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Background: Anti-tumor immunity plays a key role in tumor development and progression and the landscape of tumor immune microenvironment could affect the clinical outcome of patients. The concept of immunoscore based on immune cell infiltration has been actively applied to solid tumors including colon cancer and malignant melanoma and successfully predicted prognosis of patients. However, a potential utility of immunoscore in predicting prognosis of patients with diffuse large B-cell lymphoma (DLBCL) remains unclear. For easy application of immunoscore to daily practice, we investigated the prognostic value of tumor-infiltrating CD3+ T-cell density which is routinely stained for diagnosing malignant lymphomas, and then explored the feasibility of immunoscore application in DLBCL. Method: One-hundred-four patients with DLBCL treated with R-CHOP therapy, whose tumors were prospectively immunoprofiled for routine clinical diagnosis, were enrolled in this study. Immunohistochemistry was performed on representative whole formalin-fixed paraffin-embedded tissue sections using CD3, CD20, MYC, BCL2, BCL6, CD10 and MUM1. Cell-of-origin was determined using the Hans' algorithm and MYC/BCL2 double expressor (DE) was defined as the co-expression of MYC (in ≥ 40% of tumor cells) and BCL2 (in ≥ 70% of tumor cells). Whole-slide scanning was performed, whole tumor regions were annotated, and images were analyzed with Aperio ImageScope v.12.4.3 software (Leica Biosystems, Nussloch, Germany). The CD3+ density was quantified in three different methods: the total numbers of CD3+ cells/area (mm 2), CD3+ cells/total cells and CD3+ cells/CD20+ cells. Correlation between the CD3 density and clinicopathologic parameters and prognostic impact of the CD3 density were analyzed. To validate the findings, publicly available mRNA and clinical datasets of two DLBCL cohorts were downloaded and analyzed (Schmitz et al. 2018 and Sha et al. 2019). To dichotomizing low versus high CD3 density cases, the optimal cut-off values for overall survival were determined by ROC curve analysis using MedCalc Software v 19.4 (MedCalc Software, Ostend, Belgium). Remaining all statistical analyses were performed using SPSS version 25.0 (SPSS). Result: All three methods assessing CD3+ cell density showed high concordance (CD3+ cells/area vs CD3+ cells/total cells, k=0.540 p=0.000; CD3+ cells/total cells vs CD3+ cells/CD20+ cells, k=0.394 p=0.000; CD3+ cells/CD20+ cells vs CD3+ cells/area, k=0.739 p=0.000). Patients with low CD3 density had elevated serum LDH (all, p Conclusion: Low CD3 density was a poor prognostic factor in DLBCL independent of other poor prognostic parameters such as IPI score and DE status. Therefore, evaluating CD3 density might be suitable for immunoscoring DLBCL cases to predict prognosis. Disclosures Kim: Boryung: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeyondBIO: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca/MedImmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca-KHIDI: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GI CELL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background Myelodysplastic syndromes (MDS) are associated with the reduction in healthy blood cells produced in the bone marrow, which subsequently lead to a variety of symptoms. A review of existing patient-reported outcome (PRO) questionnaires used in MDS or acute myeloid leukemia found that few if any were developed to measure symptoms of higher-risk MDS in the context of clinical trials. An MDS symptom daily diary has been developed following conduct of a targeted review of peer-reviewed literature and advice meetings with three clinical experts who treat patients with higher-risk MDS. The primary goal of this study was to evaluate the content validity of the novel MDS symptom daily diary among adults with higher-risk MDS. Methods Qualitative interviews were conducted via telephone with 15 adults with higher-risk MDS. The interviews were composed of two parts. During the concept elicitation portion, participants were asked to spontaneously describe their experience of higher-risk MDS, with particular focus on the symptoms they experience and the impact on their lives. Participants then completed the MDS symptom daily diary and provided feedback on the instructions, items, and response options in order to evaluate its readability, comprehensibility, relevance, and comprehensiveness. Interviews were conducted in three waves. Following each wave, developers reviewed summaries of results based on detailed interviewer notes. Revisions to the daily diary were made based on interim results prior to the next wave of interviews. Following the completion of all interviews, audio-recordings of the interviews were transcribed, coded, and analyzed. Results A total of 15 participants (53.3% female, ages 36 - 81 [mean=66, standard deviation=11.3] years) completed an interview: 7 in Wave 1, 3 in Wave 2, and 5 in Wave 3. All had begun treatment with a hypomethylating agent within six months prior to screening or were treatment-naïve. Participants reported experiencing 20 different symptoms of higher-risk MDS; the most frequently reported symptoms were fatigue (n = 13, 86.6%), bruising (n = 11, 73.3%), shortness of breath (n = 11, 73.3%), lack of energy (n = 10, 66.6%), heaviness in the arms or legs (n = 9, 60.0%), weakness (n = 9, 60.0%), bleeding (n = 8, 53.3%), and bone pain (n = 4, 26.6%). Participants identified fatigue and lack of energy as the most bothersome symptoms and the most important to improve with treatment. Based upon participant feedback in Wave 1, two items were removed from the draft diary due to their overlap with other items. Additionally, one item was revised for clarity. Following Wave 2, a single item to assess shortness of breath was retained while alternate items assessing shortness of breath were removed based on participant feedback. No further revisions to the diary were made based on participant feedback in Wave 3. The final version of the MDS symptom daily diary consists of eight items assessing fatigue, weakness, lack of energy, shortness of breath, bruising, bleeding, bone pain, and heaviness in arms or legs. All participants interpreted the instructions, items, and response options as intended by the developers. Participants found the diary easy to complete and relevant to their experience, and no participants suggested removing any items from the final version. Conclusion The MDS symptom daily diary has been developed as a tool to characterize the symptom burden of MDS and to evaluate the efficacy of study medications in clinical trials. The qualitative interviews provide evidence of its content validity; in future research, the psychometric properties of the daily diary and interpretation of its scores will be evaluated using data from an upcoming Phase 3 clinical trial. Disclosures Vallow: Novartis Pharmaceuticals: Current Employment. Brandt: Novartis Pharmaceuticals: Current Employment.

Introduction: Bispecific lentiviral anti-CD20, anti-CD19 (LV20.19) CAR T-cells may improve outcomes in relapsed, refractory (R/R) B-cell malignancies by limiting relapse from single antigen downregulation (Shah et al. Nature Med. 2020). Preclinical models suggest that CAR T-cells cultured with IL7 & IL15 (IL7+15) can improve cell expansion, in vivo persistence, tumor cytotoxicity, and increase frequency of a T-stem cell memory phenotype (Xu et al. Blood 2014) In an ongoing phase 1/2 clinical trial we examined the impact of IL7+15 (in lieu of IL-2 in our prior study) and varying lengths of manufacturing (MF) on LV20.19 CAR T-cell safety and efficacy in R/R B-cell non-Hodgkin lymphoma (NHL). Methods: We conducted a Phase 1/2 single center, prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10^6 cells/kg for patients (pts) with R/R B-cell NHL. LV20.19 CAR T-cells were locally manufactured in the CliniMACS Prodigy device with IL7+15 for cell expansion with goal of fresh infusion at varying lengths of MF (8 vs 12 days). There are four cohorts in this study. Cohort 1 was a 6-patient phase 1 safety run-in of IL7+15 expanded LV20.19 CAR T-cells manufactured for 8 and 12 days respectively (n=3 in each arm). Cohort 2 & 3 were phase 1b arms comparing flexible 8/12-day MF versus fixed 12-day MF for pts with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and marginal zone lymphoma (MZL). Cohort 4 is a phase 2 arm in mantle cell lymphoma (MCL) utilizing a flexible 8/12-day MF protocol. The primary outcome of the Phase 1 cohorts is safety. Dose limiting toxicity (DLT) was evaluated during the first 28 days post-CAR treatment. Results: In total, 22 pts received LV20.19 CAR T-cells at the specified dose of 2.5x10^6 cells/kg. Median age was 63 (44-78). There were 11 pts with DLBCL, 8 with MCL, and 3 with FL. Median lines of prior therapy was 4 (2-11) (Table 1). Outcomes (all pts) There were no DLTs in the Phase 1 safety run-in allowing accrual to open in the two Phase 1b and Phase 2 MCL arms. In total, there was one DLT in the Phase 1b 12-day arm with prolonged grade 3 ICANS and grade 4 acute kidney injury. There were two non-relapse mortality (NRM) events outside the DLT period from infectious complications (pneumonia and gram-negative rod sepsis). Cytokine release syndrome (CRS) occurred in 19 pts (86%), mostly Grade 1-2 (18/19) (Table 2). ICANS occurred in 6 pts (27%); 3 pts had grade 3 ICANS (14%). Median day to CRS was day 1 (range 0-8) which correlated with rapid in-vivo expansion (Figure 1). Among all pts, the overall response rate (ORR) was 91% (55% complete response [CR]) and 2 pts had progressive disease (PD) at Day 28, one of which was a prior anti-CD19 CAR failure. Seventeen pts had ClonoSEQ minimal residual disease (MRD) testing between Days 28-60, and 13 were MRD-negative. The median follow up of survivors is 6 months. The median PFS and OS have not been reached to date (Figure 2). Twenty of 22 pts received fresh CAR T-cells without cryopreservation. Outcomes by 8 vs 12-day MF (Phase 1 & 1B cohorts) Pts with DLBCL, FL, and MZL (n=14) were assigned consecutively to either 8-day or 12-day MF schema (n=7 in each arm). ORR in the 8-day MF arm was 100% (CR 71%) vs 71% (CR 29%) in the 12-day arm. Immunophenotyping of LV20.19 CAR T-cells demonstrated that nearly all 12-day MF cells had an effector-memory phenotype and contained few, if any, less differentiated T-cells while 8-day MF cells contained T-cells with a central-memory phenotype. Rates of CRS were higher in the 8-day MF arm (100% vs 57%, p=0.05) with no difference in ICANS. MCL outcomes In total, 8 pts with MCL received LV20.19 CAR cells (3 pts in Phase 1 & 5 in the Phase 2 cohort). Six of 8 patients had LV20.19 CAR T-cells manufactured in 8 days. Median lines of therapy were 5 (4-8) and 6 progressed on covalent BTK inhibitors. The ORR at day 28 was 100% (CR=63%), and 6 of 7 evaluated for MRD were negative at day 28. At last follow-up, no patient has relapsed with median follow-up time of 5 months (1.5 to 12 months). One of the two NRM events was in the MCL phase II cohort. There was no grade ≥3 CRS and only one grade 3 ICANS. Conclusions: Bispecific LV20.19 CAR T-cells expanded with IL7+15 are safe and efficacious for R/R B-cell NHL with a high ORR and low rates of grade ≥3 CRS or ICANS. Early results demonstrate immunophenotypic differences and improved responses among pts treated with a shorter 8-day MF process. MCL outcomes were impressive with a 100% ORR and no relapses to date. Figure 1 Figure 1. Disclosures Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Legend: Consultancy; Incyte: Consultancy; Umoja: Consultancy; Kite: Consultancy; Epizyme: Consultancy. Schneider: Lentigen Technology: Current Employment. Hamadani: Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding; Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Johnson: Miltenyi Biotec: Research Funding. Hari: Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau.

Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive and emotional functioning and quality of life (QOL) are less well studied, with mechanisms of all incompletely understood. Given the known bidirectional relationship between neuroinflammation and depression, and the role of kynurenine (Kyn) metabolism in both, we studied QOL through patient-reported outcomes (PROs) and neurotoxicity and their relationship to Kyn metabolites. Methods Patients with relapsed refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia treated with CAR-20/19-T cells on our Phase I/Ib clinical trial (NCT03019055) (N=16) were included. Patients were excluded if they had a history of previous allogeneic hematopoietic stem cell transplantation. Study subjects provided serum and PROs through self-report surveys at the following time points: baseline/ apheresis, Day-14 (D14), D28, and D90 post-intervention. The following scales were used to assess QOL: Inventory of Depression and Anxiety Symptoms (IDAS), Brief Pain Inventory (BPI), Fatigue Severity Index (FSI), and Pittsburgh Sleep Quality Index (PSQI). Tryptophan and its metabolites (kynurenine (Kyn), 3-Hydroxy-anthranilic Acid (3-HAA), 3-Hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA)) and neurotoxicity grades were measured for all 16 subjects. Patients were evaluated for neurotoxicity with the CTCAE 5.0. The measurements were log-transformed to stabilize the variances and allow modeling of the expected multiplicative effects. A mixed effects longitudinal model was used for all eligible patients to evaluate the impact of time on all PRO variables over the 4 timepoints through 90 days post CAR-T infusion. Neurotoxicity was evaluated two ways: as a categorical variable with 5 levels (0 to -4) and as a continuous variable. Results Depression symptoms improved over time with the lowest value at Day 90, though the changes were not statistically significant (P = .072). Remaining QOL PRO variables did not show statistically significant changes, tending to improve or remain stable over time (Table 1 & Figure 1). Mean Kyn levels significantly changed over time (P = .028; Table 2). This effect is most pronounced in patients with Grade 3/4 neurotoxicity where Kyn levels rise at Day 14 and Day 28 followed by a decrease by Day 90 (Figure 2). Among patients who exhibited neurotoxicities, baseline levels of 3-HAA and 3-HK before CAR-T therapy were elevated; though nonsignificant, similar trends were not observed in the other metabolites (Figure 2). These observations however were significant when neurotoxicity was evaluated as a continuous variable (Table 2) with 3-HAA and 3-HK higher in patients with higher grade neurotoxicities (P = .015 and .070). Conclusions Our findings suggest that CAR-T therapy does not impair QOL and may in fact result in improved mood in the early months following cell infusion, adding to recent literature about long-term QOL in CAR-T survivors. Here, we also identify elevated baseline 3-HAA and 3-HK levels as well as increased Kyn levels following CAR-T therapy, with the first two associated with worse neurotoxicity. Most interestingly, we find higher levels of 3-HAA and 3-HK in patients who experience neurotoxicities. Correlational studies will be needed to confirm potential relationships between PROs and metabolites. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria.

Background: PT-112 is a novel pyrophosphate-platinum conjugate with a multi-modal mechanism of action that induces immunogenic cell death and is not susceptible to DNA-repair drug resistance pathways. In phase I studies in solid tumors, PT-112 demonstrated safety and efficacy as single agent and in combination with PD-L1 checkpoint inhibitor avelumab, crossing a range of dose levels (DL) and tumor types, including in heavily pre-treated patients (pts) non-responsive to immunotherapy and refractory to other modalities. Non-clinical, in vivo research using advanced imaging technology demonstrated that PT-112 reached the highest concentrations in bone tissue (osteotropism). Moreover, PT-112 was highly active in the orthotopic, immune-competent Vk*MYC mouse model of multiple myeloma, including drug-resistant transplant variants. Thus, a rationale for PT-112 as an investigational candidate in multiple myeloma was established. Here, we present results of a phase I dose escalation study of PT-112 in pts with relapsed or refractory multiple myeloma (RRMM). Methods: A 3+3 design was used to determine the recommended phase 2 dose (RP2D) for PT-112 (28-day cycle IV days 1, 8, 15) in pts with evaluable RRMM who had exhausted available therapies (Tx), with adequate bone marrow (abs neutrophil count ≥ 1.0 x 109/L; platelet count ≥ 50 x 109/L; and hemoglobin ≥ 8.0 g/dL) and renal function (calculated creatinine clearance ≥ 30 mL/min), and ECOG PS 0-2. Results: A total of 24 pts were treated with PT-112 monotherapy across 6 DLs: 125 mg/m2, 3 pts; 180 mg/m2, 4 pts; 250 mg/m2, 5 pts; 300 mg/m2, 4 pts; 360 mg/m2, 4 pts; 420 mg/m2, 4 pts. Patients had a median age of 72 years and were heavily pre-treated, with a median of 8 prior lines of systemic Tx: 22 (92%) pts were triple-class refractory with 19 (79%) pts penta-refractory, and 3 (13%) pts refractory to BCMA-based therapies. The most common treatment-related adverse events (TRAEs) were thrombocytopenia (58%), neutropenia (42%), diarrhea (38%), and nausea (38%). 38% of pts had ≥1 grade 3 non-hematologic TRAE, with no grade 4 non-hematologic TRAEs reported. One dose-limiting toxicity (DLT) of grade 4 neutropenia occurred at the 420 mg/m2 DL. In addition, due to frequent dose reductions and modifications at this DL, the safety committee declared 360 mg/m2 as the RP2D. Among 8 patients who received a starting dose at / above the RP2D, 2 had stable disease and 4 experienced responses to PT-112 Tx. These included a confirmed partial response (PR) achieved in a 79-year-old pt with kappa free light chain (FLC) disease treated at 360 mg/m2, whose previous Tx included combination regimens with most approved therapies (penta-refractory) and stem cell transplantation. FLC levels declined by 65% from baseline on PT-112 therapy and the pt remained progression free for 4.5 months. A 72-year-old pt treated at the 420 mg/m2 DL, reduced to 250mg/m2 every other week over the course of Tx due to grade 3-4 cytopenias, had a confirmed minor response. Prior Tx with multiple lines given over 9 years included stem cell transplantation, most approved therapies (penta-refractory), prior investigational antibody and CAR-T cell Tx (primary refractory to CAR-T). The patient was M-protein negative, kappa FLC levels declined by 32% following the first dose reduction, and the pt remained progression free and clinically stable without complaints for 4.5 months. Additionally, two transient, unconfirmed PRs occurred in patients at the 420mg/m2 DL: in a triple-class-refractory 82-year-old previously treated with 5 lines of Tx, with 70% reduction in kappa FLC during cycle 1; and in a penta-refractory 85-year-old, who experienced disappearance of M-protein during cycle 1 and Gr 4 neutropenia (DLT). Conclusions: PT-112 monotherapy was feasible and well tolerated in this heavily pre-treated, multi-refractory multiple myeloma population, and the Phase I clinical data appear to validate the developmental hypothesis, built upon activity in the Vk*MYC mouse model of multiple myeloma. Responses were confirmed in 25% of patients treated at / above the RP2D using single-agent PT-112, an encouraging result in a dose escalation trial conducted in heavily refractory patients. Activity of PT-112 in RRMM patients may be explained by its osteotropism and its unique mechanism of action compared to other drug classes used to treat this disease. Further clinical study of PT-112 in RRMM is warranted in a phase 2 clinical trial. Disclosures Ailawadhi: Celgene: Honoraria; Janssen: Research Funding; Pharmacyclics: Research Funding; Amgen: Research Funding; Medimmune: Research Funding; BMS: Research Funding; Cellectar: Research Funding; Phosplatin: Research Funding; Takeda: Honoraria. Vogl:Janssen: Consultancy; Celgene: Consultancy; MorphoSys: Consultancy; Takeda: Consultancy; Active Biotech: Consultancy, Research Funding; Oncopeptides: Consultancy; Karyopharm: Consultancy. Ames:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Yim:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Price:Phosplatin Therapeutics: Current Employment, Current equity holder in private company. Jimeno:Phosplatin Therapeutics: Current Employment, Current equity holder in private company.

Introduction: Increased understanding of the pathophysiology of multiple myeloma (MM) and the introduction of new drugs has led to considerable survival improvements in recent years. The International Myeloma Working Group consensus recently updated the definition for high-risk MM based on cytogenetic abnormalities. Moreover, the recent introduction of new therapeutic agents and the revision of insurance reimbursement policies have changed the clinical characteristics of MM patients in Korea. Yet, current epidemiology and the clinical characteristics of MM patients in Korea have not been fully investigated. Therefore, we aimed to understand the characteristics and management of Korean MM patients in a real-world setting by analyzing patients with high-risk cytogenetic abnormalities in the Korean Myeloma Registry. Methods: This is a retrospective observational study using the Korean Myeloma Registry, the web-based multicenter patient registry system established by the Korean Multiple Myeloma Working Party. Patients who are newly diagnosed with MM from 2010 to 2017 with at least one high-risk cytogenetic abnormality [t(4;14), t(14;16), or del(17p)] were included. Primarily, patients were classified by cytogenetic abnormality into three groups: Group 1, t(4;14) or t(14;16); Group 2, del(17p); and Group 3, t(4;14)/del(17p) or t(14;16)/del(17p). These patients were also stratified by the revised International Scoring System (R-ISS) and transplantation history for detailed analysis. We also used the number of cytogenetic abnormalities in an explanatory analysis; in this case, we included gain(1q). Progression-free survival (PFS) and overall survival (OS) were estimated, and the Hazard Ratio with the log-rank test was used for statistical comparison. Results: 391 out of 2170 MM patients from seven hospitals were identified as high-risk patients (men, 49.6%; median age, 63 years old). Median PFS for all patients was 18.9 months (95% CI 17.27-20.33), and the median OS was 44.6 months (95% CI 36.5-60.1). PFS (P OS was also significantly different between cytogenetic abnormality groups stratified by the revised International Staging System (R-ISS) (P=0.003). The lowest median OS durations were 16.9 months (95% CI 6.5-33.6) for del(17p) with R-ISS III, and 21.7 months (95% CI 9.3-N/A) for t(4;14)/del(17p) or t(14;16)/del(17p) with R-ISS III. Patients with higher R-ISS staging in the presence of del(17p) showed worse survival outcomes. Finally, PFS and OS were significantly inversely correlated with the number of cytogenetic abnormalities (P Conclusion: In real-world data from the Korean Myeloma Registry, we were able to observe the association of poor prognosis of MM patients with the number of cytogenetic abnormalities (PFS and OS) and R-ISS (OS). Moreover, we were also able to find the association of cytogenetic abnormality del(17p) and poor prognosis in MM patients. Lastly, we believe that this study provides the characteristics and management of MM patients needed to understand the real-world clinical course of high-risk MM patients in South Korea. Disclosures Kim: Amgen, BMS, Janssen, Sanofi, Takeda: Consultancy, Honoraria, Research Funding. Kim:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Janssen: Consultancy; F. Hoffmann-La Roche: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland., Research Funding; YuhanPharma: Research Funding; Kyowahako Kirin: Research Funding; Amgen: Consultancy, Honoraria. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Lee:AMGEN: Current Employment.

Background Interim 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) scan may predict outcomes in patients with diffuse large B-cell lymphoma (DLBCL). However, overall accuracy in predicting treatment outcomes on adopting 5-point Deauville score (DS) was considerably low in DLBCL because of mainly low positive predictive value of interim PET-CT scans. This suggested that additional tool might be needed to more accurately predict treatment outcomes. International prognostic index (IPI) was greatly associated with outcomes for DLBCL and considered to reflect biologic aggressiveness of DLBCL. Thus, we hypothesized that combined assessments using DS on interim PET-CT scan and baseline IPI might improve the prediction of treatment outcomes in DLBCL patients. In this study, we aimed to establish the risk predicting model integrating DS on interim PET-CT as an estimate of early metabolic response and baseline IPI as a predictor of biologic aggressiveness in patients with newly diagnosed DLBCL. Methods In this retrospective cohort study, we consecutively enrolled patients with newly diagnosed DLBCL. Patients were eligible if they were histologically confirmed with DLBCL from Jan 2007 to June 2016, received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), and had PET-CT scan data at baseline and at interim after 3 cycles of R-CHOP. Primary CNS or transformed DLBCLs were excluded. Interim PET-CT was assessed using 5-point DS and four point or higher was regarded as positive. All PET-CT scans were assessed by 2 experienced nuclear medicine physicians, who were masked to treatment outcomes of the patients. Discrepant interpretations between 2 nuclear medicine physicians were resolved by consensus through mutual discussion. Results A total of 316 patients were screened for eligibility. Ninety-six patients were excluded from the analysis due to following reasons: unavailable baseline (n=9) or interim PET-CT scans (n=48), early death before interim PET-CT (n=16), Primary CNS or transformed DLBCLs (n=15), and insufficient medical records (n=8). Thus, 220 patients were analyzed. Median age was 64 years (range, 19-87) and 132 (60%) were male. Based on the IPI risk, patients were classified as the low or low-intermediate (LI; N=126, 57%), and high-intermediate (HI) or high (N=94, 43%) groups. Interim DS was determined as 1 (n=67, 30.5%), 2 (n=65, 29.5%), 3 (n=39, 17.7%), 4 (n=36, 16.4%), and 5 (n=13, 5.9%). With a median follow-up of 56.6 months (IQR 36.0-71.8), 5-year progression-free survival (PFS) rate was 65.2% (95% CI, 58.1-72.3) and overall survival (OS) rate was 69.9% (95% CI, 63.2-76.6). Interim DS (1-3 vs 4-5) and the IPI (low-LI vs HI-high) were independently associated with PFS (for interim DS of 4-5, hazard ratio [HR], 2.96 [95% CI, 1.83-4.78], P < 0.001; for HI-high IPI, HR, 4.84 [2.84-8.24], P < 0.001) and OS (for interim DS of 4-5, HR, 2.98 [1.79-4.98], P < 0.001; for HI-high IPI, HR, 5.75 [3.14-10.51], P < 0.001) in the multivariate analysis. We stratified patients into 3 groups based on the risk of progression: Low (low-LI IPI and interim DS 1-3), Intermediate (low-LI IPI with interim DS 4-5, or HI-high IPI with interim DS 1-3), and High (HI-high IPI and interim DS 4-5) risk groups. The risk stratification model showed a significant association with PFS (for low risk vs intermediate risk, HR 3.98 [95% CI, 2.10-7.54], P Conclusion Combining interim DS with baseline IPI can improve risk stratification in patients with newly diagnosed DLBCL. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Oral arsenic trioxide (oral-As2O3)-based regimens are highly effective in the treatment of newly-diagnosed or relapsed acute promyelocytic leukemia (APL)1,2. Data on the long-term outcome of patients who received prolonged maintenance with oral-As2O3-based regimens in first complete remission (CR1) following non-arsenic-based induction is lacking. Methods Patients aged ≥ 18 years with APL in first complete remission (CR1) were recruited for maintenance treatment with oral-As2O3 (10mg/day), all-trans-retinoic acid (ATRA) (45mg/m2/day in 2 divided doses), ascorbic acid (1g/day) (AAA). AAA was administered for 2 weeks every 2 months for a total of 2 years. Prior induction treatment comprised ATRA (45mg/m2/day in 2 divided doses for 42 days) and daunorubicin (50mg/m2/day for 3 days). Consolidation comprised 2 monthly cycles of daunorubicin (50 mg/m2/day for 2 days) and cytarabine (100 mg/m2/day for 5 days). Daunorubicin induction and consolidation chemotherapy were omitted in patients aged ≥ 70 years or those with cardiac co-morbidities. Results Between 1 August 2002 and 31 July 2019, 129 patients (63 men and 66 women) with a median age of 46 (18-82) years underwent maintenance with AAA. After a median follow-up of 100 (8-215) months, 117 (90.1%) patients completed 2 years of AAA maintenance. Seventeen (13.2%) patients relapsed after a median of 19 (17-96) months from CR1 (morphologic relapse, N=14; molecular relapse; N=3). Two patients had central nervous system (CNS) involvement at first relapse (R1). There were 13 (10.1%) deaths. Five patients died from refractory APL. Eight patients died in remission (pneumonia, N=4; acute myocardial infarction, N=2; second malignancy, N=2). The 5-year and 10-year relapse-free survival (RFS) were 88.8% and 85.1% respectively. The 5-year and 10-year overall survival (OS) were 94.2% and 87.4%. On univariate analysis, PML-RARA bcr3 (short) isoform (P=0.02), FLT3-ITD (P=0.005) and CNS involvement at diagnosis (P=0.002) were associated with worse RFS. On multivariate analysis, FLT3-ITD (P=0.005) and central nervous system (CNS) involvement at diagnosis (P=0.004) were associated with worse RFS. On univariate analysis, PML-RARA bcr3 isoform (P=0.03), FLT3-ITD (P=0.01) and relapsed APL (P=0.002) were associated with worse OS. On multivariate analysis, therapy-related APL (P=0.03), FLT3-ITD (P=0.03) and relapsed APL (P=0.03) were associated with worse OS. Grade 1 leucopenia occurred in 7 (5.4%). The commonest non-hematological toxicity was headache and occurred in 38 (29.5%) (Grade 1/2, N=38; Grade 3/4, N=0). Grade 1 hepatoxicity occurred in 7 (5.4%) patients during AAA maintenance. Cutaneous herpes zoster infection occurred in 6 (4.7%) patients. Conclusion Maintenance therapy with oral-As2O3, ATRA and ascorbic acid in CR1 was safe and resulted in excellent long-term survivals in APL. References: 1. Gill H, Yim R, Lee HKK, Mak V, Lin SY, Kho B et al. Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study. Cancer 2018; 124(11): 2316-2326. 2. Gill H, Kumana CR, Yim R, Hwang YY, Chan TSY, Yip SF et al. Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study. Cancer 2019 [Epub]. Figure Disclosures No relevant conflicts of interest to declare.

Some of the recurrently occurring somatic mutations are known to be diagnostic or prognostic in myelodysplastic syndrome (MDS). Targeted gene capture and next-generation sequencing (NGS) has rapidly become routine clinical tools to detect the somatic mutations in patients with MDS. Copy number variants (CNVs) may have additional clinical significance in MDS. Chromosomal microarray analysis is a standard technique for genome-wide CNV detection, but multiple testing strategies require high costs and time. Recent advancements in NGS technologies have developed more cost-effective and rapid methods to allow simultaneous identification of targeted CNVs as well as somatic mutations using the same panel-based NGS data. In this study, we investigated whether the detection of CNVs using the targeted NGS data provided an additional value other than the clinical implications of somatic mutations. We performed targeted deep sequencing analysis on bone marrow samples obtained from 266 patients with MDS using an MDS panel targeting 28 well-known MDS-related genes (NRAS, DNMT3A, SF3B1, IDH1, TET2, NPM1, LAMB4, EZH2, JAK2, CBL, ETV6, KRAS, FLT3, IDH2, PRPF8, TP53, NF1, SRSF2, SETBP1, DNMT1, ASXL1, RUNX1, U2AF1, ZRSR2, ATRX, STAG2, MMP8, and ARID2). Sequencing libraries were generated using the AmpliSeq Library Kit 2.0 (Life Technologies, Carlsbad, CA) and the MDS panel was then sequenced using the Ion Torrent Proton system (Life Technologies) according to the manufacturer's instructions. The multiscale reference module and Rank Segmentation statistical algorithm in NEXUS software v9.0 (Biodiscovery) were used to define the CNVs for each sample. Overall survival (OS) and acute myeloid leukemia (AML)-free survival (AFS) were estimated from the date of MDS diagnosis to death or AML progression using the Kaplan-Meier method, and the differences in survival were compared using the log-rank test (for univariate analysis) and the Cox proportional hazards model (for multivariate analysis). Overall, 215 patients (80.8%) carried at least one somatic mutations, and 67 (25.2%) had one or more CNVs. The number of mutated genes per patient ranged from 0 to 6, and the number of genes with CNVs per patient ranged from 0 to 10. Of 51 patients who did not have somatic mutations, 12 (23.5%) had the targeted CNVs. The mutated genes in more than 10% of patients were 8: U2AF1 (21.8%), TET2 (17.7%), ASXL1 (13.5%), TP53 (13.2%), SETBP1 (12.8%), NF1 (10.9%), SF3B1 (10.5%), and RUNX1 (10.5%). The genes with CNVs detected in 10 or more patients were 5: EZH2 (loss in 7q, 6.8%), KRAS (gain and loss in 12p, 5.3%), ASXL1 (gain and loss in 20q, 4.5%), LAMB4 (loss in 7q, 3.8%), and RUNX1 (gain and loss in 21q, 3.8%). Interestingly, all five patients with TP53 deletion exhibited TP53 mutation as well, suggesting a bi-allelic alteration (mutation + copy loss). The higher number of genes with CNVs per patient were significantly associated with inferior OS (P Our study suggests that simultaneous detection of targeted CNVs as well as somatic mutations using the same panel-based NGS data add clinically useful information on the prognosis of MDS patients. Disclosures No relevant conflicts of interest to declare.

Background: CAR-T cell therapy directed against the CD19 antigen is a breakthrough treatment for patients (pts) with relapsed/refractory (R/R) B-cell NHL. Despite impressive outcomes, not all pts respond and many that respond still relapse. Affordability and accessibility are further considerations that limit current commercial models of CAR-T products. Commercial CAR-T manufacturing is complex, time consuming, and expensive with a supply chain starting at the treating center with apheresis of mononuclear cells, cryopreservation, and shipping to and from a centralized third-party manufacturing site. We addressed these limitations in a Phase 1 clinical trial evaluating a first-in-human bispecific tandem CAR-T cell directed against both CD19 and CD20 (CAR-20.19-T) antigens for pts with R/R B-cell NHL. Through dual targeting we hope to improve response rates and durability of response while limiting antigen escape. We eliminated third party shipping logistics utilizing the CliniMACS Prodigy, a compact tabletop device that allows for automated manufacturing of CAR-T cells within a GMP compliant environment within the hospital. Most materials and reagents used to produce the CAR-T cell product were single-sourced from the device manufacturer. Methods: Phase 1 (NCT03019055), single center, dose escalation + expansion study to demonstrate feasibility and safety of locally manufactured second generation 41BB + CD3z CAR-20.19-T cells via the CliniMACS Prodigy. Feasibility was measured by ability to generate a target CAR-20.19-T cell dose for a minimum of 75% of subjects. Safety was assessed by the presence of dose limiting toxicities (DLTs) through 28 days post-infusion. Dose was escalated in a 3+3 fashion with a starting dose of 2.5 x 10^5 cells/kg, a target DLT rate CAR-T production was set for a 14-day manufacturing process. Day 8 in-process testing was performed to ensure quality and suitability of CAR-T cells for a potential fresh infusion. On Day 10, pts eligible for a fresh CAR-T infusion initiated lymphodepletion (LDP) chemotherapy with fludarabine 30 mg/m2 x 3 days and cyclophosphamide 500 mg/m2 x 1 day, and cells were administered after harvest on Day 14. Pts ineligible for fresh infusion received cryopreserved product and LDP was delayed accordingly. Results: 6 pts have been enrolled and treated with CAR-20.19-T cells: 3 pts at 2.5 x 10^5 cells/kg and 3 pts at 7.5 x 10^5 cells/kg. Median age was 53 years (48-62). Underlying disease was MCL in 3 pts, DLBCL in 2 pts, and CLL in 1 patient. Baseline data and prior treatments are listed in Table 1. CAR-T production was successful in all runs and all pts received their target dose. Three pts received fresh CAR-T cells and 3 pts received CAR-T cells after cryopreservation. To date there are no DLTs to report. No cases of Grade 3/4 cytokine release syndrome (CRS) or neurotoxicity (NTX) were observed. One patient had Grade 2 CRS and Grade 2 NTX requiring intervention. The other had self-limited Grade 1 CRS and Grade 1 NTX. Median time to development of CRS was Day +11 post-infusion. All pts had neutrophil recovery (ANC>0.5 K/µL) by Day 28. Response at Day 28 (Table 2) is as follows: 2/6 pts achieved a complete response (CR), 2/6 achieved a partial response (PR), and 2/6 had progressive disease (PD). One subject with a PR subsequently progressed at Day 90. The 3 pts who did progress all underwent a repeat biopsy, and all retained either CD19 or CD20 positivity. Pts are currently being enrolled at the target dose (2.5 x 10^6 cells/kg) and updated results will be provided at ASH. Conclusions: Dual targeted anti-CD19 and anti-CD20 CAR-T cells were successfully produced for all pts demonstrating the feasibility of a point-of-care manufacturing process via the CliniMACS Prodigy device. With no DLTs or Grade 3-4 CRS or NTX to report, and 2/6 heavily pre-treated pts remaining in CR at 3 and 9 months respectively our approach represents a feasible and promising alternative to existing CAR-T models and costs. Down-regulation of both target antigens was not identified in any patient following CAR-T infusion, and in-process studies suggest that a shorter manufacturing timeline is appropriate for future trials (10 days). Disclosures Shah: Juno Pharmaceuticals: Honoraria; Lentigen Technology: Research Funding; Oncosec: Equity Ownership; Miltenyi: Other: Travel funding, Research Funding; Geron: Equity Ownership; Exelexis: Equity Ownership. Zhu:Lentigen Technology Inc., A Miltenyi Biotec Company: Research Funding. Schneider:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Krueger:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Worden:Lentigen Technology Inc., A Miltenyi Biotec Company: Employment. Hamadani:Sanofi Genzyme: Research Funding, Speakers Bureau; Merck: Research Funding; Janssen: Consultancy; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding; Ostuka: Research Funding; ADC Therapeutics: Research Funding. Johnson:Miltenyi: Research Funding. Dropulic:Lentigen, A Miltenyi Biotec company: Employment. Orentas:Lentigen Technology Inc., A Miltenyi Biotec Company: Other: Prior Employment. Hari:Takeda: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Kite Pharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Sanofi: Honoraria, Research Funding.

Introduction: Rivaroxaban is a target specific oral anticoagulant approved for treatment of deep venous thromboembolism (DVT), pulmonary embolism (PE) and risk reduction in patients with DVT/PE requiring continued anticoagulation. The XALIA study showed a reduced bleeding risk compared to standard anticoagulation therapy; however, there is paucity of data regarding correlates of bleeding risk amongst patients receiving rivaroxaban in the community setting. We aimed to investigate the clinical factors associated with bleeding events (BE) in patients receiving rivaroxaban for treatment of DVT/PE. Methods: A retrospective study was conducted at John H. Stroger, Jr. Hospital of Cook County. We screened the charts of 837 patients who received rivaroxaban from January 1, 2015 to April 01, 2018. Patients with DVT/PE were included in the study (n=271). Patients with atrial fibrillation and those receiving rivaroxaban for prophylaxis were excluded. Any reported BE was recorded as either major or minor bleeding event. Major BE was defined as events requiring hospitalization, blood transfusions or significant drop in hemoglobin (>2gm/dL). Rest of the BE were classified as minor BE. Socio-demographic and clinical factors were collected. Chi-square test and fisher exact test were used as the tests of trend. Multivariate logistic regression models were used to quantify the independent predictors. Odds ratios (OR) and adjusted odds ratios (aOR) with 95% confidence intervals (CI) were obtained. Results: The study included 271 patients, of which 68.3% were African-American, 14.4% were Caucasian, and 12.9% were Hispanic. Median age was 53 years and 60.9% patients were men. Bleeding events were reported in 11.4% (n=31) patients with 6.3% major bleeding events and 5.2% minor bleeding events. Only concurrent use of aspirin (23.8% vs. 9.2%; OR 3.10, 95% CI 1.34-7.17, P = 0.008) was significantly associated with bleeding events. None of the clinical parameters, like abnormal liver function tests (11.4%), cirrhosis (3.3%), chronic kidney disease stage 3 or worse (7.6%), prior use of warfarin (29.9%) or low molecular weight heparin (18.1%) were associated with bleeding events. In multivariate model adjusted for age, gender and race, concurrent use of aspirin (aOR 3.06, 95% CI 1.23-7.62, P = 0.017) remained independent predictor of bleeding events. Conclusion: In the community practice, aspirin (81mg or 325mg) is prescribed for cardio-protection. A recently concluded trial showed a better cardioprotective effect of combining rivaroxaban and aspirin, without increase in BE in patients with stable cardiovascular disease. However, such data is not evident in patients receiving rivaroxaban for DVT/PE. Our study shows an increased rate of bleeding events in such patients with concurrent use of aspirin. Our study population comprises of two-third African-American patients who are under-represented in the clinical trials. Based on our results we would suggest further investigation in safety of prescribing aspirin with rivaroxaban in patients with DVT/PE in prospective trials. Disclosures No relevant conflicts of interest to declare.

In 424 African-American and 75 white subjects, we found that the −5 (TPI 592 A→G), −8 (TPI 589 G→A), and −24 (TPI 573 T→G) variants in the triosephosphate isomerase (TPI) gene occurred frequently (41.0%) in the African-American subjects but did not occur in the whites. These data suggest that this set of polymorphisms may turn out to be one of the higher-incidence molecular markers of African lineage, a surprising finding because others had reported that these nucleotide substitutions were restricted to a small subset of African Americans who had been characterized as TPI-deficiency heterozygotes. Additionally, we investigated the relationship of these variants to TPI-enzyme activity. Although the variant substitutions (occurring in three haplotypes: −5 alone, −5 −8, and −5 −8 −24) were associated with moderate reduction in enzyme activity, severe-deficiency heterozygotes could not be identified with certainty, and none of the haplotypes were restricted to subjects with marked reduction of enzyme activity. Three subjects were homozygous for the −5 −8 haplotype, a finding inconsistent with the putative role of this haplotype as the cause of a null variant incompatible with life in homozygotes. Despite these findings, the possibility remains that the −5 −8 or −5 −8 −24 haplotypes may in some instances contribute to compound heterozygosity and clinical TPI deficiency.© 1998 by The American Society of Hematology.

We postulated that MIR34B/C, a direct transcriptional target of TP53, might be inactivated by promoter hypermethylation in multiple myeloma (MM). MIR34B/C promoter methylation was studied in 8 normal marrow controls, 8 MM cell lines, 95 diagnostic, and 23 relapsed/progressed MM samples by methylation-specific PCR. MIR34B/C was methylated in 6 (75.0%) MM cell lines but not normal controls. 5-Aza-2′-deoxycytidine led to MIR34B/C promoter demethylation and MIR34B reexpression. Moreover, restoration of MIR34B led to reduced cellular proliferation and enhanced apoptosis of myeloma cells. In primary samples, methylation of MIR34B/C occurred in 5.3% at diagnosis and 52.2% at relapse/disease progression (P < .001). In 12 MM patients with paired samples at diagnosis and relapse/progression, MIR34B/C methylation was acquired in 6 at relapse/progression. In conclusion, MIR34B/C is a tumor suppressor in myeloma. Hypermethylation of MIR34B/C is tumor-specific. Frequent MIR34B/C hypermethylation during relapse/progression but not at diagnosis implicated a role of MIR34B/C hypermethylation in myeloma relapse/progression.

IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.

Regulation of osteoclast differentiation is key to understanding the pathogenesis and to developing treatments for bone diseases such as osteoporosis. To gain insight into the mechanism of the receptor activator of nuclear factor (NF)–κB ligand (RANKL)–specific induction of the osteoclast differentiation program, we took a suppression-subtractive hybridization screening approach to identify genes specifically induced via the RANKL-Rac1 signaling pathway. Among identified targets, we show that RANKL selectively induces cyclooxygenase (COX) 2 expression via Rac1 that results in turn in production of prostaglandin E2 (PGE2) in RAW 264.7 cells. By using transient transfection assays, we found that the –233/–206 region of the COX-2 promoter gene was critical for RANKL-induced promoter activity. This RANKL-responsive region contained an NF-κB site that, when mutated, completely abolished the induction of NF-κB DNA-binding activity by RANKL. Blockade of COX-2 by celecoxib inhibits differentiation of bone marrow-derived monocyte/macrophage precursor cells (BMMs) into tartrate-resistant acid phosphatase-positive (TRAP+) osteoclastic cells. This inhibition can be rescued by the addition of exogenous PGE2, suggesting that COX-2–dependent PGE2 induction by RANKL in osteoclast precursors is required for osteoclast differentiation.

Introduction Imatinib (IM) is an effective treatment in patients with chronic phase chronic myeloid leukemia (CML-CP). In the previous report (Leukemia research, 2012;36:689-693), we demonstrated that IM could be discontinued in CML patients achieved undetectable minimal residual disease (UMRD) after the treatment of front-line IM therapy. These observations were confirmed by prospective STIM1 and TWISTER studies. However, in both studies, approximately half of patients were treated with front-line interferon therapy, which might be a confounding factor when considering the impact of prior interferon on treatment free remission (TFR) in the previous IM discontinuation studies. Thus, the aim of this study was to investigate the long-term outcomes of IM discontinuation in patients with CML-CP, who have treated with front-line IM therapy and achieved UMRD. Patients and methods We consecutively enrolled patients with CML-CP, discontinued IM therapy after achieving UMRD for at least 12 months in 2 Korean institutions from June 2009 to Jan 2013. Patients with a prior history of any other treatment (>1 months) for CML before IM administration were excluded. UMRD was defined by undetectable levels of BCR-ABL transcript by RQ-PCR with sensitivity of at least 0.0046%IS. After discontinuation, BCR-ABL/ABL ratio was monitored by RQ-PCR monthly during the first 6 months and every 3 months thereafter, and molecular relapse was defined by detectable levels of BCR-ABL transcript in two successive assays. Results Nineteen patients (8 male, 11 female) with a median age of 52 years (range, 29-78) were included. The reasons for discontinuing IM were shared decision between physicians and patients with long undetectable BCR-ABL transcript (n=9), chronic adverse events of IM (n=6), patient’s request (n=3), and wish for pregnancy (n=1). At initial diagnosis, the Sokal score was low to intermediate in 11 patients and high in 8 patients. All patients started IM at a dose of 400mg/day and median interval between IM initiation and UMRD was 21.5 months (range, 7.0-61.9). IM therapy was then maintained during a median of 34.8 months (range, 12.1-72.4). With a median follow-up of 52.1 months (range, 17.5-60.5), the overall probability of UMRD persistence at 4-year was 22.1% (95% CI, 11.6-32.6). Fourteen patients (73%) lost UMRD after a median of 4.0 months (range, 1.1-22.8). 12 patients relapsed within first 9 months and 2 late relapse were identified at 20.5 and 22.8 months, respectively. No patients included in this analysis were progressed to advanced stage CML or died. IM therapy was resumed in all patients with molecular relapse, but 2 patients were switched to dasatinib owing to chronic adverse events of IM. At the time of this analysis, all patients were still sensitive to IM and dasatinib therapy. 12 patients re-achieved UMRD and 2 patients maintained stable major molecular response. In univariate analysis for molecular relapse, high risk of Sokal score (P Conclusion This study represents that IM discontinuation in patients who have received front-line IM therapy and achieved UMRD would be feasible, as approximately one-fourth of these patients could enjoy long-term TFR. Moreover, no molecular relapse was observed after 2 year of IM discontinuation. Although the Sokal score, time to deep molecular response, and duration of IM therapy were suggested as clinical factors for predicting molecular relapse in this analysis, further studies would be necessary to confirm the results in this population. Disclosures No relevant conflicts of interest to declare.

In 424 African-American and 75 white subjects, we found that the -5 (TPI 592 A--G), -8 (TPI 589 G--A), and -24 (TPI 573 T--G) variants in the triosephosphate isomerase (TPI) gene occurred frequently (41.0%) in the African-American subjects but did not occur in the whites. These data suggest that this set of polymorphisms may turn out to be one of the higher-incidence molecular markers of African lineage, a surprising finding because others had reported that these nucleotide substitutions were restricted to a small subset of African Americans who had been characterized as TPI-deficiency heterozygotes. Additionally, we investigated the relationship of these variants to TPI-enzyme activity. Although the variant substitutions (occurring in three haplotypes: -5 alone, -5 -8, and -5 -8 -24) were associated with moderate reduction in enzyme activity, severe-deficiency heterozygotes could not be identified with certainty, and none of the haplotypes were restricted to subjects with marked reduction of enzyme activity. Three subjects were homozygous for the -5 -8 haplotype, a finding inconsistent with the putative role of this haplotype as the cause of a null variant incompatible with life in homozygotes. Despite these findings, the possibility remains that the -5 -8 or -5 -8 -24 haplotypes may in some instances contribute to compound heterozygosity and clinical TPI deficiency.