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Purpose: mAbs such as anti-CD20 rituximab are proven therapies in B-cell malignancies, yet many patients develop resistance. Novel therapies against alternative targets are needed to circumvent resistance mechanisms. We sought to generate mAbs against human B-cell–activating factor receptor (BAFF-R/TNFRSF13C), which has not yet been targeted successfully for cancer therapy.Experimental Design: Novel mAbs were generated against BAFF-R, expressed as a natively folded cell surface immunogen on mouse fibroblast cells. Chimeric BAFF-R mAbs were developed and assessed for in vitro and in vivo monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors.Results: Chimeric antibodies bound with high affinity to multiple human malignant B-cell lines and induced potent antibody-dependent cellular cytotoxicity (ADCC) against multiple subtypes of human lymphoma and leukemia, including primary tumors from patients who had relapsed after anti-CD20 therapy. Chimeric antibodies also induced ADCC against ibrutinib-resistant and rituximab-insensitive CD20-deficient variant lymphomas, respectively. Importantly, they demonstrated remarkable in vivo growth inhibition of drug-resistant tumor models in immunodeficient mice.Conclusions: Our method generated novel anti–BAFF-R antibody therapeutics with remarkable single-agent antitumor effects. We propose that these antibodies represent an effective new strategy for targeting and treating drug-resistant B-cell malignancies and warrant further development. Clin Cancer Res; 24(5); 1114–23. ©2017 AACR.

Supp. Fig. 1 Anti human BAFF-R monoclonal antibody generation and clone selection. Supp. Fig. 2 Verification that selected hybridoma clones bind MCL cells. Supp. Fig. 3 Dose-dependent binding of purified mAbs to human BAFF-R. Supp. Fig. 4 (h)BAFF-R mAbs recognized non-Hodgkin lymphoma cell lines in vitro. Supp. Fig. 5 (h)BAFF-R mAbs recognized lymphoma patient samples. Supp. Fig. 6 BAFF-R antibody specific binding was correlated to BAFF-R expression on NHL lines and primary samples. Supp. Fig. 7 Chimeric antibodies required NK cells for cytotoxicity against tumor cells. Supp. Fig. 8 Limited internalization was observed with BAFF-R mAbs. Supp. Fig. 9 BAFF-R antibody induced cytotoxicity in BAFF-R expressing lines. Supp. Fig. 10 BAFF-R mAb induced ADCC in BAFF-R expressing primary MCL samples. Supp. Fig. 11 CD20 knock out clones generated with CRISPR Supp. Fig. 12 Ibrutinib treatment failed to protected mice challenged with ibrutinib-resistant Z-138 cells. ( Supp. Fig. 13 Chimeric antibodies targeting human BAFF-R elicited in vivo therapeutic effects against Z-138 ibrutinib-resistant tumors. Supp. Fig. 14 Characterization of BAFF-R binding against normal B cells. Supp. Fig. 15 BAFF-R mAb elicited ADCC effects on normal human B cells.

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30- and 60-day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p = .879). Results were unchanged after stratification by age (or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial.

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)–keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.

Acute myeloid leukemia (AML) is historically associated with poor prognosis, especially in older AML patients unfit for intensive chemotherapy. The development of Venetoclax, a potent oral BH3 (BCL-2 homology domain 3) mimetic, has transformed the AML treatment. However, the short duration of response and development of resistance remain major concerns. Understanding mechanisms of resistance is pivotal to devising new strategies and designing rational drug combination regimens. In this review, we will provide a comprehensive summary of the known mechanisms of resistance to Venetoclax and discuss Venetoclax-based combination therapies. Key contributing factors to Venetoclax resistance include dependencies on alternative anti-apoptotic BCL-2 family proteins and selection of the activating kinase mutations. Mutational landscape governing response to Venetoclax and strategic approaches developed considering current knowledge of mechanisms of resistance will be addressed.

Programmed cell death protein 1 (PD-1) and PD-ligand 1 (PD-L1) expression is upregulated in cluster of differentiation 34 (CD34)+ bone marrow cells from patients with myelodysplastic syndromes (MDS). Hypomethylating agent (HMA) treatment results in further increased expression of these immune checkpoints. We hypothesised that combining an anti-PD-1 antibody with HMAs may have efficacy in patients with MDS. To test this concept, we designed a phase II trial of the combination of azacitidine and pembrolizumab with two cohorts. In the 17 previously untreated patients, the overall response rate (ORR) was 76%, with a complete response (CR) rate of 18% and median overall survival (mOS) not reached after a median follow-up of 12·8 months. For the HMA-failure cohort (n = 20), the ORR was 25% and CR rate was 5%; with a median follow-up of 6·0 months, the mOS was 5·8 months. The most observed toxicities were pneumonia (32%), arthralgias (24%) and constipation (24%). Immune-related adverse events requiring corticosteroids were required in 43%. Overall, this phase II trial suggests that azacitidine and pembrolizumab is safe with manageable toxicities in patients with higher-risk MDS. This combined therapy may have anti-tumour activity in a subset of patients and merits further studies in the front-line setting.

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS.

BACKGROUND TP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193). METHODS Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines. RESULTS Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone. CONCLUSIONS Patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

Background: TP53 mutation (TP53mut) confers adverse prognosis in acute myeloid leukemia (AML) with limited response to chemotherapy. 10-day decitabine (DEC) regimen has shown high efficacy in TP53mut AML (Welch et al. NEJM 2016). We hypothesized that adding venetoclax (VEN) to 10-day DEC may further improve outcomes in high-risk AML (NCT03404193). However, preclinical data suggests that TP53mut confers resistance to VEN in AML (Nechiporuk et al. Cancer Discov. 2019). Herein, we investigated outcomes of patients (pt) with TP53mut AML who received frontline therapy on this prospective trial of 10-day DEC and VEN (DEC10-VEN). Methods: Patients 60 years of age and older with newly diagnosed previously untreated AML were treated with DEC 20 mg/m2 for 10 days every 4 to 6 weeks for induction followed by DEC for 5 days after CR/CRi. VEN dose was 400 mg daily or equivalent. Reduction of VEN duration was allowed in cases of cytopenias and/or myelosuppression. TP53mut was assessed in bone marrow samples using a PCR-based 81-gene Next Generation Sequencing panel targeting the entire coding regions. A MiSeq platform (Illumina, San Diego, CA, USA) was used with an analytical sensitivity established at 5% mutant reads in a background of wild type reads. Full protocol of the study has been published previously (DiNardo et al. Lancet Haematol. 2020. In press). Results: Between January 2018 and April 2020, 121 pts received frontline therapy with DEC10-VEN on this trial. The median age of the cohort was 72 yrs (range 49-89), 34 (28%) pts had ECOG performance status ≥2 and 81 (67%) pts had ELN adverse risk AML. 37 (31%) pts had TP53mut. Pts with TP53mut were more likely to have therapy-related AML (t-AML) in 43% pts compared to 11% in pts with TP53 wild type (TP53WT, p The rate of CR/CRi in the whole cohort was 69% (n=84) with negative measurable residual disease (MRD) by flow cytometry (FCM) in 42% pts (n=51). Pts with TP53mut had a lower rate of CR at 35% compared to 57% in pts with TP53WT (p=.026), lower rate of CR/CRi at 54% vs. 76% in pts with TP53WT (p=.015), and lower rate of MRD negativity by FCM in 19% compared to 52% in TP53WT AML (p=.001, Table 2). The median time to response in TP53mut pts was 1.2 mo (IQR 1.0-1.4) and in TP53WT pts was 1.7 mo (IQR 1.2-2.8) and median number of cycles to response for both groups were 1 cycle (IQR 1-2; p=.259). The 60-day mortality was higher in the TP53mut pts at 27% (n=10/37) compared to 2% in TP53WT pts (n=2/84, p Median overall survival (OS) was 5.2 months (mo) in pts with TP53mut compared to 19.4 mo in TP53WT AML (hazard ratio [HR] 4.68, 95% CI 2.50, 8.78, p Conclusion: TP53 mut is associated with inferior response with shorter response duration, higher MRD positivity and inferior survival outcomes in pts with AML receiving frontline therapy with VEN and DEC. Novel therapies are needed to overcome TP53-mediated resistance to VEN with hypomethylating agents in AML. Disclosures Maiti: Celgene: Research Funding. Kadia:Abbvie: Honoraria, Research Funding; Pulmotec: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Research Funding; Fate Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding. Pemmaraju:Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Plexxikon: Research Funding; MustangBio: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria; Affymetrix: Other: Grant Support, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding. Borthakur:Treadwell Therapeutics: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Jannsen: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Polaris: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; NS Pharma: Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Short:Amgen: Honoraria; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Alvarado:Daiichi-Sankyo: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; FibroGen: Research Funding. Jabbour:Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Jain:Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding. Garcia-Manero:Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onconova: Research Funding; Amphivena Therapeutics: Research Funding; Merck: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Abbvie: Honoraria, Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Immunogen: Research Funding. DiNardo:MedImmune: Honoraria; Jazz: Honoraria; Novartis: Consultancy; Syros: Honoraria; Calithera: Research Funding; ImmuneOnc: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Konopleva:Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Calithera: Research Funding; Cellectis: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Ablynx: Research Funding; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding.

Biphasic pulmonary blastoma is a rare but lethal type of lung malignancy with characteristic histology of both epithelial and mesenchymal components. Previously reported cases have been limited to presentation at advanced stages, suggesting that the clinical course of the disease is usually aggressive. Here, we report a case of incidental diagnosis of biphasic pulmonary blastoma by imaging surveillance in a patient previously treated for adenocarcinoma of the lung. The patient was diagnosed with stage 1 disease and underwent successful resection. Next‐generation sequencing (NGS) revealed a high mutation burden, a finding not previously reported in a patient with biphasic pulmonary blastoma., Here, we report a rare case of incidental early diagnosis of biphasic pulmonary blastoma while a patient was undergoing imaging surveillance for primary lung adenocarcinoma. Next‐generation sequencing revealed distinct second primary cancer with a high mutation burden which might have therapeutic implications in further studies.

The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene’s normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.

We describe a rare presentation of diffuse large B-cell Lymphoma (DLBCL) with recurrent episodes of syncope. During the workup for syncope, the patient was incidentally found to have an extensive mass in the left thorax, which was later diagnosed as stage 2 bulky disease DLBCL. This is the rare case of lymphoma presenting as recurrent syncope without cardiac involvement. The patient did not have any further episodes of syncope after her successful treatment of DLBCL.

The use of direct-acting oral anticoagulants (DOACs) has increased rapidly in the last decade; becoming the mainstay for both the prophylaxis and the treatment of venous thromboembolism in various situations including non-valvular atrial fibrillation, joint replacement surgeries and acute DVT/PE, etc. In the present times, DOACs are possibly one of the most widely prescribed medications in the developed world. The worldwide epidemic caused by COVID-19 caused significant changes in the practice of medicine worldwide. Patients who developed severe respiratory illness caused by COVID-19 were noted to develop a wide range of complications, including both arterial and venous thromboembolic complications including deep vein thrombosis and pulmonary embolism, etc. This review is an attempt to identify the role of DOACs in the treatment and prevention of these complications as well as the safety of continuing therapy with DOACs in the patients who were receiving them before contracting the infection.

Background : AML is a life-threatening, rapidly progressive malignancy that frequently presents with uncontrolled leukocytosis, organ infiltration, and the need for urgent chemotherapy. Recent advances in genomic profiling have identified significant heterogeneity in AML, that is best addressed with individualized, targeted approaches, often on clinical trials. The requisite cytogenetic and molecular data to inform definite treatment, however, is not rapidly available. Studies have suggested that delaying initial therapy in newly diagnosed AML may worsen OS. Implementing formal cytoreduction strategies may allow time for treatment selection and clinical trial enrollment without adversely affecting outcomes. Methods: We piloted an approach with our frontline clinical trials in AML to allow cytoreductive therapy with hydroxyurea (HA) and/or higher doses of Cytarabine (Ara-C) for disease control prior to definitive therapy. 3 frontline chemotherapy protocols were designed to allow HA and up to 2 grams/m2 of Ara-C for urgent disease control prior to starting therapy. We reviewed the feasibility and outcomes of this approach in older and younger pts with newly diagnosed AML treated between April 2014 and May 2020. Results: We reviewed 276 patients, 97 (35%) which received cytoreductive therapy prior to starting definitive therapy. Baseline characteristics of patients who did or did not receive cytoreductive therapy are summarized in Table 1. The median time from presentation to definitive treatment was 6 days (range 1-21 days) and 6 days (1-46 days) in patients with or without cytoreduction, respectively. Patients with cytoreduction had higher median peripheral blasts 44% (Interquartile Range, IQR : 46-79) vs. 6% (IQR: 4-7) than patients without cytoreduction. More patients with cytoreduction were female (64%; p=0.007), ECOG performance status (PS) >1 (27%; p 1(OR 3.5, 95% CI 1.6-8.0), FLT3 mutation (OR 2.7, p=0.006), female gender (OR 2.4, CI 1.3-4.3) were also associated with a higher likelihood to get cytoreductive therapeutics. Response rates and outcome are summarized in Table 2. There was no difference in rate of CR/CRi (89% vs. 87%; P=0.72) among patients with or without cytoreduction, respectively. Similarly, there was no difference in 30- and 60-day mortality between the groups. When stratified with cytoreduction treatment regimen, there was no significant difference in CR and/or CRi. Of the 16 patients who died within 60 days of diagnosis, only 5 (31%) had documented CR or CRi at the time of death. Median overall survival among patients with or without cytoreduction was 11.3 vs. 11.5 months, respectively (P=0.57) (Figure 1). There remained no difference in OS after adjustment of age, secondary AML, ECOG, ELN, TP53, and type of frontline treatment: Hazard Ratio of 1.1 (95% CI 0.7-1.7). Similarly, there was also no difference in progression free survival between the 2 groups (p=0.59). Conclusions: Pretreatment cytoreductive therapy was safe and feasible in pts with newly diagnosed AML who are in need of urgent therapy, allowing collection of genomic data and enrollment on clinical trials. Despite having higher baseline WBC, blast %, incidence of FLT3 mutations, advanced PS, and higher ELN risk among pts who received cytoreduction, there was no difference in OS, PFS, or early mortality between the 2 groups. These data suggest that urgent cytoreduction may be reasonable alternate option to immediate induction. Disclosures Konopleva: AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding; Amgen: Consultancy; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Research Funding. DiNardo:MedImmune: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Takeda: Honoraria; Calithera: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; Syros: Honoraria. Borthakur:Treadwell Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; AstraZeneca: Research Funding; FTC Therapeutics: Consultancy; PTC Therapeutics: Research Funding; Incyte: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; GSK: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Curio Science LLC: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Polaris: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding. Garcia-Manero:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Pemmaraju:Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; Blueprint Medicines: Honoraria; DAVA Oncology: Honoraria; Plexxikon: Research Funding; SagerStrong Foundation: Other: Grant Support; Roche Diagnostics: Honoraria; Samus Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo: Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jabbour:Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Jain:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; ADC Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Short:Astellas: Research Funding; Amgen: Honoraria; Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Kantarjian:BMS: Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding. Kadia:JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Novartis: Honoraria; Amgen: Research Funding; Pulmotec: Research Funding; Astra Zeneca: Research Funding; Abbvie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Cyclacel: Research Funding.

Over the past two decades, tyrosine kinase inhibitors (TKIs) have changed the management of patients with Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL), and this has led to significant improvement in their outcome. In this review, we will provide an overview of the current understanding of treatment of Ph+ ALL focusing on TKIs, alloHSCT, and novel therapies. The advent of more potent TKIs and the novel therapeutic options including blinatumomab, inotuzumab ozogamicin, and CD19 CAR-T therapy has changed the role of allogeneic hematopoietic stem cell transplant (alloHSCT) and intensive chemotherapy. To avoid toxicity from the historical treatment strategies, a more individualized, targeted approach to therapy including detection and monitoring of measurable residual disease (MRD) has become of interest. The treatment of patients with Ph+ ALL has been rapidly evolving with a more individualized, targeted treatment and use of TKIs and novel therapy.

e19087 Background: T-cell prolymphocytic leukemia (T-PLL) is an ultra-rare and aggressive mature T-cell leukemia associated with a poor prognosis. First-line therapy is with CD52 monoclonal antibody alemtuzumab and allogenic stem cell transplant (SCT), but treatment is rarely curative. There is a critical need for more active therapies to improve outcomes. The BCL-2 inhibitor venetoclax (VEN) has demonstrated activity in T-PLL. We studied a combination of cladribine plus VEN in 5 patients (pts) with R/R T-PLL to investigate the safety and efficacy of this combination. Methods: We retrospectively analyzed pts ≥ 18 years with R/R T-PLL treated with a backbone of cladribine 5 mg/m2 intravenous (IV) for 5 days with VEN at a target dose of 600-800 mg orally daily (reduced for concomitant drug interactions) on a 28-day cycle. Two pts concomitantly received alemtuzumab, 1 received ruxolitinib, and 2 pts received both. Baseline demographics, cytogenetics and mutations were collected and summarized using descriptive statistics. Response criteria were defined according to the T-PLL consortium and survival analyzed by Kaplan-Meier method. Results: Five pts with a median age of 64 years (range, 59-66) were treated with cladribine + VEN. Pts had a median of 1 prior therapy (range, 1-3), including 3 (60%) with prior SCT. Overall response rate was 100%, including 2 (40%) complete remission with incomplete count recovery (CRi) (with 1 MRD negative CR), and 3 (60%) partial response (PR). A median of 2 cycles were given (range, 1-4). Baseline characteristics are summarized in Table. All five pts had abnormalities of chromosomes 8, 14, and TCL-1 (positive by FISH); 3 had a STAT5B mutation and 1 each had mutations in JAK1, JAK3, and IL7R. Pts had rapid reductions in all T-PLL-related symptoms and signs (i.e., WBC, splenomegaly, effusions, skin lesions, nodes) within the 2 weeks of starting. The regimen was well-tolerated. Two pts had transient grade 1 creatinine elevations and 4 had grade 4 neutropenia that returned to baseline in a median of 67 days (range, 2-93 days). At the time of data review, 1 patient was alive at 8.3 months. The median overall survival (OS) was 5.8 months. Conclusions: The combination of cladribine and VEN in patients with T-PLL refractory to first-line alemtuzumab was well-tolerated and effective. It was associated with rapid disease control, including splenomegaly, fatigue, pleural infiltrates, and skin infiltration. Staging studies to be presented. This encouraging experience should prompt further study as salvage therapy for T-PLL.[Table: see text]

This review examines the pathophysiological features of microsatellite instability (MSI) high colorectal cancer and discusses recent clinical studies of immune checkpoint inhibitors for MSI high colorectal cancer. Emerging clinical data demonstrated durable clinical activity and safety of PD-1 blockade agents in diverse cancers, and PD-1 blockade agents have led to a paradigm shift in the cancer therapy. Although initial clinical data showed disappointing result of anti-PD-1 therapy in unselected metastatic colorectal cancer, recent data demonstrated promising results with significant anticancer activity of PD-1 blockade in colorectal cancers with microsatellite instability which have highly immunogenic tumor microenvironment. Anti-PD-1 therapy demonstrated durable clinical activity and safety, and it has changed the landscape of cancer therapy in MSI high colorectal cancer. Further studies with better understanding of tumor microenvironment will improve clinical outcomes of colorectal cancer.

Antibodies targeting the programmed cell death protein 1/programmed death-ligand 1 (PD-L1) interaction have shown clinical activity in multiple cancer types. PD-L1 protein expression is a clinically validated predictive biomarker of response for such therapies. Prior studies evaluating the expression of PD-L1 in primary prostate cancers have reported highly variable rates of PD-L1 positivity. In addition, limited data exist on PD-L1 expression in metastatic castrate-resistant prostate cancer (mCRPC). Here, we determined PD-L1 protein expression by immunohistochemistry using a validated PD-L1-specific antibody (SP263) in a large and representative cohort of primary prostate cancers and prostate cancer metastases. The study included 539 primary prostate cancers comprising 508 acinar adenocarcinomas, 24 prostatic duct adenocarcinomas, 7 small-cell carcinomas, and a total of 57 cases of mCRPC. PD-L1 positivity was low in primary acinar adenocarcinoma, with only 7.7% of cases showing detectable PD-L1 staining. Increased levels of PD-L1 expression were noted in 42.9% of small-cell carcinomas. In mCRPC, 31.6% of cases showed PD-L1-specific immunoreactivity. In conclusion, in this comprehensive evaluation of PD-L1 expression in prostate cancer, PD-L1 expression is rare in primary prostate cancers, but increased rates of PD-L1 positivity were observed in mCRPC. These results will be important for the future clinical development of programmed cell death protein 1/PD-L1-targeting therapies in prostate cancer.

Background : Hypocellular myelodysplastic syndrome(MDS) is a distinct subset of MDS. It is defined as cellularity less than 30% in patients' age ≤70, or less than 20% in patients' age>70. More studies suggest that hypocellular MDS has distinct biology and clinical characteristics. Here we investigated clinical, pathological characteristics of patients with hypocellular MDS and their outcome. Methods : Patients with newly diagnosed MDS from January 2010 to June 2021 at the University of Texas MD Anderson Cancer Center were retrospectively reviewed. Patient and disease characteristics were collected to compare between hypocellular MDS and normo-/hypercellular MDS groups. Further detailed analysis focusing on patients who were investigated 28-gene or 81-gene mutation panels were conducted including de novo MDS and therapy-related MDS(t-MDS). Survival data for detailed analysis was updated in July 2021, and multivariate analyses were conducted with step-wise selection(p-value cutoff 0.10). IPSS-R was used to confirm risk stratification in hypocellular MDS patients. Results : Out of 1,789 newly diagnosed MDS patients, 179 patients were identified as hypocellular MDS. Hypocellular MDS patients present with lower CBC counts(p A total number of 153 hypocellular MDS patients were available for 28- or 81-gene panels. 78 patients (51%) had t-MDS. They presented with lower Hb (p= 0.045) and platelets (p=.016) than de novo MDS patients at diagnosis. Treatment history was similar; 54% of t-MDS patients were treated with HMA compared to 56% patients of de novo MDS with HMA treatment(p=.870). t-MDS patients had frequent TP53 (33% vs 15%, p=.008) and RUNX1 mutation(10% vs 0%, p=.007)(Figure 2). AML transformation rates of t-MDS(29%) were similar to that of de novo MDS (20%, p=.313). t-MDS has shorter median survival at 24.8 months compared with de novo MDS at 60.1 months (p= .018) (HR 1.75 in OS for t-MDS, 95% CI 1.09-2.81, p=.020). 17 patients were diploid without mutation, which includes 5% of t-MDS patients and 17% of de novo MDS patients. Median survival was longer at 60.1 months in those patients without significance(p=.479). Multivariate models for OS selected t-MDS, TP53, TET2 and Age 70. IPSS-R risk group of very low and low, intermediate and high were not well separated(Figure 3a), especially in t-MDS patients(Figure 3b). However, simplified mode of IPSS-R into very low, low vs. intermediate, high vs. very high has good prediction of survival including t-MDS and de novo MDS(Figure 3c). Patients with TP53 mutation had worse survival and TET2 mutation had better survival distinctively, compared to patients without those mutations(Figure 3d). Conclusion : Hypocellular MDS patients did not have survival difference compared to rest of MDS patients. These patients present with lower blood counts, and more frequently having t-MDS. t-MDS patients with hypocellularity tend to have high risk mutations of TP53 and RUNX1. IPSS-R does not stratify well to either hypocellular or t-MDS with hypocellularity patients. Risk stratification model with integration of molecular characteristics will be a study of interest. Figure 1 Figure 1. Disclosures Kadia: Astellas: Other; AstraZeneca: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Alvarado: FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; CytomX Therapeutics: Consultancy; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kantarjian: Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; Aptitude Health: Honoraria; Pfizer: Honoraria, Research Funding; Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Astellas Health: Honoraria; KAHR Medical Ltd: Honoraria; Amgen: Honoraria, Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Astra Zeneca: Honoraria; NOVA Research: Honoraria; Taiho Pharmaceutical Canada: Honoraria; Daiichi-Sankyo: Research Funding.

Background The advent of tyrosine kinase inhibitors (TKIs) has been dramatically improved outcome of Chronic Myeloid Leukemia (CML) patients. In TKI era, patients with CML has similar life expectancy compared to general population. Adult Comorbidity Evaluation 27 score (ACE-27) is a scoring system assessing the burden of co-morbidities reviewing 27 factors related to twelve organ systems, which has been extensively studied as a predictor of outcome in various medical settings. We hypothesized that ACE-27 has prognostic impact of newly diagnosed, chronic phase CML patients, treated TKI as a frontline therapy, in long-term outcome. Methods We reviewed patients with newly diagnosed chronic phase CML at the University of Texas MD Anderson Cancer Center from 2000 to 2014 who were enrolled in clinical trials. Patients who received TKIs (imatinib, dasatinib, nilotinib, or ponatinib) as a frontline therapy were included. Patient and disease characteristics, treatment details were collected prospectively, and further collected by retrospective chart review. ACE-27 score was calculated accordingly. We studied its association to treatment response, overall survival (OS) and event-free survival (EFS). Complete cytogenetic remission (CCyR) was defined as the absence of Philadelphia chromosome (Ph) by karyotyping. Major cytogenetic response (MCyR) is defined as less than 35% of metaphases with Ph chromosome. Major molecular response (MMR), molecular response (MR) 4.0, and MR4.5 are defined as BCR-ABL1 transcript ≤ 0.1%, ≤ 0.01%, and ≤ 0.0032% on the international scale, respectively. Results In a total of 524 patients, median age was 49 (range 15-86) with 16% of patients over age 65. Median follow-up time was 98 months. 267 (51%) patients were on imatinib, compared to 21% on dasatinib, 20% on nilotinib and 8% on Ponatinib. ACE-27 score was 0, 1, 2, and 3, in 284 (54%), 164 (31%), 64 (12%), and 13 (2%) patients, respectively. Detailed patient characteristics were summarized in Table 1. Patients with ACE-27 2-3 were less likely to achieve CCyR, MMR, MR4 or MR4.5 compared with those with ACE-27 0-1 (p=.010)(table 2). For ACE-27 2-3 patients, odds ratio (OR) for achieving CCyR, MMR, MR4 and MR4.5 compared to ACE-27 0-1 patients were 0.39 (p=.003), 0.43(p=.005), 0.52(p=.012), 0.60(p=.046), respectively. Time to response in each remission was similar between ACE-27 0-1 and ACE-27 2-3 groups. Overall survival was worse in ACE-27 2,3 patients with median survival at 12.5 years compared to not reached in patients with ACE-27 0 or 1, or 0 and 1 (p Conclusion ACE-27 score predicts outcome including overall survival and event-free survival well in chronic phase CML patients. Our study demonstrated that co-morbidities has significant impact on outcome of chronic phase CML on TKI treatment, and the potentials of ACE-27 as a part of prognostic instrument. Figure 1 Figure 1. Disclosures Kantarjian: AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Prelude: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Foghorn: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding. Konopleva: Cellectis: Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; KisoJi: Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Stemline Therapeutics: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding. Jain: ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; Pharmacyclics: Research Funding; Servier: Honoraria, Research Funding; Fate Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Pfizer: Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria; Janssen: Honoraria; Aprea Therapeutics: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Pemmaraju: Celgene Corporation: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Clearview Healthcare Partners: Consultancy; CareDx, Inc.: Consultancy; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Consultancy; Sager Strong Foundation: Other; Bristol-Myers Squibb Co.: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Springer Science + Business Media: Other; MustangBio: Consultancy, Other; Daiichi Sankyo, Inc.: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Cellectis S.A. ADR: Other, Research Funding; Blueprint Medicines: Consultancy; Affymetrix: Consultancy, Research Funding; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; ImmunoGen, Inc: Consultancy; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Plexxicon: Other, Research Funding. Borthakur: ArgenX: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Protagonist: Consultancy. Kadia: Cure: Speakers Bureau; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Jazz: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; Sanofi-Aventis: Consultancy; Ascentage: Other; Genfleet: Other; AstraZeneca: Other; Astellas: Other; BMS: Other: Grant/research support; Cellonkos: Other; Pulmotech: Other; Liberum: Consultancy; Novartis: Consultancy; Amgen: Other: Grant/research support. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding. Sasaki: Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding.

Background : CPX-351 is a dual-drug liposomal encapsulation of cytarabine(araC) and daunorubicin at a 5:1 molar ratio that is approved for treatment of newly diagnosed therapy-related AML or AML-MRC. Compared to 7+3, CPX-351 was associated with higher response rates (47.7% vs 33.3%) and improved overall survival (OS) in these patients. In an earlier phase I study, CPX-351 produced a CR/CRi rate of 23% in patients with R/R AML. Based on the activity of venetoclax (VEN) with lower intensity therapy in newly diagnosed AML, we investigated safety and efficacy of VEN combined with CPX-351 in pts with newly diagnosed (frontline) and R/R AML who are considered fit for intensive chemotherapy. Methods : The study was designed with a safety lead-in phase to establish the safe dose and schedule in R/R AML, followed by 2 expansion cohorts to explore efficacy in R/R AML (Cohort A) and frontline AML (Cohort B). Patients aged ≥ 18 years with adequate organ function, and ECOG PS ≤2 were eligible. Prior VEN use was allowed for pts with R/R AML. The dose of CPX-351 was fixed : daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 IV on D1,3,5 of induction, and daunorubicin 29 mg/m2 + cytarabine 65 mg/m IV on D1,3 during consolidation. The starting effective dose of Ven was 300mg (at the -1 dose level) on D2-21 for the safety lead-in cohort. with appropriate dose adjustment for concomitant CYP3A inhibitors. Interruption of VEN after D14 was implemented if a D14 bone marrow (BM) was hypocellular and without evidence of leukemia. Results : A total of 31 patients were treated on the trial. 26 (84%) patients with R/R AML were treated on study: 12(46%) in the lead-in phase, and 14 (54%) in the expansion cohort (A). 5 (16%) patients with frontline AML were treated on expansion cohort B. Patient characteristics are summarized in Table 1. Median number of prior treatments in R/R AML was 1 (range 1-7). Notably, 3 (60%) pts with frontline AML and 10 (42%) with R/R AML had a complex karyotype; 3 (60%) frontline AML patients and 6 (23%) R/R AML patients had TP53-mutated AML. 4 of the 5 (80%) patients in the frontline cohort had treatment for a prior myeloid neoplasm before transforming to AML (treated secondary-AML). Among the 5 frontline AML patients, 4 (80%) achieved CR/CRi including 1 (20%) CR and 3 (60%) CRi. Of 26 R/R AML patients, there were 12 (46%) CR/CRi including 4(15%) CR and 8(31%) CRi. Rates of MRD negativity by flow cytometry were 75% and 78% in frontline and R/R AML, respectively. 4 out of 4 (100%) responding pts in the frontline AML cohort transitioned to SCT, and all are alive to date. 10 out of 12 responding patients in the R/R cohort (83%) underwent SCT. The 4- and 8-week mortality was 12% and 19% for the R/R cohort - all were patients with persistent AML; there were no early deaths in the frontline cohort (Table2). The median OS in frontline AML was not reached, compared to 7.1 months in R/R AML patients (Figure 1a). 1-year estimated OS was 75% (95% CI 13-96%) and 39% (95% CI 18-60%) in frontline and R/R AML, respectively. The median RFS was 6.7 months and 10.9 months in frontline and R/R AML, respectively (P=0.71; Figure 1b). Among R/R AML, the median OS in responding pts was 26.9 months (Figure 1d). Achieving MRD negativity was associated with better OS in R/R AML, with median OS of 26.9 months compared to 2.6 months in responders with detectable MRD (P=.061)(Figure 1c). Serious adverse events (SAEs) are summarized in Table 3. The most common grade 3/4 SAEs were infection NOS (19), pneumonia (7) and febrile neutropenia without source (4). Myelosuppression was universal. Grade 5 SAEs included 1 each of sepsis, pneumonia, intracranial bleed, and respiratory failure. Conclusion The combination of CPX-351 + 7 days of VEN was safe and tolerable, demonstrating encouraging rates of CR/CRi in adverse-risk frontline AML (80%) and R/R AML (52%), respectively. Median OS was not reached in frontline AML, and 7.1 months in R/R AML patients. 80% of frontline AML patients and 42% R/R AML patients overall successfully transitioned to SCT. Further investigation into efficacy in frontline AML and confirmation in R/R AML is planned. Figure 1 Figure 1. Disclosures Kantarjian: Jazz: Research Funding; Ascentage: Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Taiho Pharmaceutical Canada: Honoraria. Borthakur: Ryvu: Research Funding; Astex: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy. Takahashi: Celgene/BMS: Consultancy; GSK: Consultancy; Novartis: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Short: Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Research Funding; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Daver: Genentech: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Sevier: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Pemmaraju: Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; LFB Biotechnologies: Consultancy; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; DAVA Oncology: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; MustangBio: Consultancy, Other; Roche Diagnostics: Consultancy; Springer Science + Business Media: Other; Sager Strong Foundation: Other; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; Cellectis: Honoraria, Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding. Wierda: Loxo Oncology, Inc.: Research Funding; Cyclacel: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AstraZeneca: Research Funding; KITE Pharma: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Juno Therapeutics: Research Funding; Xencor: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; Janssen: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; Genentech: Research Funding; Karyopharm: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. Verstovsek: PharmaEssentia: Research Funding; Ital Pharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Konopleva: Cellectis: Other: grant support; Ascentage: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Agios: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Ablynx: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding. Ravandi: Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Prelude: Research Funding; Novartis: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria; Taiho: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kadia: Astellas: Other; Ascentage: Other; Genfleet: Other; AstraZeneca: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. OffLabel Disclosure: currently FDA approved CPX-351 for t-AML or AML with myelodysplastic changes, we are conducting trial including frontline AML patients or relapsed/refractory AML patients.

Introduction: Hyperbaric oxygen therapy (HBO) is approved for difficult-to-treat tissue injury. It also been used as a second-line treatment for refractory infection in hematologic malignancies. However, data on the efficacy of HBO in such population are limited. Here, we reviewed our single-center experience of HBO used in patients with hematologic malignancies. Methods: We identified patients undergoing HBO treatment by insurance authorization data between December 2012 and October 2019 at MD Anderson Cancer Center. Patients with a diagnosis of hematologic malignancies with or without history of stem-cell transplant were included. Clinical and demographic data were collected by retrospective chart review. Results: A total of 50 patients were included: 26 (52%) patients had Acute Myeloid Leukemia, 31 (62%) patients had received an SCT, and 34 (68%) patients had active disease, of whom 28 (56%) had relapsed/refractory disease. The most common infections were: 19 (38%) BK cystitis and 17 (34%) fungal sinusitis. Median number of HBO sessions was 5 (range 1–60), and median HBO duration was 17 days (range 0–109). All patients received initial HBO in the hospital; 25 (50%) patients were discharged from hospital at either completion of HBO or after transition to outpatient treatment. Sixteen (32%) patients were discharged to hospice, and 8 (16%) patients died during the hospitalization. Ninety-day and 1-year mortality were high at 52% and 78%, respectively. Median survival was 3.1 months. Patients with BK cystitis were less likely to respond to HBO (odds ratio 0.16, p=.004). Eight patients had response to HBO and achieved remission of infection at last follow-up. These patients had a higher proportion (50%) of underlying disease in remission, compared to 29% in rest of patients (n=42). The treatment indications in the responding group were 2 BK cystitis, 2 fungal sinusitis, 2 cellulitis, and 2 non-BK cystitis. Other patient characteristics were similar to the rest of the patients. Patients with response/infection remission had better survival with HR 0.18 (95% CI .063–.529, p=.002). Conclusion: A small subset of patients with hematologic malignancies, 16% in our study, had meaningful recovery from infection after HBO treatment. In our experience, patients whose underlying malignancy was in remission and patients with non-BK infection had better outcomes. Additional studies are needed to better identify the population who would benefit from HBO.

Hearing loss is associated with an accelerated decline in social, cognitive, and physical functioning among older adults. However, little is known about its impact and barriers to hearing health care in any ethnic minorities. The aim of this study was to explore experiences related to hearing loss and barriers to hearing health care among older Korean Americans (KAs). We conducted four focus groups with 19 older KAs with hearing loss and four communication partners. Qualitative content analysis revealed four themes: (a) impact of hearing loss, (b) self-perception of hearing loss, (c) coping strategies for hearing loss, and (d) barriers to hearing health care (price, language, lack of collaborative communications, perceptions about hearing aids, and lack of knowledge). Older KAs were significantly impacted by hearing loss but tended not to seek care due to multiple factors. Culturally tailored hearing interventions are urgently needed to promote hearing health in the KA community.

Introduction Thrombocytopenia is common in liver cirrhosis patients, which often complicates with patients' frequent issue with gastrointestinal bleeding and procedural needs. Based on biologic understanding of decreased thrombopoietin(TPO) level in liver cirrhosis patients, use of TPO agonists in liver cirrhosis have been actively studied. Over the period of time, new studies have come out about 2 FDA-approved TPO agonists, Avatrombopag and Lusutrombopag, for prophylaxis before procedure in liver cirrhosis patients with thrombocytopenia. In the past, there have raised concerns of increased risk of portal vein thrombosis and other thrombotic risks in other agents. In our study, we aimed to study the effectiveness and safety of TPO receptor agonists for pre-procedural use in patients with liver cirrhosis. Study design Study was conducted from August 2018 to July 2019. Previous studies were identified through database searching MEDLINE, CENTRAL, Clinicaltrial.gov and google search. Randomized clinical trials with active treatment arm with TPO receptor agonists in the use of liver cirrhosis patients, with intention of pre-procedural prophylaxis, and having placebo for direct comparisons were included. One of the major exclusions was TPO receptor agonists to increase platelet counts for anti-viral treatment in cirrhosis patients. 14 studies were identified. Studies were reviewed and eligibility was determined by two independent clinically trained researchers. 5 duplicated studies were removed, and in total of 7 studies were included for quantitative and qualitative analysis. Details of studies were collected by 2 independent researchers and compared. When there is a discrepancy, repeat review of the study was conducted. Studies were conducted or published from 2012 to 2018. 1 trial from Eltrombopag, 3 trials from Avatrombopag, and 3 trials from Lusutrombopag were included. Result Characteristics of included studies are summarized in table 1. Our studies found that 5.5(95% CI : 4.35-7.15) times higher risk ratio(RR) of reaching platelet target before procedure compared to placebo. Target platelet number goal was 50,000 to 80,000 depending on the study. Studies showed homogenous result with I-squared was 30.8% and q-statistics of p-value 0.193.(Figure 1) Subgroup analysis by FDA-approved medication of Avatrombopag and Lusutrombopag showed statistically significant higher risk ratio of 4.74(3.36-6.68) and of 5.52(3.65-8.34) each compared to placebo. Risk ratio for preventing platelet transfusion was not able to be calculated with heterogeneity of study with I-square higher than 90%. Lusutrombopag study showed significant benefits (RR 6.33, 95% CI 2.95-13.58) with heterogeneity inside the same medications, which might be explained with different doses in studies. No statistical significance in risk ratio in a study with Avatrombopag. Subgroup analysis limited to phase 3 studies showed risk ratio of preventing transfusion of 2.87(95% CI 2.15-3.82) but heterogeneity with q-statistics of p-value at 0.029. Relative risk for adverse event related to portal vein thrombosis was not statistically significant with RR of 0.99(95% CI : 0.35-2.85) in total of 1,229 patients.(Figure 2) Study result was homogenous result by I-square 0%, q-statistics of p-value 0.794. Other severe adverse events, major bleeding risk, overall thrombosis risk were not statistically significant. Only increased risk without statistical significance was reported in trail with Eltrombopag which was early terminated. Conclusion Our meta-analysis of pre-procedural use of TPO agonist in liver cirrhosis patients showed statistically significant benefit of reaching platelet count goal by 5.58 times with risk ratio, but no benefit of preventing transfusion. Compared to prior studies including use of TPO agonists for Interferon-Ribavirin treatment, meta-analysis limited to pre-procedural use did not show statistically significant increase in portal vein thrombosis. Serious adverse events including thrombosis events and bleeding risk were not statistically significant. Most studies described that portal-vein thrombosis events were often related to high platelet counts about 200,000 and longer use of TPO agonist. In current era with lesser use of Interferon and Ribavirin as an anti-viral therapy, TPO agonists use in setting of pre-procedure mostly with lower platelet targets can be safely used. Disclosures No relevant conflicts of interest to declare.

Introduction Diffuse Large B-cell Lymphoma(DLBCL) is the most common type of Non-Hodgkin's Lymphoma, accounting for approximately 30% of adult lymphomas. Survival among patients with DLBCL has improved significantly in past years with the introduction of effective treatment modalities including Rituximab. Despite of improvement of survival, many patients undergo course of early death and disparities related to early death in DLBCL remains unclear. Our study was aimed to identify the characteristics and associated factors in patients with early mortality by retrospective study using a single-institutional patient data. The institution is a community hospital serving medically underserved population in urban setting, which is a unique setting to address disparities study. Study design Dataset was obtained from the institutional cancer registry and retrospective chart review. Patients diagnosed with biopsy proven DLBCL between January 2007 to December 2017 were included. Survival data was updated in July 2019. A total of 159 patients were included. Median survival was 99.5 months. Overall 2-year survival was 60.4% in all included patients. 90-day and 180-day mortality was defined as patients who survived less than 90 days or 180 days from diagnosis. Chi-square test was used for descriptive statistics. Cox-proportional hazard regression was used for survival analysis. Result Among 159 patients, 25 and 34 patients (15.7% and 21.4%) had 90-day and 180-day mortality. The distribution of survival time was right skewed with more frequent death in early period(figure 1). Median survival of 90-day and 180-day mortality patients were 19 days and 33 days. Among 25 patients with 90-day mortality, causes of death included rapid progression(48%), sepsis(32%), GI bleeding (32%), tumor lysis syndrome(24%), and withdrawal of care as not a treatment candidate with co-morbidities(16%). 56% of patients were discharged to comfort measure only. 16% patients underwent CPR. 25%(5 out of 25) in 90 day mortality group were started on Rituximab or other treatment measures compared to 100%(9 out of 9) between 90 -180-day mortality group(Chi-square Patients with 90-day mortality were more likely to be older age(over 60), African-American, a resident at low average income zip code, poor performance status, having stage 4 disease, B symptoms and high R-IPI score with statistical significance. Adjusted Cox-proportional regression with demographic, tumor and clinical characteristics showed statistical significance both 90-days and 180-days with poor performance status with ECOG 2 or more(HR 15.28 and 6.22 in 90- and 180-day, both p-value Conclusion Our study suggested poor performance status and old age is the most significant variables associated with early mortality than other characteristics. R-IPI or other tumor-associated factors have been known for predicting prognosis, which was supported by our previous study using same data, however this was not applied in association of early mortality after adjustment. It is notable that two groups of patients with 90-day and with 180-day showed discrepancies in risk of mortality by being uninsured or having high LDH. Within early mortality group, there might be heterogeneity of clinical characteristics. For example, patients who not able to receive treatment or treatment was stopped with rapid progression or complications mostly died within 90 days, however patients who died between 90 days and 180 days all received Rituximab or other forms of treatment. Many of our patients were old, African-American, residing in low-income area, advanced DLBCL with high ECOG. Only 56% of patients were discharged to hospice care or comfort measure only and 16% patient underwent CPR in patients with 90-day mortality while most of patients were not able to receive any treatment. Our study also implies the special need of addressing goals of care discussion in DLBCL patients early in the setting of underserved population. Disclosures No relevant conflicts of interest to declare.

Purpose: mAbs such as anti-CD20 rituximab are proven therapies in B-cell malignancies, yet many patients develop resistance. Novel therapies against alternative targets are needed to circumvent resistance mechanisms. We sought to generate mAbs against human B-cell–activating factor receptor (BAFF-R/TNFRSF13C), which has not yet been targeted successfully for cancer therapy. Experimental Design: Novel mAbs were generated against BAFF-R, expressed as a natively folded cell surface immunogen on mouse fibroblast cells. Chimeric BAFF-R mAbs were developed and assessed for in vitro and in vivo monotherapy cytotoxicity. The chimeric mAbs were tested against human B-cell tumor lines, primary patient samples, and drug-resistant tumors. Results: Chimeric antibodies bound with high affinity to multiple human malignant B-cell lines and induced potent antibody-dependent cellular cytotoxicity (ADCC) against multiple subtypes of human lymphoma and leukemia, including primary tumors from patients who had relapsed after anti-CD20 therapy. Chimeric antibodies also induced ADCC against ibrutinib-resistant and rituximab-insensitive CD20-deficient variant lymphomas, respectively. Importantly, they demonstrated remarkable in vivo growth inhibition of drug-resistant tumor models in immunodeficient mice. Conclusions: Our method generated novel anti–BAFF-R antibody therapeutics with remarkable single-agent antitumor effects. We propose that these antibodies represent an effective new strategy for targeting and treating drug-resistant B-cell malignancies and warrant further development. Clin Cancer Res; 24(5); 1114–23. ©2017 AACR.

251 Background: Combination chemotherapy with nab-paclitaxel/gemcitabine is a standard of care option in metastatic pancreatic cancer management with increasing use due to an improvement in median overall survival of 1.8 months compared to gemcitabine alone. It is also used in practice in the second and third-line settings for patients that have progressed on fluorouracil based regimens. As the utility of this combination chemotherapy has grown, dose intensity (DI) in relation to survival outcome is an important measure for real world application. Methods: Fifty-six patients that were 18 years or older with metastatic pancreatic cancer treated with nab-paclitaxel/gemcitabine as first-line therapy from January 1, 2013 to December 31, 2014 at Moffitt Cancer Center were identified through medical records. The subjects were retrospectively reviewed, and demographic, treatment outcomes (survival and progression), and DI were collected. Overall survival was calculated with Kaplan Meier survival curves. Multi-Cox regression models estimated multivariable-adjusted hazard ratio with 95% confidence intervals. Results: There was no significant relationship between receiving a DI > 85% regimen in relation to independent variables of age > 65, sex, primary site, and known distant metastasis; however DI > 85% was significant for patients that received additional chemotherapy following nab-paclitaxel/gemcitabine (p = 0.044). The DI > 85% group compared to the < 85% group had a hazard ratio (HR) for all-cause mortality of 0.285 (0.106-0.764, p = 0.013). Six and 12-month survival were higher in the DI > 85% group (p = 0.009, p = 0.02 respectively). Conclusions: DI > 85% for nab-paclitaxel/gemcitabine compared to DI < 85% may have a lower all-cause mortality and higher 6 and 12-month survival.

Background: Despite major advances in the treatment of multiple myeloma (MM) only a minority of patients achieve long-term disease control. Immunotherapy combined with autologous hematopoietic stem cell transplantation (auto-HCT) may reduce relapse rates. Vaccination with Ig idiotype (Id) conjugated with a carrier protein, keyhole limpet hemocyanin (KLH), was associated with superior disease-free survival in a randomized trial in follicular lymphoma (Schuster S. et al. JCO 2011), and Id is also a tumor-specific antigen in MM. In addition, anti-CD3/-CD28 costimulated adoptive T-cell transfer augmented immune responses to pneumococcal vaccination despite cytotoxic therapy (Rapoport A et al. Nat Med 2005). We therefore hypothesized that Id-KLH vaccine + the vaccine-primed costimulated T cells will result in a robust Id-specific humoral and cellular response, compared with control vaccine (KLH only). Methods: In this randomized, phase II trial, eligible patients were randomized 1:1 to receive either KLH-only or Id-KLH vaccine, followed by auto-HCT, and then vaccine- primed costimulated T cells followed by two booster doses of the vaccine to which they were randomized. Immune response (IR) was evaluated by gene expression profiling (GEP) using NanoString nCounter. Results: A total of 36 patients were enrolled between 1/2013 and 5/2015, 20 to KLH-only and 16 to Id-KLH arm, and completed their assigned treatments. There were no significant differences between the groups in age, gender, stage, cytogenetic risk, induction regimen or response to induction (Table). Nineteen (95%) and 16 (100%) patients received maintenance therapy after protocol treatment in KLH-only and Id-KLH, respectively (p=0.42). No infusion reactions or dose-limiting toxicity was seen in either arm. There was no non-relapse mortality at 100-day and 1-year in either arm. At last evaluation, 5 (25%) and 7 (44%) had achieved CR in KLH-only and Id-KLH, respectively (p=0.29). Six (30%) and 9 (56%) achieved at least nCR in KLH-only and Id-KLH, respectively (p=0.17), and 12 (60%) and 12 (75%) achieved at least a VGPR in KLH-only and Id-KLH, respectively (0.48). Ten (50%) and 8 (50%) patients, for whom there were sufficient samples available underwent IR analysis in KLH-only and Id-KLH, respectively at baseline and at 30, 90 and 180 days after activated T cell infusion. In an initial 568 gene panel analyzed for IR, compared with KLH-only, there was a greater change in IR genes in CD8+ T cells in Id-KLH at days 30, 90 and 180 (Figure 1A). In a 30-gene panel of the most upregulated IR genes in CD8+ cells, there was a significantly higher expression of these genes in Id-KLH at all post-treatment time points (Figure 1B). Specifically, at day 180 post-treatment, there was higher expression of immune co-stimulatory genes in Id-KLH in both CD8+ and CD4+ T cell subsets. This increased co-stimulatory gene expression in Id-KLH vaccinated CD4+ (Figure 1C) and CD8+ T cells (not shown) was most marked in patients who had achieved a CR. After a median follow up of 38.3 months, 3-year PFS in KLH-only and Id-KLH was 64% and 53%, respectively (p=0.25). Conclusion: Id-KLH vaccine and vaccine-primed costimulated T cells can be safely administered in the setting of auto-HCT. In this randomized trial we detected a trend towards a deeper clinical response in the Id-KLH arm. There were significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm,which also correlated withdepth of clinical response. Future trials should focus on selection of patients most likely to mount a robust IR to Id vaccines. Download : Download high-res image (185KB) Download : Download full-size image Disclosures Shah: TeneoBio, Inc.: Honoraria; Indapta Therapeutics: Other: Stock Ownership; Celgene: Research Funding; Celgene, Indapta Therapeutics, Takeda: Consultancy. Patel: Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Orlowski: BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen: Celgene: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy. Vogl: Constellation: Research Funding; Karyopharm: Consultancy; GSK: Research Funding; Calithera: Research Funding; Takeda: Consultancy, Research Funding; Teva: Consultancy; Amgen: Consultancy; Celgene: Consultancy. June: Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kwak: Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership.

A defining hallmark of primary and metastatic cancers is the migration and invasion of malignant cells. These invasive properties involve altered dynamics of the cytoskeleton and one of its major structural components β-actin. Here we identify AIM1 (absent in melanoma 1) as an actin-binding protein that suppresses pro-invasive properties in benign prostate epithelium. Depletion of AIM1 in prostate epithelial cells increases cytoskeletal remodeling, intracellular traction forces, cell migration and invasion, and anchorage-independent growth. In addition, decreased AIM1 expression results in increased metastatic dissemination in vivo. AIM1 strongly associates with the actin cytoskeleton in prostate epithelial cells in normal tissues, but not in prostate cancers. In addition to a mislocalization of AIM1 from the actin cytoskeleton in invasive cancers, advanced prostate cancers often harbor AIM1 deletion and reduced expression. These findings implicate AIM1 as a key suppressor of invasive phenotypes that becomes dysregulated in primary and metastatic prostate cancer., Invasion of malignant cells involves changes in cytoskeleton dynamics. Here the authors identify absent in melanoma 1 as an actin binding protein and show that it regulates cytoskeletal remodeling and cell migration in prostate epithelial cells, acting as a metastatic suppressor in cancer cells.

Background: Despite major advances in the treatment of multiple myeloma (MM) only a minority of patients achieve long-term disease control. Immunotherapy combined with autologous hematopoietic stem cell transplantation (auto-HCT) may reduce relapse rates. Immunoglobulin idiotype (Id) conjugated with a carrier protein, Keyhole limpet hemocyanin (KLH), is a tumor-specific antigen in MM. Vaccine-primed, anti-CD3/anti-CD28 costimulated adoptive T-cell transfer can augment humoral and cellular immune responses to vaccination despite cytotoxic therapy. We hypothesized that Id-KLH vaccine + the vaccine-primed costimulated T cells will result in a robust Id-specific humoral and cellular response, compared to a control vaccine (KLH only). Methods: In this randomized, phase II trial, the primary objective was to determine if Id-KLH primed, costimulated T cells will induce a more robust Id-specific immunity than KLH-primed T cells. Eligible patients had IgG monoclonal protein. Patients were randomized 1:1 to receive either Id-KLH vaccine or KLH-only vaccine, followed by auto-HCT, and then vaccine- primed costimulated T cells followed by two booster doses of the vaccine to which they were randomized. This study was supported by The MD Anderson Cancer Center SPORE in Multiple Myeloma. Results: A total of 36 patients were enrolled between 1/2013 and 5/2015. Sixteen (44%) were randomized to Id-KLH and 20 (55%) to KLH-only. The Table below summarizes the patient characteristics. There was no significant difference between the two groups in terms of age, risk status or induction therapy. No treatment-related mortality, infusion reactions or dose-limiting toxicity was seen in either arm. Five (31%) and 3 (15%) patients achieved complete remission (CR) by day+180 in the Id-KLH and KLH arms, respectively (p=0.42). Initial analysis of a subgroup of patients revealed a significantly higher mRNA expression of immune activation genes IL-2, CCR6 and CD40 by NanoString nCounter in the Id-KLH group compared with the KLH only group (Figure). Eleven (68%) and 17 (85%) went on to receive maintenance therapy with lenalidomide or lenalidomide + ixazomib in the Id-KLH and KLH arms, respectively (p=0.42). After a median follow up of 26 months, 2-year PFS was 81% and 83% in Id-KLH and KLH arms, respectively (p=0.35). Conclusion: Id-KLH vaccine and vaccine-primed costimulated T cells can be safely administered in the setting of auto-HCT.There was a more robust immune response and a trend towards higher CR rate in the Id-KLH group. Disclosures Stadtmauer: Teva: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Takada: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Garfall:Medimmune: Consultancy; Bioinvent: Research Funding; Novartis: Consultancy, Research Funding. Cohen:Janssen: Consultancy; Bristol-Meyers Squibb: Consultancy, Research Funding. June:Johnson & Johnson: Research Funding; Immune Design: Consultancy, Equity Ownership; Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Celldex: Consultancy, Equity Ownership; Tmunity: Equity Ownership, Other: Founder, stockholder ; Pfizer: Honoraria.

Antigen activation of the B-cell receptor (BCR) may play a role in the pathogenesis of human follicular lymphoma (FL) and other B-cell malignancies. However, the nature of the antigen(s) recognized by tumor BCRs has not been well studied. Here, we used unbiased approaches to demonstrate that 42 (19.35%) of 217 tested FL immunoglobulins (Igs) recognized vimentin as a shared autoantigen. The epitope was localized to the N-terminal region of vimentin for all vimentin-reactive tumor Igs. We confirmed specific binding to vimentin by using recombinant vimentin and by performing competitive inhibition studies. Furthermore, using indirect immunofluorescence staining, we showed that the vimentin-reactive tumor Igs colocalized with an anti-vimentin monoclonal antibody in HEp-2 cells. The reactivity to N-terminal vimentin of IgG FL Igs was significantly higher than that of IgM FL Igs (30.4% vs. 10%; P=0.0022). However, vimentin-reactive FL Igs did not share complimentarity determining region 3 motifs and were not homologous. Vimentin was expressed in the T-cell rich regions of FL, suggesting that vimentin is available for binding with tumor BCRs within the tumor microenvironment. Vimentin was also frequently recognized by mantle cell lymphoma and multiple myeloma Igs. Our results demonstrate that vimentin is a shared autoantigen recognized by nonstereotyped FL BCRs and by the Igs of mantle cell lymphoma and multiple myeloma and suggest that vimentin may play a role in the pathogenesis of multiple B-cell malignancies. These findings may lead to better understanding of the biology and natural history of FL and other B cell malignancies.

Available therapies for lymphoplasmacytic lymphoma (LPL) provide no survival advantage if started before symptoms of end organ damage develop. Current recommendations are to follow a program of observation while patients are in the asymptomatic phase of disease. In this clinical study we will use idiotypic determinants of B-cell lymphoma surface immunoglobulins as tumor-specific antigens (idiotype) to develop a patient-specific vaccine against LPL. By activating the host immune system through vaccination to eradicate tumor cells, we postulate that disease control of asymptomatic phase lymphoplasmacytic lymphoma can be maintained. This novel 2nd generation idiotype vaccine was initially developed by genetic fusion of idiotype antigen in single-chain format with a pro-inflammatory chemokine. The central hypothesis is that antitumor immunity can be triggered by targeting antigen delivery to antigen-presenting cells in vivo by chemokine receptor-mediated binding, uptake and processing of idiotype antigens for more efficient presentation to T cells. A large body of preclinical data demonstrated that the immunogenecity of the idiotype antigen was considerably enhanced by such a genetic modification by a mechanism of facilitating antigen presentation. As a consequence, vaccine-induced prophylactic and therapeutic antitumor effects were significantly potentiated. To translate our vaccine therapy from bench to bedside, we established a CLP laboratory for vaccine preparation. Furthermore, we developed reliable technology to differentiate lymphoma idiotype antigens from idiotypic cell-surface immunoglobulins on normal B cells. Using this technology, we successfully cloned the cDNA encoding variable regions of heavy and light chains of LPL idiotype, and generated patient-specific plasmid constructs containing LPL idiotype single chain in fusion with macrophage inflammatory protein 3 alpha (MIP3a). All three engineering rounds of down-stream GMP amplification of clinical-grade plasmid DNA have been accomplished, which eventually paves the way for us to take a lab-grown agent to a first-in-human clinical trial. Citation Format: Hong Qin, Soungchul Cha, Sheetal S. Rao, Kunhwa Kim, Dongho Gwak, Sung-doo Kim, Sapna R. Parshottam, Sheeba K. Thomas, Larry W. Kwak. Bench-to-bedside development of a novel idiotype vaccine against lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2891. doi:10.1158/1538-7445.AM2014-2891