasone: A Post-Hoc Analysis of the STORM Study

T-Cell Mediated Cytopenias in Patients with Myelodysplastic Syndromes Respond to Intravenous Immunoglobulin

Background: Patients with Myelodysplastic Syndrome (MDS) with cytopenias have limited treatment options to improve blood counts apart from immune-modulatory drugs (IMIDS), hypomethylating agents (HMA), cytokines and transfusional support. Immune dysregulation is common in MDS and occurs in up to 35% of pts (LR Silverman, Cancer Med, 2017). Expanded T-cell clonal populations in the peripheral blood and bone marrow in the presence of MDS may play a role in aggravating MDS related cytopenias, increasing the need for transfusions or exacerbating symptoms. Intravenous immunoglobulin (IVIG) may interact with Fc receptors on T cells or have suppressive effects on the concurrent large granular lymphocytic leukemia (LGL) clone. Targeted therapy with IVIG could be a novel strategy to mitigate the cytopenias in MDS and other bone marrow failure pts. Methods: We reviewed in a single-center series 27 consecutive pts who had either MDS, aplastic anemia (AA), or a myeloproliferative neoplasm (MPN) along with an LGL clone seen on TCR-rearrangement studies and/or peripheral blood flow cytometry in the blood and/or bone marrow. Of the 27 pts, 22 had MDS, 2 had MPN, and 1 each with AA, LGL, or Multiple Myeloma. IVIG was initially used as a single agent administered at a dose of 500mg/kg/day over 4 hours once weekly x4 weeks. After "induction", administration was changed to every other week, and then in responding pts, the interval was extended to every 3-4 weeks. In pts with a stable response, IVIG was discontinued and pts observed. After the initial 4 pts, pts were treated concurrently with prednisone 20 mg/d with a taper over 4 weeks, except in pts in which prednisone was a relative contra-indication. Overall hematologic improvement was determined by MDS IWG 2006 criteria, while hemolytic response was determined to be either a complete normalization (CR) or a partial normalization (PR) if there was >50% improvement in deviation from normal LDH, reticulocytes, indirect bilirubin, or haptoglobin values from baseline. Results: All pts received IVIG administered at 500mg/kg, once weekly, to be spaced out maximally as tolerated. 74% (20/27) of pts received steroids. Baseline characteristics of the pt population: median age of 70 years (range 39-87), representing 21 males and 6 females. Of the pts with MDS evaluable for risk stratification by IPSS-R criteria [n=18], 3 were very low, 5 low, 6 intermediate, 2 high, and 2 very high risk categories. By WHO criteria, the greatest representation was 11/20 RCMD, followed by 3/20 with RAEB2. Baseline cytogenetics [n=21] included 3 pts with very poor, 2 poor, 3 intermediate, 11 good, and 2 very good risk profiles. Pts had a range of 0-6 mutations, most common were SETBP1, ASXL1, TP53 (n=4) and SRSF2, U2AF1, PDGFRB (n=3). 24/27 pts had positive TCR beta and 13/27 had positive TCR gamma gene rearrangements. ORR for any cytopenia was 77.8% (21/27), and for any hemolytic response was 76.2% (16/21). ORR for individual cell lines included: 59.2% (16/27) erythroid, 48.1% (13/27) neutrophil, and 33.3% (9/27) platelet responses. For hemolytic responses, CR/PR rate were measured by LDH (29.6%/11.1%), bilirubin (22.2%/14.8%), retic (33.3%/14.8%), and haptoglobin (22.2%/11.1%). For the 14 MDS pts with very low, low, and intermediate IPSS-R risk, ORR was: 64.3% (9/14) any cytopenia, 35.7% (5/14) erythroid, 50.0% (7/14) neutrophil, 14.3% (2/14) platelets. Combined CR+PR rates for hemolysis in the lower risk categories were 42.9% LDH, 21.4% bili, 42.9% retic, 28.6% haptoglobin responses. For the 5 non-MDS pts, ORR for any cytopenia was 100%, and 60% for any hemolytic response. There were no reported significant adverse events with IVIG administration. Conclusions: IVIG can be used as a first line treatment for pts with autoimmune cytopenias associated with LGL clones and MDS (along with other hematological malignancies). Treatment with IVIG yields an ORR of 77.8% in the entire cohort and 64.3% in pts with lower risk MDS, with a reduction in hemolysis as well. This report expands on a previous analysis and demonstrates further evidence of efficacy for the use of IVIG in treating cytopenias exacerbated by LGL T-cell clones. IVIG therapy can permit a delay in the start of an HMA or IMID treatment, lowering transfusion burden, and increasing ANC to help prevent infectious complications. Further evaluation in a larger cohort of pts is warranted. Studies exploring the mechanism of action are underway. Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Silverman:Onconova Therapeutics Inc: Patents & Royalties, Research Funding; Celgene: Research Funding; Medimmune: Research Funding.

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Development of an Allogeneic Anti-Bcma T Cell Therapy Utilizing a Novel Dimeric Antigen Receptor (DAR) Structure

Background: Multiple myeloma remains an incurable malignancy of plasma cells. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a protein that is selectively expressed by B-lineage cells, including Multiple Myeloma (MM) cells, and represents a suitable target for T cell therapy. We have developed an allogeneic T cell therapy approach utilizing genetic engineering of donor-derived T cells to express an anti-BCMA Dimeric Antigen Receptor (DAR) using a proprietary non-viral vector Knock out/knock in (KOKI) technology. Preclinical data demonstrate potent anti-tumor activity both vitro and in vivo against BCMA-expressing MM cell lines. Methods: Anti-BCMA DAR-T cells were generated through genetic engineering of T cells derived from healthy donors by inserting the anti-BCMA DAR construct into the TRAC gene locus, resulting in loss of endogenous TCR expression while expressing the DAR. Distinct DAR constructs were utilized differing only in their intracellular signaling components, namely combinations of 4-1BB, CD28, and CD3zeta. The anti-BCMA DAR-T cells were expanded and purified for subsequent preclinical studies. Using in vitro assays, the different anti-BCMA DAR-T cells were evaluated against multiple myeloma cell lines for specific cytotoxicity as well as stimulus-induced cytokine secretion and cell expansion. The in vivo anti-tumor activity was assessed using luciferase-expressing RPMI8226 cells in NSG mice in a model of disseminated disease. A single dose of anti-BCMA DAR-T cells or relevant control cells was administered, and tumor burden was assessed weekly using bioluminescence imaging. Results: After purification, the anti-BCMA DAR T cells population contained less than 1% TCR-expressing ab T cells. The DAR-positive T cell population was between 20-50%. All anti-BCMA DAR-T cells exhibited BCMA-specific activation, including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. The DAR-T cells using a third generation signaling configuration containing components from 4-1BB, CD28 and CD3zeta signaling domains performed best overall. Conclusions: All tested anti-BCMA DAR-T cells exhibited effective anti-tumor activity. Direct comparison of different cytoplasmic signaling compositions of the DAR allowed for selection of the most potent construct, namely the anti-BCMA DAR utilizing a 3rd generation signaling domain configuration. Based on these data, further development of anti-BCMA DAR-T therapy for hematological malignancies is warranted. These allogeneic abTCR-negative anti-BCMA DAR-T cells have been selected for clinical development. Disclosures Ding: Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Gray:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Cao:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Krapf:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Deng:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Wei:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zeldis:Sorrento Therapeutics Inc: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Guo:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)

A Phase 1b/2 Study of Selinexor, Carfilzomib, and Dexamethasone (SKd) in Relapsed/ Refractory Multiple Myeloma (RRMM)

Development of a Genetically-Engineered Allogeneic Anti-CD38 T Cell Therapy Utilizing a Novel Antigen Receptor Structure

Background: Autologous Chimeric Antigen Receptor (CAR) T cell therapy has shown great promise as a treatment modality for a variety of hematological malignancies. But autologous cell therapies still face several practical hurdles, including reliance on patient immune cells and manufacturing difficulties. Sorrento has pioneered an allogeneic T cell therapy approach utilizing genetic engineering of donor-derived T cells to express a Dimeric Antigen Receptor (DAR). The first DAR-T cell therapy being developed is targeted against CD38, a clinically-validated antigen in multiple myeloma. Preclinical data demonstrate potent anti-tumor activity in both in vitro assays and in vivo studies against CD38-expressing lymphoma and multiple myeloma (MM) cell lines. Methods: Anti-CD38 DAR-T cells were generated through genetic engineering of T cells derived from healthy donors inserting the anti-CD38 DAR construct into the TRAC gene locus resulting in loss of endogenous TCR expression while expressing the DAR. Three distinct DAR constructs were utilized differing only in the intracellular signaling components, namely CD28/CD3zeta, 4-1BB/CD3zeta and CD28/4-1BB/CD3zeta. The CD38 DAR-T were expanded and purified for subsequent preclinical studies. Using in vitro assays, the 3 different CD38 DAR-T cells were evaluated against multiple myeloma and lymphoma cell lines for specific cytotoxicity as well as stimulus-induced cytokine secretion and cell expansion. The in vivo anti-tumor activity was assessed using luciferase-expressing RPMI8226 cells in NSG mice in a model of disseminated disease. A single dose of anti-CD38 DAR-T cells or relevant control cells was administered and tumor burden was assessed weekly using bioluminescence imaging. Results: An anti-CD38 DAR gene was efficiently integrated into TRAC locus of T cells from healthy donors by one step knock out/knock in (KOKI) methodology with high efficiency (~40-80% CD38 DAR expression and ~90% TCR knock out). Following a CD3-depletion step, the TCR-positive T cells were less 1%. When co-cultured with CD38-positive tumor cells, anti-CD38 DAR T cells killed as effectively as retroviral anti-CD38 CAR-T cells with similar cytokine secretion profiles while no cytotoxicity was observed against CD38-negative cancer cells. Moreover, in vivo DAR-T cells showed better killing activity against multiple myeloma cell lines than CAR-T cell with anti-CD38 4-1BB/CD3zeta DAR demonstrating the best anti-tumor activity in an NSG mouse model. The anti-CD38 DAR-T cells with 41BB/CD3 zeta internal signals have been selected for clinical development. Conclusions: All tested anti-CD38 DAR-T cells exhibited potent in vitro and in vivo anti-tumor activity. Direct comparison of three different cytoplasmic signaling compositions of the DAR allowed for selection of the most potent construct, namely the anti-CD38 DAR utilizing 4-1BB and CD3zeta signaling domains. Based on these data, further development of CD38 DAR-T therapy for hematological malignancies is warranted. GMP manufacturing of the allogeneic anti-CD38 DAR-T cells has been initiated. Disclosures Ding: Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Gray:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Krapf:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Deng:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Wei:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zeldis:Sorrento Therapeutics Inc: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Guo:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Preclinical Characterization of an ANTI-CD38/CD3 T CELL-Redirecting Bispecific Antibody

Introduction: Multiple Myeloma (MM) and Non-Hodgkin Lymphoma (NHL) are hematologic malignancies that remain difficult to treat. While autologous CAR-T cell therapies have shown promise in treating these diseases, these therapies are not without issues, including lack of response in many patients, lengthy time to produce CAR-T cells, occasional production failures, as well as high manufacturing costs. As an alternative approach, protein-based T cell engaging and redirecting bispecific antibodies (BsAbs) have been developed. We have generated anti-CD38/CD3 BsAbs to redirect T cells against CD38, a clinically validated antigen in MM and studied their ability to elicit target-dependent tumor cell lysis. The lead molecule is a humanized, stability-engineered CD3-engaging and CD38 antigen affinity-optimized BsAb with reduced effector function to mitigate antigen-independent T cell toxicity. Preclinical data demonstrate potent anti-tumor activity in vitro assays and in vivo studies against CD38-expressing lymphoma and MM cell lines. Methods: Anti-CD38/CD3 BsAbs were generated by CH3 Fc domain interface engineering for heterodimerization of a CD38-targeting Fab arm and anti-CD3-scFv-Fc fusion chain with hinge mutations for reduced FcR affinities. Novel bispecific molecules that bind to CD38 with various affinities/binding kinetics were evaluated in a series of in vitro and in vivo studies, including target-specific redirected T cell cytotoxicity (RTCC) against cancer cell lines. T cell response profiles, and cytokine release. The lead CD38/CD3 BsAb was selected and further evaluated for its ability to inhibit tumor growth and prolong survival in a disseminated luciferase-expressing Raji xenograft mouse model co-implanted with primary human peripheral blood mononuclear cells (hPBMC). Results: Our lead CD38/CD3 BsAb possesses the desired CD38 and CD3, affinities resulting in effective tumor antigen and T cell engagement for RTCC. The CD38/CD3 BsAb induced potent T cell-dependent lysis of CD38-positive cancer cells in vitro, with the CD38 antigen density positively correlating with the cytotoxicity potency. Antigen dependent and dose-dependent T cell activation and cytokine release were studied in vitro, with the level of T cell activation and cytokine release being indicative of the anti-tumor potency but not necessarily anti-CD3 affinity. In an in vivo study, we evaluated the impact of CD38 affinity of the BsAb on anti-tumor activity of the BsAbs. The data showed that a balanced CD38 vs CD3 affinity was shown to be preferred for T cell stimulation and prolonged anti-tumor activity. In preclinical cytotoxicity assays against a cancer cell line panel using hPBMC from healthy donors, our lead CD38/CD3 BsAb was benchmarked against daratumumab, a marketed anti-CD38 antibody for MM, and demonstrated more potent tumor cell killing. These data suggest a more robust anti-tumor activity exerted by the CD38/CD3 BsAb through RTCC than daratumumab through antibody-dependent cellular cytotoxicity (ADCC). In Raji tumor cell-bearing NSG mice implanted with previously unstimulated hPBMCs, our CD38/CD3 BsAb induced tumor growth inhibition and prolonged survival compared to control BsAb or hPBMCs-only treated animals. Conclusions: Our preclinical data demonstrate that our lead CD38/CD3 BsAb recruits T cells against CD38-positive tumor MM and lymphoma cells in a potent target and dose-dependent manner in preclinical studies. These preclinical characterizations support the rationale for clinical investigation of the lead BsAb in selected CD38-positive malignancies. Disclosures He: Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Lai:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Baguley:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Li:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Cao:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Yan:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Takeshita:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Zeldis:Sorrento Therapeutics Inc: Employment, Equity Ownership. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties.

Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Efficacy of Bosutinib in Imatinib-Resistant Vs Dasatinib/Nilotinib-Resistant Chronic Phase Chronic Myeloid Leukemia: Results from the Phase 4 BYOND Study

Utility and Patterns of Use of PET/CT and Bone Marrow Biopsy for Staging in Non-Hodgkin Lymphoma in the Clinical Setting: A Retrospective Analysis Using the LEO Database

Utility and Patterns of Use of PET/CT and Bone Marrow Biopsy for Staging in Non-Hodgkin Lymphoma in the Clinical Setting: A Retrospective Analysis Using the LEO Database

Preclinical Development of a Bcma Targeting Antibody-Drug Conjugate with Novel Payload for Multiple Myeloma Therapy

BCMA (B-cell maturation antigen) is an integral membrane protein that belongs to the TNF receptor family with expression restricted to B cell lineage cells. The RNA is near universally detected in multiple myeloma (MM) cells and the protein is expressed on the surface of malignant plasma cells from patients with MM. In contrast, BCMA expression in normal tissues is very limited, making BCMA a promising target for antibody-drug conjugate (ADC) therapy. We have developed a BCMA-targeting ADC, employing a fully human anti-BCMA monoclonal antibody (mAb) identified from Sorrento's G-MAB antibody library, which was conjugated using proprietary Concortis linker-Duo 5.2 toxin technology resulting in BCMA-077 ADC. The mAb has a unique binding profile for BCMA and demonstrated strong preferential binding for BCMA-overexpressing cells but showed much less binding to lower BCMA-expressing cells. This property allows for more selective binding of the ADC on high BCMA-expressing cells, which are usually tumor cells while sparing low BCMA-expressing normal cells. In addition, we modified the Duo 5.2 payload decreasing the potency of the unconjugated toxin while retaining activity when conjugated to the mAb. The resulting ADC, BCMA-024, was compared to BCMA-077 using in vitro assays, including binding, internalization and cytotoxicity against tumor cell lines. The two ADCs exhibited strong activity and no difference in cytotoxic potency evident. The toxicity of the payload derivative was evaluated in a rodent model and it was found to be well tolerated not showing toxicity at a dose 10 times higher than the lethal dose of the parental toxin. Both ADCs carrying either the parental Duo 5.2 toxin or the derivative toxin payload were evaluated in vivo for anti-tumor activity in three different multiple myeloma xenograft models using different dose regimens. The data showed that both ADCs demonstrated potent BCMA-dependent in vivo anti-tumor activity in all xenograft BCMA-positive tumor models. The PK of the parental anti-BCMA mAb was investigated in non-human primates (NHP) and the parameters indicated a T1/2 of about 10 days. The GLP toxicity studies are ongoing. Our BCMA-ADCs have shown favorable anti-tumor activities combined with good safety profiles resulting in an expanded therapeutic window. The data make BCMA-077 and BCMA-024 promising candidates for continued preclinical development. Based on the totality of our preclinical data, we anticipate selecting a BCMA ADC clinical candidate for the treatment of multiple myeloma. Disclosures Hau: Concortis Biotherapeutics: Employment, Equity Ownership. Zhu:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties. Wang:Concortis Biotherapeutics: Employment, Equity Ownership. Lau:Levena Biopharma: Employment, Equity Ownership. Li:Concortis Biotherapeutics: Employment, Equity Ownership. Li:Levena Biopharma: Employment, Equity Ownership. Sun:Levena Biopharma: Employment, Equity Ownership. Kovacs:Levena Biopharma: Employment, Equity Ownership. Khasanov:Levena Biopharma: Employment, Equity Ownership. Deng:Levena Biopharma: Employment, Equity Ownership. Yan:Levena Biopharma: Employment, Equity Ownership. Knight:Sorrento Therapeutics, Inc.: Employment, Equity Ownership. Kaufmann:Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Ji:Sorrento Therapeutics Inc: Employment, Equity Ownership, Patents & Royalties; Celularity, Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Li:Levena Biopharma: Employment, Equity Ownership, Patents & Royalties; Sorrento Therapeutics, Inc.: Employment, Equity Ownership, Patents & Royalties. Zhang:Concortis Biotherapeutics: Employment, Equity Ownership, Patents & Royalties.

CTX-712, a Novel Clk Inhibitor Targeting Myeloid Neoplasms with SRSF2 Mutation

Splicing factors (SFs) are among the most frequent mutational targets in myeloid neoplasms, particularly in myelodysplastic syndromes (MDS) and a subset of acute myeloid leukemia (AML), designated as 'chromatin/spliceosome-mutated AML, where major SFs mutated include SF3B1, SRSF2, U2AF1, and ZRSR2. These SF mutations are largely mutually exclusive and except for ZRSR2 mutations, are invariably heterozygous, showing prominent hotspots, suggesting that mutations have neomorphic functions and might cause a synthetic lethality when they are homozygous or two SFs are mutated. Thus, SF functions might be a plausible target of therapy for MDS/AML. Of potential interest in this regard is serine/arginine-rich (SR) domains ubiquitously shared by many SFs, including U2AF1, SRSF2, and ZRSR2, which need to be phosphorylated for their nuclear translocation by evolutionally conserved kinases, known as CLK family of proteins. CLK family kinases regulate mRNA splicing by phosphorylating various SR proteins, and inhibition of CLK family kinases resulted in reduction of phosphorylation levels of SR proteins, induction of splicing alterations and protein depletion for multiple genes, including those involved in growth and survival pathways such as S6K, EGFR, EIF3D, and PARP. In addition, a recent report showed that CLK inhibition can induce skipped exons, cell death, and cell growth suppression, which are dependent of CLK2 expression levels. Thus, CLK family kinases are possible targets of inhibition by small molecules to induce synthetic lethality in SF-mutated MDS/AML and for this purpose, we have recently developed an orally available and highly potent CLK inhibitor, CTX-712 and evaluated its anti-leukemic activities both in vitro and in vivo. When tested in human myeloid cell lines (K562 and THP1), CTX-712, strongly inhibited phosphorylation of multiple SR proteins including SRSF3, SRSF4, SRSF5, and SRSF6 that bind to SRSF2. To further investigate the efficacy of CTX-712 in vivo, we established 5 AML-derived xenograft (PDX) models, which treated with varying doses of CTX-712. Among these 5 PDX models, SRSF2 mutation was found in only one case, which had a SRSF2 p.P95H, mutation, while others (a subcutaneous and 3 leukemia model) were negative for SRSF2 mutations. The SRSF2-mutated model showed a significant response to CTX-712 in a dose-dependent manner. Of note, 4 out of 5 mice treated using a high dose protocol (12.5 mg/kg) achieved complete remission (the tumor shrank completely to unmeasurable size). Two-week after treatment, tumor volumes (mm3) were 762 ± 147 (vehicle), 331 ± 64 (low dose of CTX-712: 6.25mg/kg, P=0.028), and 39 ± 39 (high dose, P=0.0014) (N=5 each, mean ± SEM). CTX-712 also significantly improved the survival of PDX #1. Median survivals (days after engraftment) were 34.5 (vehicle) vs. 93.5 (12.5mg/kg, P=0.015) (N=2 each). Interestingly, another leukemic model carrying KRAS, NF1, and TP53 but not SRSF2 mutations also showed a significant reduction of leukemic burden 2 weeks after CTX-712 treatment; leukemic burden after therapy, as measured by frequency of hCD45+cells in PB (%), were 82 ± 2.2 (vehicle), 17 ± 3.6 (low dose, P<0.0001), and 0.89 ± 0.43 (complete remission, high dose, P<0.0001), (N=4 each, mean ± SEM). In the third PDX model with mutations of FLT3, RAD21, RUNX1, and WT1, CTX-712 administration reduced subcutaneous AML tumors in a dose-dependent manner and achieved partial remission (high dose, P=0.0008) (N=6 each). CTX-712 also significantly improved the survival of the PDX #3 model (high dose, P=0.0069) (N=6 each). In PDX #4, leukemic model with mutations of ASXL1, BCOR, and TET2, high dose CTX-712 therapy strongly reduced the leukemic cell burden than vehicle control (P=0.0027), (N=4 each). CTX-712 also significantly improved the survival of this model (P=0.016) (N=5 each). The last AML PDX #5 model with U2AF1, BCOR, DNMT3A, IDH1, KDM6A, RUNX1, and TET2 mutations was refractory for CTX-712 therapy. Overall, 4 out of 5 PDX AML models showed anti-tumor effect of CTX-712. Complete disappearances of tumors were obtained in 2 cases, including an SRSF2-mutated model. These results provide mechanistic insights of CLK inhibition and a rationale for further investigation of the novel CLK inhibitor in MDS/AML. CTX-712 is currently in clinical phase 1 trials for relapsed and refractory malignancies. Disclosures Yoda: Chordia Therapeutics Inc.: Research Funding. Morishita:Chordia Therapeutics Inc.: Employment, Equity Ownership. Mizutani:Chordia Therapeutics Inc.: Employment, Equity Ownership. Satoh:Chordia Therapeutics Inc: Employment, Equity Ownership. Miyake:Chordia Therapeutics Inc.: Employment, Equity Ownership. Ogawa:Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; RegCell Corporation: Equity Ownership; Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties.

A Machine Learning Approach Identifies a 30-Gene Model That Predicts Sensitivity to Selinexor in Multiple Myeloma

A Machine Learning Approach Identifies a 30-Gene Model That Predicts Sensitivity to Selinexor in Multiple Myeloma

Microenvironmental Signatures Reveal Biological Subtypes of Diffuse Large B-Cell Lymphoma (DLBCL) Distinct from Tumor Cell Molecular Profiling

Research in DLBCL pathogenesis has largely focused on the lymphoma cells that defined molecular subtypes. To elucidate the role of the lymphoma microenvironment (LME) in this process, we developed and deconvoluted transcriptomics signatures of LME cells and pathways from 3,026 DLBCLs from 13 datasets including our new cohort of 127 pts. Mutations were available for 562 pts of the datasets and for 22 pts from our cohort (WES with matched normal). Applying density-based clustering we identified 4 LME signatures, independent of reported transcriptional and genetic classifications based on lymphoma cells: LME-1 DLBCLs (n=726, 24% - GCB/ABC: 35%/36%) were characterized by an "immunosuppressive" ME enriched for Tregs, myeloid-derived suppressor cells, CD8PD1high, natural killer and macrophages type 2 and prevalence of genetic mechanisms of immune escape in malignant cells such as mutations in B2M (33%) and CD70 (10%). Malignant cells in LME-1 DLBCL presented high activity of NF-kB and JAK/STAT signaling pathways, likely due to high frequency of co-occurring MYD88L265and CD79B mutations (40%) and the presence of a cytokine rich milieu including high expression of IL10, IL6 and TNFS13B. Good outcome genetic groups BN2 and EZB constituted 46% of pts LME-2 DLBCLs (n=484, 16% - GCB/ABC: 55%/30%) were characterized by an "anti-tumor immunity" ME enriched for T cells, follicular TH and follicular dendritic cells (FDC). Lymphoma cells presented the highest number of BCL2 translocations and EZH2 mutations (40%, p=0.001 vs. other LME groups) and activation of cell motility and chemotaxis pathways that likely account for the advance stage at presentation (70% were stages III/IV p=0.02 vs. 40-50% in the other LME groups). Lymphoma cells expressed higher levels of CCL20, CCR6 and CXCR5. Good outcome genetic groups BN2 and EZB constituted 74% of pts. Notably, ABC LME-2 DLBCLs had better prognosis that any other ABC DLBCL (p<0.007 n=848) and similar to GCB DLBCLs LME-3 DLBCLs (n=847, 28% - GCB/ABC: 56%/25%) were characterized by a "mesenchymal" ME enriched for cancer-associated fibroblasts (CAFs), reticular DC, FDC and endothelial cells. Lymphoma cells showed higher mutations in BCR/Pi3K signaling intermediates SGK1 and GNA13 (20 and 13%) and activation of the TGFB signaling and matrix remodeling pathways. LME-3 DLBCLs expressed higher levels of MMP9, MMP2, TIMP1 and TIMP2. Good outcome genetic groups BN2 and EZB constituted 75% of pts, and were no patients harboring NOTCH1 mutations. LME-3 DLBCL also had the higher proportion of non-cellular LME component represented by the extracellular matrix (ECM). Patients with DLBCL with higher ECM proportion had better progression free survival (p=0.0004). We specifically tested the ECM effect in a murine DLBCL model by analyzing changes in ECM proteins associated with disease progression by serial proteomics. DLBCL progression was accompanied by increase in lymphoma cells in detriment of CAFs and ECM proteins. Among them, we identified the small proteoglycan decorin (DCN). Accordingly, parental administration of recombinant DCN to DLBCL mice (n=10 vs vehicle n=10) decreased tumor volume (p<0.001) and lymphoma cell proliferation while improving the LME immune infiltrate LME-4 DLBCLs (n=969, 32% - GCB/ABC: 46%/38%) were characterized by a "depleted" ME with increased proportion of lymphoma cells with mutations in MYD88, PIM1 and HLA-C (36, 38 and 13%), higher genomic instability and epigenetic heterogeneity (by DNA methylation). Good outcome genetic groups BN2 and EZB constituted 68% of pts. Lymphoma cells showed activation of Pi3K signaling and hypermethylation and low expression of the TGFB mediator SMAD1 (p<0.01 vs other LME groups). In agreement with our demonstration that pharmacologically reversible SMAD1 hypermethylation drives chemoresistance in DLBCL (Cancer Discovery 2013), patients with LME-4 DLBCL had less favorable outcomes in overall survival (HR=1.65 P<0.005 n=1,980) and response to immunochemotherapy (p<0.0001 n=810) than any other LME groups; likely reflecting the acquisition of ME-autonomous survival mechanisms by lymphoma cells. The bad outcome of LME-4 DLBCLs was not dependent on MYC/BCL2 or BCL6 double translocations, or the overall mutational load. In sum, ME signatures in DLBCL associate with clinical outcomes independently of existing molecular subtypes, contribute to explain DLBCL biology and provide potential novel therapies Disclosures Rutherford: Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria. Martin:Celgene: Consultancy; Teneobio: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy. Leonard:Nordic Nanovector: Consultancy; Nordic Nanovector: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy; Merck: Consultancy; Miltenyi: Consultancy; Sandoz: Consultancy; Epizyme, Inc: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; ADC Therapeutics: Consultancy; Gilead: Consultancy; Karyopharm Therapeutics: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Sutro Biopharma: Consultancy; Celgene: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; MorphoSys: Consultancy; Sutro Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; ADC Therapeutics: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Merck: Consultancy.

Synergistic Effect of DHODH Inhibitor PTC299 with DNA Demethylating Agent Decitabine in Myelodysplastic Syndromes

Background:Myelodysplastic Syndrome (MDS) is a clonal bone marrow disorder characterized by ineffective and clonal hematopoiesis accompanied by morphological dysplasia and variable cytopenia. There are few treatment options for MDS, and allogenic hematopoietic stem cell transplantation is the only curative option. Dihydroorotate dehydrogenase (DHODH) catalyzes a rate-limiting step in de novo pyrimidine synthesis, the conversion of DHO to orotate. DHODH inhibition has been described recently as a new approach for treating acute myeloid leukemia (AML) by inducing differentiation of diverse AML subclasses. PTC299 represents a novel potent DHODH inhibitor and recently clinical development of PTC299 as a potential treatment option for acute leukemia was initiated. Here, we explored the efficacy of DHODH inhibitor PTC299 for MDS. Methods:Anti-MDS efficacy of PTC299 was studied using human MDS cell lines and primary MDS cells in vitro. PTC299 was synthesized at PTC Therapeutics Inc. Mechanistic studies were conducted via flow cytometric analysis and RNA-sequencing (RNA-seq). Gene expression levels were analyzed by quantitative PCR (qPCR). Results:PTC299 inhibited proliferation of AML cell lines and induced their differentiation. As previously reported in other DHODH inhibitors, upregulation of CD11b was observed after PTC299 treatment in both HL-60 and THP-1 cells. In addition, PTC299 inhibited the proliferation of MDS cell lines, MDSL and SKM-1 cells, with EC50s of 12.6 nM in MDSL cells and 19.7 nM in SKM-1 cells. The inhibitory effect was reversed by the exogenous addition of 100 µM uridine, which bypasses the requirement for de novo pyrimidine synthesis by feeding into the salvage pathway, thereby negating the need for DHODH. Because the basal expression levels of CD11b are high in MDS cells, we examined the expression levels of CD38. Both cell lines showed dose-dependent upregulation of CD38 after PTC299 treatment. To investigate the possible synergism between PTC299 and decitabine, we treated MDSL and SKM-1 cells with increasing concentrations of PTC299 and decitabine as single agents or in combination. After 3 days of culture, cells were analyzed by MTS assays. PTC299 and decitabine exerted a enhanced cytotoxic effect on MDSL and SKM-1 cells. Similar results were obtained with primary MDS samples. In Annexin/PI assays, the percentage of apoptotic cells was increased by combination of PTC299 with decitabine in both cell lines. Mechanistically, treatment with PTC299 induced an intra-S-phase arrestfollowed by entry intoapoptotic cell death. It has also been reported that the expression of p53 is increased in response to the intra-S-phase arrest. To understand the genome-wide effects and target genes of PTC299 and the combination with decitabine, we performed RNA-seq of MDSL and SKM-1 cells treated with PTC299, decitabine, or the combination of both agents versus DMSO-treated cells. Gene set enrichment analysis (GSEA) using our RNA-seq data confirmed that MYC target gene sets were negatively enriched in both PTC299-, decitabine- and combination- treated cells. KEGG pathway enrichment analysis revealed activation of genes associated with apoptosis in both cell lines. To better elucidate a synergistic effect of PTC299 and decitabine, we performed qPCR of CDKN1A, which is a major target of p53 activity. The mRNA expression levels of CDKN1A were upregulated after treatment with PTC299, which was further enhanced by the combination with decitabine. Conclusions:Our result indicate that the DHODH inhibitor PTC299 suppresses the growth of MDS cells in vitro and acts in at least an additive and possibly synergistic manner with decitabine in this process. This combination therapy could be a new therapeutic option for the treatment of MDS. Disclosures Lennox: PTC Therapeutics: Employment. Weetall:PTC Therapeutics: Employment. Sheedy:PTC Therapeutics: Employment.

Prognostic Significance of Hospitalization Status at Second Cycle of Hypomethylating Agent Induction Therapy in Acute Myeloid Leukemia Patients Ineligible for Intensive Chemotherapy

Introduction: Hypomethylating agents (HMAs) are used as induction therapy for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA therapy is frequently initiated in the hospital and some patients remain hospitalized through the initiation of cycle 2 (C2). Clinicians are often faced with the decision to administer C2 while the patient is still hospitalized, however, there is a paucity of prognostic information to guide treatment decisions in this common scenario. Methods: We conducted a retrospective review of patients diagnosed with treatment naïve, de novo and secondary AML who were ineligible for induction chemotherapy (at the discretion of the treating physician based on advanced age, comorbidities, or other reasons) at a single, tertiary, referral center. Patients were included if they received induction therapy with an HMA, including azacitidine and decitabine between 7/1/2008 and 7/1/2018. Exclusion criteria included receipt of intensive induction chemotherapy and inadequate electronic medical documentation. Patients were divided into four groups: patients who were discharged after completion of C1 and received C2 as an outpatient (discharged after C1), patients who received C1 and C2 during the same hospitalization (C1-C2 continuous hospitalization), those who received one total cycle (C1 only), and patients who received C1 as an outpatient (C1 outpatient). The groups were analyzed separately for the primary outcome of overall survival (OS), calculated by Kaplan Meier analysis. Results: Out of 105 patients identified who received an HMA, 100 patients were identified who met inclusion/exclusion criteria and their baseline characteristics are shown in Table 1. Most patients had de novo AML (39.0%), although 33.0% and 19.0% of patients had AML secondary to myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN), respectively. Additionally, 8 patients (8.0%) had therapy related AML. The majority of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 2 at induction. Patients who received C1 as an outpatient had a significantly better performance status than those who did not (p= 0.033) Decitabine was the most common HMA (57.0%) administered and was most often on 5-day schedule. Eight patients (8.0%) were continually hospitalized until C2, 5 because of active medical issues (most often fevers requiring intravenous antibiotics), 2 had physical debility precluding discharge home, and 1 was receiving intrathecal chemotherapy twice weekly for central nervous system involvement of AML. The median OS was 15.6 months (95% CI 2.66-28.6) in patients who received C1 outpatient, 10 months (95% CI 6.67-13.43) in patients discharged after C1, 4 months (95% CI 2.40-6.40) in the C1-C2 continuous hospitalization group, and 1 month (95% CI 0.61-1.30) in those who only received C1 as shown in Figure 1. Patients discharged after C1 had a significantly longer OS compared to the C1-C2 continuous hospitalization group (p=0.003). There was a trend (p=0.054) towards worse survival in patients who received C1 only compared to patients hospitalized continually from C1-C2. Conclusions: Continued hospitalization from C1 to C2 of HMA therapy led to an extremely poor median survival of 4 months in this cohort, compared to 10 months in patients who were able to be discharged after C1 and receive C2 as an outpatient. Patients who only received a single cycle of HMA did not have a significantly different survival as compared to patients who were continually hospitalized from C1 to C2. While this is a small retrospective series, these data suggest that AML patients still requiring hospitalization at time of C2 of HMA therapy should be re-evaluated for alternative therapeutic approaches including hospice given poorer outcomes. Although this grouping selects for patients who are sicker and unable to leave the hospital, there is apparent lack of significant benefit of continued HMA therapy in the majority of patients while inpatient. The impact on hospital length of stay, unnecessary utilization of healthcare resources, and patient's quality of life should also be considered in these cases. Prospective identification of these patients with a poorer prognosis could lead to better alternatives for therapeutic approaches. Disclosures Kremyanskaya: Incyte, Celgene, Constellation, Protagonist.: Research Funding; La Jolla: Consultancy. Navada:Onconova Therapeutics Inc: Research Funding. Mascarenhas:Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Promedior: Research Funding; Roche: Consultancy, Research Funding; Janssen: Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

Selinexor, Pomalidomide, and Dexamethasone (SPd) in Patients with Relapsed or Refractory Multiple Myeloma

North American Practice Patterns for PET-2 Positive Hodgkin Lymphoma

North American Practice Patterns for PET-2 Positive Hodgkin Lymphoma