Artigos de revistas sobre o tema "M. P. Möller Organ Company"

Background:Systemic lupus erythematosus (SLE) is an autoimmune disease that can not only cause systemic symptoms, such as fever and arthritis, but can also damage important organs, such as those of the central nervous system and the kidneys. Prevention of irreversible organ damage is important for better prognosis [1]. Additionally, the importance of maintaining the quality of life (QOL) of patients has recently been emphasized. However, only a few studies have examined the relationship between irreversible organ damage and patient QOL.Objectives:To assess the relationship between organ damage and QOL, and to survey which organs have more significant effects on QOL.Methods:We conducted a questionnaire-based survey of 183 patients with SLE at Kyoto University Hospital from September to December 2019. We used the SLICC/ACR Damage Index (SDI) to evaluate organ damage [2]. The following five scales were employed to evaluate QOL: the physical (PCS) and mental component summary (MCS) of the Medical Outcome Study (MOS) 36-Item Short-Form Health Survey version 2.0 (SF-36v2) [3], health (HRQOL) and non-health-related QOL (N-HRQOL) of LupusPRO [4], and SLE Symptom Checklist (SSC) [5].Results:Linear regression analysis showed significant correlation between the SDI score and all QOL scales except for N-HRQOL, suggesting negative effects of organ damage on QOL (Table 1). Next, we analysed whether there was a significant difference in the SF-36 score between those who were positive and negative for each SDI item (41 in total), using the Wilcoxon rank sum test. Muscle atrophy or weakness (p= 3.0×10-10), osteoporosis with fracture or vertebral collapse (p= 9.7×10-8), claudication (p= 7.4×10-5), and cognitive impairment or major psychosis (p= 9.9×10-5) significantly correlated (p< 1.2×10-3) with PCS, and scarring chronic alopecia (p= 3.4×10-4) with MCS (Table 2). In addition, the five SDI items significantly correlated with the remaining three QOL scales (HRQOL, N-HRQOL, and SSC;p< 0.05).Table 1.Relationship between the SDI score and QOLSF-36LupusPROSSCPCSMCSHRQOLN-HRQOLp-value<2.0×10-161.7×10-32.2×10-110.231.9×10-8Table 2.Relationship between each SDI item and the SF-36 score (p< 1.2×10-3SDI itemPCS scorep-valuePositive(Median (IQR))Negative(Median (IQR))Muscle atrophy/weakness33 (19-45)50 (43-54)3.0×10-10Osteoporosis with fracture/vertebral collapse24 (12-32)49 (38-54)9.7×10-8Claudication31 (19-35)49 (38-54)7.4×10-5Cognitive impairment/psychosis27 (17-33)49 (38-54)9.9×10-5SDI itemMCS scorep-valuePositive(Median (IQR))Negative(Median (IQR))Scarring chronic alopecia42 (29-51)49 (39-54)3.4×10-4Conclusion:We demonstrated that organ damage has negative effects on patient QOL, indicating the importance of preventing irreversible organ damage for maintaining QOL. Moreover, muscle atrophy/weakness, osteoporosis with fracture/vertebral collapse, claudication, cognitive impairment/major psychosis, and scarring chronic alopecia significantly correlated with QOL deterioration, suggesting that these items should be examined with special care in clinical practice.References:[1]Lopez R, et al. Rheumatology (Oxford). 2012; 51:491-498.[2]Gladman D, et al. Arthritis Rheum. 1996; 39:363-369.[3]Fukuhara S, et al. J Clin Epidemiol. 1998; 51:1037-1044.[4]Inoue M, et al. Lupus. 2017; 26:849-856.[5]Grootscholten C, et al. Qual Life Res. 2003; 12:635–644.Disclosure of Interests:Yudai Takase: None declared, Hiroshi Doi: None declared, Takeshi Iwasaki: None declared, Motomu Hashimoto Grant/research support from: Bristol-Myers Squibb, Eisai, and Eli Lilly and Company., Speakers bureau: Bristol-Myers Squibb and Mitsubishi Tanabe Pharma., Ryuta Inaba: None declared, Tomohiro Kozuki: None declared, Masashi Taniguchi: None declared, Yuya Tabuchi Paid instructor for: Astellas Pharma, GlaxoSmithKline, Mitsubishi Tanabe Pharma, and Nippon Shinyaku., Speakers bureau: AbbVie, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Nippon Shinyaku, and Novartis Pharma. (Outside the field of the present study.), Koji Kitagori: None declared, Syuji Akizuki: None declared, Kosaku Murakami Speakers bureau: AbbVie, Eisai, and Mitsubishi Tanabe Pharma., Ran Nakashima Grant/research support from: Takeda Pharmaceutical. (Outside the field of the present study.), Speakers bureau: Astellas Pharma, Medical & Biological Laboratories, AstraZeneca, and Boehringer Ingelheim. (Outside the field of the present study.), Hajime Yoshifuji Grant/research support from: Astellas Pharma. (Outside the field of the present study.), Speakers bureau: Chugai Pharmaceutical. (Outside the field of the present study.), Wataru Yamamoto: None declared, Masao Tanaka Grant/research support from: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Ayumi Pharmaceutical, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Taisho Pharmaceutical, and UCB Japan., Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Pfizer, Taisho Pharmaceutical, Takeda Pharmaceutical, and UCB Japan., Koichiro Ohmura Grant/research support from: Astellas Pharma, AYUMI Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, Japan Blood Products Organization, Mitsubishi Tanabe Pharma, Nippon Kayaku, Nippon Shinyaku, Sanofi, and Takeda Pharmaceutical., Speakers bureau: AbbVie, Actelion Pharmaceuticals Japan, Asahi Kasei Pharma, AYUMI Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, and Sanofi.

Introduction: Selection of an appropriate donor is important for the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). In general, an HLA-matched related donor (M-RD) and an HLA-matched unrelated donor (M-UD) are considered to be the first and second preferred donors in allo-HCT. On the other hand, the most suitable alternative donor remains unclear, when M-RD and M-UD are unavailable. In addition, the information on a suitable donor selection for elderly patients are limited. We hypothesized that the patient age might change the donor selection priority in allo-HCT, because related donor age, organ function, or endurance against graft-versus-host disease or infection differ between younger and older patients. Therefore, we conducted a nationwide, large retrospective study to investigate the donor selection priority in allo-HCT, classified according to patient age. Methods: We analyzed 17848 adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, or myelodysplastic syndrome who underwent a first all-HCT between 2007 and 2017 in Japan. We compared the transplant outcomes among M-RD (n=4106), HLA 1-antigen-mismatched related donor (1MM-RD) (n=592), HLA 2,3-antigen-mismatched related donor (23MM-RD) (n=882), M-UD (n=3927), HLA 1-locus-mismatched unrelated donor (1MM-UD) (n=2474), and unrelated cord blood (U-CB) (n=5867), in the whole cohort and in subgroups of patients aged &lt;50 years (n=8572) and those aged ≥50 years (n=9275). All P-values were two sided, and P-values &lt;0.05 were considered statistically significant. Results: Results of multivariate analyses of overall survival (OS), non-relapse mortality (NRM) and relapse are summarized in Table 1. For all patients, 1MM-RD, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS and NRM (hazard ratio [HR] 1.26, p&lt;0.001 and HR 1.93, p&lt;0.001 for 1MM-RD; HR 1.46, p&lt;0.001 and HR 2.15, p&lt;0.001 for 23MM-RD; HR 1.12, p=0.0032 and HR 1.68, p&lt;0.001 for 1MM-UD; and HR 1.19, p&lt;0.001 and HR 1.70, p&lt;0.001 for U-CB) compared to M-RD. On the other hand, there was no significant difference in OS between the M-RD and M-UD groups (HR 0.94, p=0.093), although NRM in the M-UD was inferior to that in the M-RD group (HR 1.27, p&lt;0.001). The risk of relapse in the 1MM-RD, 23MMRD, M-UD, 1MM-UD, and U-CB groups were significantly lower than that in the M-RD group. An interaction test revealed that the effect of M-UD on OS and NRM differed between the patient age &lt;50 years and ≥50 years (HR 0.88, p=0.055 and HR 0.78, p=0.019). Next, we compared transplant outcomes among these donor source within subgroups of patients grouped according to patient age. For the patients aged &lt;50 years, 23MM-RD, 1MM-UD, and U-CB were independent significant adverse factors for OS (HR 1.46, p&lt;0.001, HR 1.18, p&lt;0.001 and HR 1.20, p&lt;0.001), and 1MM-RD tended to be an adverse factor for OS (HR 1.19, p=0.052). On the other hand, OS in the M-UD group was comparable to that in the M-RD group (HR 1.02, p=0.72). For the patients aged ≥50 years, 1MM-RD, 23MMRD, and U-CB were independent significant adverse factors for OS (HR 1.29, p=0.0013, HR 1.42, p&lt;0.001 and HR 1.17, p&lt;0.001). 1MM-UD was not a significant adverse factor for OS (HR 1.07, p=0.18). Conversely, OS in the M-UD group was superior to that in the M-RD group (HR 0.89, p=0.012). In addition, we classified the M-UD group according to donor age (M-UD-Y, donor age &lt;50 years; M-UD-O, donor age ≥50 years). For the patients aged ≥50 years, OS in the M-UD-Y group was superior to that in the M-RD group (HR 0.86, p=0.035), although there was no significant difference in OS between the M-UD-O and M-RD groups (HR 1.08, p=0.70). However, for the patients aged &lt;50 years, OS in the both M-UD-Y and M-UD-O groups were comparable to those in the M-RD group (HR 1.02, p=0.73 and HR 1.04, p=0.82). The probabilities of adjusted OS at 3 years for the patients aged &lt;50 years and aged ≥50 years were 63.6% and 41.6% in the M-RD group, 58.4% and 38.8% in the 1MM-RD group, 52.3% and 30.4% in the 23MM-RD group, 63.6% and 46.8% in the M-UD group, 58.9% and 42.3% in the 1MM-UD group, and 60.1% and 40.3% in the U-CB group (Figure 1). Conclusions: Donor selection priority in all-HCT might be different according to patient age. In particular, young M-UD might be the first preferred donor for patients aged 50 years or older. We should reconsider donor selection priority in allo-HCT based on patient and donor age. Disclosures Kanda: Takeda: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Bristol-Meyers Squib: Honoraria; JCR Pharmaceuticals: Honoraria; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392. Kimura:JSPS KAKENHI: Research Funding. Ozawa:Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria. Atsuta:Kyowa Kirin Co., Ltd: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria. Kanda:Pfizer: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; CSL Behring: Research Funding; MSD: Research Funding; Pfizer: Research Funding; MSD: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Tanabe Mitsubishi: Research Funding; CSL Behring: Research Funding; Novartis: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Asahi-Kasei: Research Funding; Otsuka: Research Funding; Tanabe Mitsubishi: Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Taisho-Toyama: Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Taiho: Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Otsuka: Research Funding; Celgene: Consultancy, Research Funding; Dainippon Sumitomo: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Sanofi: Research Funding; Takara-bio: Consultancy, Honoraria; Taisho-Toyama: Research Funding; Taiho: Research Funding; Nippon-Shinyaku: Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Mochida: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Takara-bio: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Nippon-Shinyaku: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy, Honoraria, Research Funding.

Background Systemic AL amyloidosis is a clonal plasma cell disorder in which amyloid fibrils are deposited in tissues and organs, leading to multi-system organ dysfunction. The most frequently involved organs are the heart and kidney (individually or together), with advanced cardiac involvement conferring particularly poor outcomes. Achievement of hematologic response and improved organ function result in better outcomes. There are currently no approved treatments for AL amyloidosis; multiple myeloma (MM) treatment strategies are used for these pts. Active, tolerable treatment options specific for AL amyloidosis are needed. The oral proteasome inhibitor (PI) ixazomib (ixa) is active and approved in combination with lenalidomide (L)-dexamethasone (Dex) for the treatment of MM pts who have received ≥1 prior therapy. Methods RRAL pts with measurable disease and major organ involvement (cardiac/renal) who required treatment after 1-2 prior therapies (and were not refractory to prior PI therapy) were randomized to ixa (4.0 mg, d 1, 8, 15) plus Dex (20 mg, d 1, 8, 15, 22) or physician's choice (Dex alone or plus melphalan [M], cyclophosphamide [C], thalidomide [T], or lenalidomide [L]) in 28-d cycles until disease progression or unacceptable toxicity (or best response plus 2 cycles or maximum 18 mos therapy/600 mg total dose for MDex). Randomization was stratified by cardiac risk stage, relapsed vs refractory disease, and prior PI exposure. Primary endpoints were 1) overall hematologic response rate (ORR) centrally adjudicated, and 2) death or vital organ deterioration at 2 yrs. Key secondary endpoints were overall survival (OS) and hematologic complete response (CR) rate; other secondary endpoints included hematologic/vital organ progression-free survival (PFS), time to vital organ deterioration or mortality, duration of hematologic response (DOR), and safety. Results 168 pts were randomized to ixa-Dex (n=85) or physician's choice (n=83; 47 LDex, 24 MDex, 10 CDex, 2 TDex); median age was 65 (range 38-84) vs 66 (33-82) yrs, 60% vs 55% were male, 56% vs 63% had cardiac and 66% vs 58% had renal involvement (33% vs 23% had both) at initial diagnosis (plus 9% vs 12% liver, 12% vs 18% gastrointestinal tract, and 11% vs 10% peripheral nerve involvement), 47% vs 47% had prior bortezomib, and 47% vs 37% had prior transplant. Median time since diagnosis was 14.7 vs 15.9 mos. Hematologic responses were seen in 45 (53%) vs 42 (51%) pts receiving ixa-Dex vs physician's choice (odds ratio 1.10 [95% CI 0.60-2.01], p=0.762). Higher CR rates were seen with ixa-Dex vs physician's choice (26% vs 18%). Overall survival, overall/hematologic/vital organ PFS, time to vital organ deterioration/death, DOR, time to treatment failure, and time to subsequent therapy data all favored pts treated with ixa-Dex vs physician's choice (Figure). Vital organ response rates were 36% in the ixa-Dex arm vs 11% with physician's choice (cardiac response rate: 18% vs 5%; renal response rate: 28% vs 7%). At data cut-off, pts had received a median treatment duration of 11.7 vs 4.9 mos with ixa-Dex vs physician's choice, and 21% vs 6% of pts remained on treatment. Grade ≥3 adverse events (AEs) were seen in 59% vs 56% of pts, including 33% vs 41% with drug-related grade ≥3 AEs, 45% vs 33% had serious AEs, 25% vs 20% had AEs resulting in discontinuation, and there were 6% vs 5% on-study deaths. AEs of clinical importance included diarrhea (34% vs 30%), rash (33% vs 20%), cardiac arrhythmias (25% vs 15%), nausea (24% vs 14%), pneumonia (22% vs 16%), and peripheral neuropathy (20% vs 15%). Common (≥5% overall) grade ≥3 AEs were fatigue (9% vs 9%), anemia (2% vs 10%), cardiac failure, dyspnea (each 6% vs 4%), peripheral edema, and pneumonia (each 5% vs 5%). Conclusions Treatment with ixa-Dex significantly prolonged duration of composite survival and vital organ function, PFS, and time to subsequent therapy vs physician's choice. Moreover, ixa-Dex resulted in an improved CR rate and DOR and, although the primary endpoint of hematologic response was not met, all clinically relevant time-to-event endpoint data favored ixa-Dex vs physician's choice. Ixa-Dex was generally well tolerated and associated with a doubling of treatment duration vs physician's choice; no new safety signals were seen. TOURMALINE-AL1 is the first phase 3 trial in RRAL to show significant outcome improvements, suggesting ixa-Dex represents a new option for RRAL pts, who have limited access to therapies. Disclosures Dispenzieri: Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy. Kastritis:Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Genesis: Honoraria. Wechalekar:Takeda: Honoraria; GSK: Honoraria; Celgene: Honoraria; Amgen: Research Funding; Janssen-Cilag: Honoraria. Schönland:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Landau:Pfizer: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Suzuki:Takeda: Honoraria; BMS: Honoraria, Research Funding; Ono: Research Funding; Celgene: Honoraria; Janssen: Honoraria. Comenzo:Takeda: Research Funding; Caelum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Prothena Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Myself: Patents & Royalties: Patent 9593332, Pending 20170008966. Berg:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Employment, Patents & Royalties. Liu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faller:Phoenicia Biosciences: Equity Ownership; Briacell Pharmaceuticals: Equity Ownership; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Viracta Pharmaceuticals: Equity Ownership; Boston University: Employment. Off Label Disclosure: Investigation of the oral proteasome inhibitor ixazomib in combination with dexamethasone versus physician's choice (of which there are no approved treatment options) for the treatment of relapsed/refractory primary systemic amyloidosis.

Abstract Background: Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). The combination of tacrolimus (Tac) and methotrexate (MTX) is a standard regimen for GVHD prophylaxis; however, it is associated with several toxicities and patients are often not able to complete the full MTX regimen. The combination of Tac, reduced dose ("mini")-MTX, and mycophenolate mofetil (MMF) has been investigated with a well-tolerated toxicity profile and low incidence of GVHD, although comparison with standard dose MTX has not been done. We performed a randomized non-inferiority trial comparing Tac/MTX (Full-MTX) to Tac/mini-MTX/MMF (Mini-MTX) for prevention of GVHD after myeloablative related and unrelated donor HCT. Methods: Patients &lt;70 years in age receiving first myeloablative allogeneic HCT using 8/8 HLA-matched related or unrelated donor were eligible; all diagnoses and both bone marrow and peripheral blood stem cell grafts were allowed. Full-MTX patients received MTX dose of 15 mg/m 2 day +1, and 10 mg/m 2 days +3, +6, and +11. Mini-MTX patients received doses of 5 mg/m 2 on days +1, +3, and +6 plus MMF 1000 mg BID. MTX and MMF doses were adjusted for body weight in pediatric recipients. Primary endpoints were incidence of acute GVHD, mucositis, and hematopoietic engraftment. Secondary endpoints included incidence of chronic GVHD, organ toxicity, infection, relapse, non-relapse mortality (NRM), and overall survival (OS). Based on our local incidence rates, 45 patients/arm were needed to detect a hazard ratio of at most 1.7 for acute GVHD (no difference between two arms) using a one-sided non-inferiority log-rank test with 5% significance and 80% power. Results: We enrolled 101 patients; 5 were excluded due to change in eligibility or withdrawal of consent prior to HCT. Analysis is based on 96 patients who were randomized to receive Full-MTX (N=49) or Mini-MTX (N=47). Patient characteristics are described in the Table, and were generally balanced between the two groups . All patients in the Mini-MTX arm received their 3 planned doses of MTX; in the Full-MTX arm, 71% received all 4 doses, 26% received 3 doses, and 1 patient received 2 doses of MTX. There was no significant difference in cumulative incidence of grade 2-4 acute GVHD by day 100 between arms (28% Mini-MTX vs 27% Full-MTX, P=0.41) (Figure 1); however, there was a trend toward higher grade 3-4 acute GVHD in Mini-MTX arm (13% vs 4%, P=0.07). Mini-MTX recipients had lower incidence of severe WHO grade 3-4 mucositis (57% vs 82%, P=0.010), shorter duration of mucositis (median 11 vs 18 days, P&lt;0.001), and had faster engraftment of both neutrophils (median 15 vs 17 days, P&lt;0.001) and platelets (median 23 vs 27 days, P=0.023), with resultant shorter hospital stay (median 27 vs 31 days, P&lt;0.001). There were no significant differences between the two arms in any grade of chronic GVHD (36% vs 25%, P=0.09) or moderate-severe chronic GVHD at 1 year (23% vs 20%, P=0.14). There were also no differences in bacterial (P=0.18), viral (P=0.52) or fungal (P=0.74) infections. There were no significant differences in hepatotoxicity, but lower proportion of patients receiving Mini-MTX experienced nephrotoxicity (creatinine ≥3X upper limit of normal: 2% vs 26%, P&lt;0.001). Mini-MTX recipients also had less respiratory failure in the first 6 months (6% versus 22%, P=0.026). There was no difference in relapse between arms (2-year incidence 22% vs 21%, P=0.89), although Mini-MTX was associated with lower NRM (11% vs 25% at 2 years) (Figure 2), and non-significant but higher OS (70% vs 52% at 2 years; P=0.06). Conclusions: Compared to Full-MTX, a Mini-MTX regimen that incorporates MMF was associated with no difference in acute or chronic GVHD incidence and a more favorable toxicity profile, with faster engraftment, less mucositis, less organ toxicity, and lower NRM. The combination of Tac/mini-MTX/MMF is an acceptable alternative to Tac/MTX after myeloablative related and unrelated donor HCT. Figure 1 Figure 1. Disclosures Hamilton: Syndax: Membership on an entity's Board of Directors or advisory committees; Equilium: Membership on an entity's Board of Directors or advisory committees. Gerds: Imago: Research Funding; AbbVie: Consultancy; Constellation: Consultancy; Brystol Myers Squibb: Consultancy; Sierra Oncology: Consultancy; Incyte: Research Funding; PharmaEssentia: Consultancy; Novartis: Consultancy; Constellation: Research Funding; Krtos: Research Funding; CTI Biopharma: Research Funding; Accutate: Research Funding. Hill: Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding. Copelan: Amgen: Consultancy. Majhail: Anthem, Inc: Consultancy; Incyte Corporation: Consultancy.

Background:Systemic sclerosis (SSc) is a complex autoimmune connective tissue disease, characterized by autoimmune inflammatory microvascular damage with progressive loss of capillaries, fibrosis and ischemia of skin and internal organs. (1) Nailfold videocapillaroscopy (NVC) is a safe toll for early diagnosis of SSc, it identify morphological changes of vessel that are predictive for clinical disease progression and organ involvement.(2) About clinical complication the loss of bone mass and body composition abnormalities, particularly muscle mass and strength loss (sarcopenia), are recognized in advanced disease.(3)Objectives:To evaluated in SSc patients, the body composition and the bone status according to the microvascular condition, assessed and scored by nailfold videocapillaroscopy (NVC, “Early”,”Active”,”Late” patterns).Methods:Body composition and bone mineral density (BMD) were assessed by DEXA in 35 female SSc patients classified according to the 2013 EULAR/ACR criteria and 32 sex-matched healthy subjects. Clinical, laboratory, body composition and bone parameters were analysed according to the different NVC patterns. Means were compared by the Student’s t test or one way analysis of variance; medians were compared by the Kruskall Wallis test; and frequencies by the chi square test.Results:Higher prevalence of vertebral (26.4%vs 9.3%) and femoral (32.3% vs 9.3%) osteoporosis (OP) was found in SSc. Particularly SSc patients with “Late” NVC pattern showed a significantly higher prevalence of vertebral (p=0.018) and femoral OP (p=0.016). Regional assessment of bone mass (BM) in 7 different body areas showed a significant lower BMD only at the total spine (P=0.008) and femoral neck (p=0.027) in advanced microvascular damage. Patients with “Late” NVC pattern showed lower whole body lean mass (LM) compared to “Early” and “Active” NVC patterns, particularly at upper limbs. To note, in all body sites, BMD correlate with LM and BMC according to NVC pattern severity.Conclusion:SSc patients with most severe microvascular damage show a significantly altered body composition and bone status suggesting a strong link between microvascular failure and associated muscle/bone sufference.References:[1]Cutolo M et al. Expert Rev Clin Immunol 2019; 15(7):753-64[2]Cutolo M et al. Clin Rheumatol 2019; 38(9):2293-7[3]Corallo C et al. Rheumatol Int 2019;39(10):1767-75.Disclosure of Interests:Sabrina Paolino: None declared, Emanuele Gotelli: None declared, Andrea Casabella: None declared, Francesco Cattelan: None declared, Carlotta Schenone: None declared, Massimo Patanè: None declared, Greta Pacini: None declared, Carmen Pizzorni: None declared, Alberto Sulli Grant/research support from: Laboratori Baldacci, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Maurizio Cutolo Grant/research support from: Bristol-Myers Squibb, Actelion, Celgene, Consultant of: Bristol-Myers Squibb, Speakers bureau: Sigma-Alpha

Abstract Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP &gt; 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p&lt;0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV + PTLD) can be an aggressive, often deadly disease without any approved treatments. Current available treatments for EBV + PTLD may include cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). However, the long-term consequences of CHOP are poorly understood in immunocompromised transplant patients with cancer who may have different outcomes than immunocompetent cancer patients. This study reviewed and described the evidence for the long-term consequences associated with components of CHOP in transplant recipients. Methods: Potential long-term consequences of the components of CHOP were identified from the Children's Oncology Group Long-Term Follow-Up (COG LTFU) Guidelines. Abstracts were screened and eligibility was based on reporting data for the identified COG LTFU long-term consequences along with pre-specified criteria (English, systematic review, randomized controlled trial n&gt;100, observation study n&gt;100, case series n&gt;20). Relevant studies that met the criteria were extracted and synthesized; of these, studies were selected if they evaluated patients who received any type of transplantation as part of their primary cancer treatment. Results: A total of 7 studies met the pre-specified selection criteria, all of which evaluated patients with hematopoietic stem cell transplantation (HCT) and none assessed solid organ transplant (SOT). None of the studies focused specifically on the CHOP regimen or EBV + PTLD. Long-term consequences of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment reported in these HCT studies included: hormone deficiencies and infertility (n=4 studies), osteonecrosis (n=2), and health status and quality of life (QoL; n=1). Results from three studies suggested that cancer survivors who received alkylating agents experienced hormone deficiencies and those with a HCT had a high risk. One quantified this by showing that, compared with cancer survivors without a history of HCT (CS), cancer survivors with a history of HCT (CS-HCT) and a history of total body irradiation had significantly impaired follicle stimulating hormone (40.42 vs 9.39 mIU/ml, P&lt;0.001), Estradiol (15.09 vs 25.13 pg/ml, P=0.04), Inhibin B (10.61 vs 32.92 pg/ml, P=0.003), anti-Müllerian hormone (0.01 vs 1.28 ng/ml, P&lt;0.001), antral follicle count (0.71 vs 17.78, P&lt;0.001) and ovarian volume (1.82 vs 8.21 ml, P&lt;0.001). In one study on the risk of osteonecrosis, the CS-HCT group had a significantly increased risk of developing osteonecrosis compared to the CS group treated with chemotherapy (6.8% vs 1.4%, respectively); cumulative incidence of osteonecrosis was 3.8% in the CS group for a steroid dose &gt;5,835 mg/m 2 and 23.8% in the CS-HCT group for a post-transplant steroid dose &gt;2,055 mg/m 2; and patients developed symptomatic osteonecrosis within a median of 2.4 years in the CS group with chemotherapy and 0.9 years after the first transplant in the CS-HCT group. A second study showed the rate ratio (RR) of osteonecrosis compared with a sibling comparison group was highest among the CS-HCT for acute lymphoblastic leukemia, acute myelogenous leukemia, and chronic myelogenous leukemia (RR = 26.9, 66.5, and 93.1, respectively; P&lt;0.001 for all). One study reported that childhood acute leukemia survivors treated with HCT with preparative regimen with either busulfan-cyclophosphamide or total body irradiation/cyclophosphamide had a significantly lower QoL short-form (SF)-36 mental and physical composite scores in both treatment groups compared with norms. Conclusions: Since only a small number of studies (7) of long-term consequences in transplant recipients were identified and none were seen in patients with EBV + PTLD or in SOT recipients, more research is needed to evaluate adverse consequences of CHOP or its components in EBV + PTLD, especially in SOT patients where no studies were found. Results from this review suggest that immunocompromised HCT recipients who were cancer survivors are significantly more impaired by long-term consequences (hormone deficiencies and infertility, osteonecrosis, and QoL) of alkylating agents (eg, cyclophosphamide) and corticosteroids as primary treatment compared with other cancer survivors without HCT. Disclosures Watson: Atara Biotherapeutics: Current Employment, Current holder of individual stocks in a privately-held company. Gadikota: Maple Health Group: Current Employment. Barlev: Atara Biotherapeutics: Current Employment. Beckerman: Maple Health Group: Current Employment.

Abstract Introduction: Light chain (AL) amyloidosis is a plasma cell disease characterized by the deposition of insoluble amyloid fibrils into organs leading to organ dysfunction and death. The analysis at 6 and 12 months of the ANDROMEDA study (NCT03201965) showed that the addition of subcutaneous (SC) daratumumab to the standard of care combination of bortezomib, cyclophosphamide, and dexamethasone (VCd) was superior to VCd alone, with higher rates of hematologic complete response (CR) and an acceptable safety profile. Based on these findings daratumumab with VCd (D-VCd) was approved for newly diagnosed AL amyloidosis in January 2021 in the US and June 2021 in the EU. Here, we present data from the analysis at 18 months of the ANDROMEDA study. Methods: ANDROMEDA is a randomized, open-label, active-controlled phase 3 study including patients with newly diagnosed AL amyloidosis with measurable hematologic disease, ≥1 involved organ, cardiac stage I-IIIA, estimated glomerular filtration rate ≥20 mL/min, and absence of symptomatic multiple myeloma. Patients were randomized (1:1) to D-VCd or VCd for 6 28-day cycles. Bortezomib (1.3 mg/m 2), cyclophosphamide (300 mg/m 2 up to 500 mg per week), and dexamethasone (20-40 mg) were administered weekly. SC daratumumab (1800 mg co-formulated with recombinant human hyaluronidase PH20 in 15 mL) was administered once weekly in cycles 1 and 2 and every 2 weeks in cycles 3 to 6. Patients in the D-VCd arm received only SC daratumumab after cycle 6, every 4 weeks (up to a total of 24 cycles from first dose). The primary endpoint was overall (ie, at any time) hematologic CR rate, defined here as normalization of free light chain (FLC) levels and ratio (FLCr) and negative serum and urine immunofixation, confirmed at a subsequent visit; normalization of uninvolved FLC level and FLCr were not required if involved FLC was lower than the upper limit of normal. Secondary endpoints included major organ deterioration progression-free survival (PFS), organ response rate, time to hematologic response, overall survival (OS), and safety. Results: A total of 388 patients were randomized to receive D-VCd (N=195) or VCd alone (N=193). At the May 2021 clinical cutoff, the median duration of treatment for D-VCd and VCd arms was 21.3 and 5.3 months, respectively. In the D-VCd arm, 149 patients (77.2%) received daratumumab monotherapy after completing 6 cycles of D-VCd; of those, 17 (11.4%) were still receiving treatment. The rates of deep hematological responses favored the D-VCd treatment arm (Table). At a median follow-up of 25.8 months, the rate of hematologic CR was significantly higher in the D-VCd arm vs the VCd arm (59.5% vs 19.2%; odds ratio [95% confidence interval (CI)], 6.03 [3.80-9.58]; P&lt;0.0001). Similarly, more patients achieved a very good partial response or better (≥VGPR) (D-VCd vs VCd, 79.0% vs 50.3%; odds ratio [95% CI], 3.74 [2.39-5.86]; P&lt;0.0001). Among patients who responded, the median time from randomization to ≥VGPR was shorter in the D-VCd arm (0.56 months) vs the VCd arm (0.82 months). Comparable to the cardiac response analysis at 6 months (D-VCd vs VCd, 42% vs 22%), greater cardiac response rates were achieved with D-VCd compared with VCd at 18 months (53% vs 24%). Similarly, renal response rates remained superior with D-VCd vs VCd alone at 18 months (58% vs 26% compared with 6 months [54% vs 27%]). A total of 79 deaths occurred (D-VCd, N=34; VCd, N=45). In the D-VCd arm, only 1 additional grade 3/4 treatment-emergent adverse event occurred over 18 months vs 12 months (119 [61.7%] vs 118 [61.1%] patients) and no additional infusion-related reactions were reported. OS will be analyzed and major organ deterioration PFS will be updated after approximately 200 events have occurred. Conclusions: These results demonstrate the sustained clinical benefits of D-VCd vs VCd in terms of hematologic and organ responses with longer follow-up, although it should be noted that many patients in the D-VCd arm received daratumumab monotherapy following 6 cycles of D-VCd, while patients in the VCd group stopped study treatment. Nevertheless, the study continues to support the use of D-VCd over VCd alone in patients with newly diagnosed AL amyloidosis. Following its recent approval, D-VCd represents a new SOC for patients with AL amyloidosis. Figure 1 Figure 1. Disclosures Comenzo: Prothena Biosciences: Consultancy, Research Funding; Takeda: Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Caelum: Consultancy, Research Funding; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Patents & Royalties: WO2016187546A1, Research Funding. Palladini: Pfizer: Honoraria; Siemens: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Kastritis: Pfizer: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria. Minnema: Janssen: Consultancy; BMS: Consultancy; Kite/Gilead: Consultancy; Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy. Wechalekar: Amgen: Research Funding; Janssen: Consultancy; Takeda: Honoraria; Celgene: Honoraria; Caelum Biosciences: Other: Clinical Trial Funding; Alexion, AstraZeneca Rare Disease: Consultancy. Jaccard: Pfizer: Honoraria; Abbvie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees. Dispenzieri: Janssen: Consultancy, Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Lee: Karyopharm: Consultancy; Celgene: Consultancy; Takeda Pharmaceuticals: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Sanofi: Consultancy; Genentech: Consultancy; Legend Biotech: Consultancy; Janssen: Consultancy, Research Funding; Oncopetides: Consultancy; Bristol Myers Squibb: Consultancy; Regeneron: Research Funding. Sanchorawala: Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria; Proclara: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Research Funding. Gibbs: AbbVie: Consultancy; Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria. Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Venner: BMS: Honoraria; Amgen: Research Funding; Celgene: Research Funding; Amgen: Honoraria; Takeda: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria; Takeda: Honoraria, Other: Travel grants; Prothena: Honoraria, Other: Travel grants; Sanofi: Research Funding. Suzuki: Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Kim: BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Cibeira: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees. Beksac: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Libby: Genentech: Research Funding; BMS: Research Funding; GSK: Research Funding; Janssen: Consultancy, Research Funding. Valent: Caelum Biosciences: Other: Clinical Trial Funding; Celgene Corporation: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Amgen: Speakers Bureau. Hungria: Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel ; Abbvie: Honoraria; Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria. Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Rosenzweig: Janssen: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Akcea: Speakers Bureau; Takeda: Speakers Bureau; Onocopeptides: Speakers Bureau. Bumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Tran: Janssen: Current Employment, Current equity holder in publicly-traded company. Qin: Janssen: Current Employment. Khaled: Jazz: Honoraria; Astellas: Honoraria; Alexion: Honoraria, Speakers Bureau; Omeros: Honoraria; Janssen: Current Employment. Vermeulen: Janssen: Current Employment, Current equity holder in publicly-traded company.

Abstract Background: Despite recent improvements, myeloma is still incurable. There is need to add new therapeutic tools. The combination of the proteasome inhibitor (PI) Bortezomib, an alkylator (Cyclophosphamide or Melphalan) and Dexamethasone (Dex) /Prednisone is a widely used first-line therapy. Most patients achieve a rapid response within the first two cycles. The lack of a deep response to the bortezomib-based therapy predicts an inferior outcome, a poor response to newer PIs and limited therapeutic options. Different studies highlighted the role of the PD1/PDL1 pathway in myeloma immune escape and progression. The expression of PDL1 by myeloma cells is higher in relapsed or refractory disease and on minimal residual disease cells. At least one preclinical study showed that the binding of PD1 to PDL1 expressed by the myeloma cells leads to a reverse signal that induces resistance to bortezomib and melphalan. Also, Bortezomib is known to enhance anti-myeloma immune response by different mechanisms, including stimulating myeloma cell apoptosis, sensitizing myeloma cells to natural killer cell mediated killing and enhancing antigen presentation by dendritic cells. This suggests a mutual potentiation between Pembrolizumab and Cyclophosphamide, Bortezomib and Dex (CyBorD). An early immune-based intervention is likely more beneficial. With time and disease progression, the host is more immune-compromised and the disease is more refractory with redundant escape mechanisms. The benefits of early intervention are carefully weighed against the potential risks and other available therapeutic options. The adaptive design of this CMRG-006 trial is meant to select the population with the highest need for treatment improvement while still in the early phase of therapy. We expect the combination of Pembrolizumab and CyBorD to be more effective and well tolerated. Design and Methods: Phase 2A, pilot study. Non-transplant eligible newly diagnosed myeloma patients (NTE-NDMM) will start their standard nine cycles of CyBorD (Cyclophosphamide 300 mg/m 2 PO, Bortezomib 1.5 mg/m 2 SC, and Dex 40 mg PO, all given on days 1, 8, 15 and 22 of 28-day cycle). Patients not having primary disease progression and achieving less than Very Good Partial Response (VGPR) after 2 cycles will be screened for this study during cycle 3. Eligible patients will receive Pembrolizumab 200 mg IV every 3 weeks starting with day 1 of cycle 4 (P-CyBorD). After completion of cycle nine of CyBorD, Pembrolizumab will be administered as a single agent for up to total of 35 doses. The objectives are to evaluate the efficacy and tolerability of P-CyBorD. The key inclusion criteria are having a NTE-NDMM with a measurable disease; no primary progressive disease and not achieving VGPR after two cycles of CyBorD; adequate performance status; and adequate organ functions. The key exclusion criteria include previous exposure to anti-PD1 therapy, intolerance to CyBorD, adverse cardiac history, pulmonary disease, central nervous system disease, congenital or acquired immune suppression, and AL amyloidosis. S ample Size: A maximum of 20 patients will be enrolled to ensure 16 or more patients evaluable for response. Patients with less than VGPR after two cycles of CyBorD have ≤20% probability to achieve ≥VGPR after cycle 9. With the addition of Pembrolizumab, a minimal clinically important difference (MCID) of 10% would be meaningful, and a 50% response rate (≥VGPR) in 16 evaluable patients will be statistically significant. This study is currently recruiting. Clinicaltrials.gov #: NCT04258683. Disclosures Kotb: Amgen: Honoraria; BMS: Honoraria; Merck: Honoraria, Research Funding; Karyopharm: Current holder of individual stocks in a privately-held company; Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Sanofi: Honoraria, Research Funding; Akcea: Honoraria; Pfizer: Honoraria. Othman: Takeda: Honoraria; Roche: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Reece: Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria; Millennium: Research Funding; BMS: Honoraria, Research Funding; Karyopharm: Consultancy, Research Funding; Amgen: Consultancy, Honoraria; GSK: Honoraria.

Background: Blockade of PD-1/PD-L1 pathways enhances anti-leukemic responses in pre-clinical studies. PD1 inhibition alone had limited clinical activity in AML. CLTA4 inhibition demonstrated encouraging single-agent CR's in postASCT patients (pts), especially for extra-medullary (EMD) relapses (Davis M et al, NEJM 2016). AZA+Nivo up-regulated CTLA4 on bone marrow (BM) CD8 cells in both responders (R) and non-responders (NR) on treatment (Daver N, et al, Cancer Discovery 2019), suggesting a triplet of AZA+Nivo+Ipi may abrogate PD-1 mediated resistance. Methods: Pts were eligible for the AZA+Nivo (cohort 1, n=59) if they had R/R AML, ECOG ≤ 2, and adequate organ function. This cohort has completed enrollment. A cohort of AZA+Nivo+Ipi was opened (cohort 2), with the same eligibility criteria. Ipi 1mg/kg Q6 weeks was added to the established AZA+Nivo schedule and found to be safe in a lead-in dose cohort. Results: Cohort 1 (59 R/R AML) pts were treated with Aza+Nivo (Daver et al., Cancer Discovery 2019). CR/CRi and OS were superior to contemporary historic HMA-based clinical trial controls at MDACC (Table 1). Pts with low pretherapy BM blasts (&lt;20% BM blasts) and early salvage (salvage 1) had encouraging median (med) OS 11 months (mos), indicating progressive T-cell exhaustion with multiple relapses. Importantly, on 40-parametric CYTOF assessment, Rs to AZA+Nivo had a higher frequency of pre-therapy BMA CD3+ and CD8+ cells compared with NRs (optimal CD3+ cutoff 13.2%: ORR 56% versus 23%), suggesting pre-existing BM T-cell infiltration may be a pre-requisite of response to PD1 based therapies, as PD1 inhibitors have limited ability to mobilize peripheral T-cells (Fig 1A). The pre-therapy BM CD4 polyfunctional strength index (PSI) defined as percentage of polyfunctional cells in the sample, multiplied by the intensities of the secreted cytokines, assessed by single cell cytokine analysis was dramatically different between Rs and NRs (P=0.03). Single-cell RNA-seq on 113,394 BM cells collected longitudinally from 8 pts (3R, 2 stable disease (SD), 3NR) demonstrated that deletion 7/7q, LSC signature enrichment, and activated metabolic/oxidative pathways, were associated with resistance to AZA+Nivo (Abbas H et al, ASH 2020). Importantly, AZA+Nivo induced novel and expanded T cell clonotypes, almost exclusively in Rs. Cohort 2 (36 R/R AML) pts were treated with Aza+Nivo+Ipi, with med age 67 years (25-83), secondary AML (50%), ELN unfavorable cytogenetics (67%), TP53 (36%), med salvage 2 (range, 1-3), and prior HMA based therapies in 67%. All 36 pts are evaluable. Per ELN 2017, CR/CRi was noted in 7 (19%) and PR in 1 (3%). Five (14%) pts had durable stable disease (SD) (defined as absence of CR, CRi, PR; with SD on treatment for ≥6 months), and 23 (64%) were NRs (Table 1). Interestingly, 4 pts with EMD were enrolled and 3 had CR/PR [med DOR 8 (5-13) mos]. The 4- and 8-week mortalities were 0 and 6%, respectively. Grade 3/4 immune toxicities noted in 8 pts (19%), including rash, pneumonitis, colitis, pyrexia. One pt required ICU stay, but no deaths attributed to immune toxicity. Other grade ≥2 toxicities were as expected for R/R AML population and were mostly infections/febrile neutropenia. Converse to AZA+Nivo, on CYTOF, R did not have a higher frequency of pre-therapy BM CD8+ infiltration, but did have progressive BM CD8+ infiltration on therapy, compared with NRs, demonstrating that Ipi (unlike Nivo) may be able to mobilize peripheral T-cells to the BM (Fig 1B). Expansion of a cluster of antigen experienced CD8+ T cells was associated with response (Fig 1B). In all salvage the med OS with Aza+Ipi+Nivo versus Aza+Nivo versus contemporary HMA-controls in R/R AML, were 7.6, 5.9, and 4.6 mos, respectively (P=0.01) (Fig 1C). The 1-year OS in R/R AML pts with AZA+Nivo+Ipi was 25%. The med OS with Aza+Ipi+Nivo was comparable to med OS 6-8 mos reported with HMA+VEN salvage in numerous studies. Conclusion: The OS with Aza+Nivo+Ipi was modestly improved over AZA+Nivo and HMA-controls in R/R AML. Single-cell cytokine profiling and single-cell RNA-seq from Aza+Nivo showed striking pre- and on-treatment differences among R and NR not only in T-cell fitness and clonality, but also in the tumor microenvironment. Ipi may be uniquely able to mobilize peripheral T-cell to BM and EMD. This underappreciated immune diversity suggests a critical need for biomarker-based trials (as we are doing with molecular therapies) for immunotherapies in AML. Disclosures Daver: 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; 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. Garcia-Manero:Merck: Research Funding; Onconova: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva:Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; AstraZeneca: Research Funding; Ascentage: 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; Sanofi: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astellas: Research Funding; Cellenkos: Research Funding; Amgen: Research Funding; Genentech: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Celgene: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Ascentage: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria, Research Funding. DiNardo:AbbVie: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy. Borthakur:Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; Curio Science LLC: Consultancy; FTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; DAVA Oncology: Honoraria; Incyte Corporation: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding; SagerStrong Foundation: Other: Grant Support; Plexxikon: Research Funding; LFB Biotechnologies: Honoraria; Blueprint Medicines: Honoraria; Samus Therapeutics: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; MustangBio: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding. Jabbour:Takeda: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Yilmaz:Pint Pharma: Honoraria; Pfizer: Research Funding; Daicho Sankyo: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding. Andreeff:Amgen: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Ravandi:Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding. Allison:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAB: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Kantarjian:Cyclacel: Research Funding; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astex: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Sharma:Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Nivolumab and Ipilimumab based combinations for AML, will be discussed. These agents do not have an on label indication for AML at this time.

Abstract Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with &gt;20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,; attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% &gt;65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del; with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR; HR: 0.44; p&lt;0.001; see Figure). The PFS was significantly better for IR in patients with IGHV unmutated CLL (HR: 0.41; p&lt;0.001), but not for patients with IGHV mutated CLL at this follow-up (HR: 0.66; p=0.179). There was no difference in overall survival between the two arms (HR: 1.01; p=0.956) with a total of 29 deaths in FCR arm (including 4 from CLL, 3 Richter's [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the IR arm (including 3 CLL, 1 RT, 0 AML/MDS, 3 COVID-19 and 8 cardiac/sudden). Second line treatment was initiated for 59 patients after FCR (including 38 BTKi, 7 venetoclax+R [venR], 4 BendamustineR [BR] and 3 CHOP-R [RT]) and 21 after IR (including 7 FCR, 5 venR, 1 BR, 1 CHOP-R [RT], 1 ABVD [Hodgkin's]). Overall, 88.1% of patients have received targeted therapies for CLL progression after FCR. The overall survival with FCR in FLAIR is significantly improved compared to FCR in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, the same Centres and an identical FCR schedule, but were conducted prior to widespread availability of targeted therapies in the relapse (recruited between 2009 and 2012). The 4 year overall survival for FCR in FLAIR was 94.5% compared to 84.2% for FCR between 2009 and 2012. SAEs were reported in 53.7% of patients on FCR and 53.4% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 27.1%; blood and lymphatic in 19.8% vs 10.7%; and cardiac in 1.1% vs 8.3%. With current follow-up, there were 10 sudden or cardiac deaths: 8 IR and 2 FCR. Further analysis indicated that 7 of the 8 cardiac or sudden deaths in the IR arm had a history of hypertension or cardiac disease (further detailed in additional abstract; Munir et al.). Neither of the sudden deaths in the FCR arm had a prior cardiac or hypertensive history or were on cardiac or anti-hypertensive treatment. There were 6 cases of secondary MDS/AML in the FCR arm and 1 in the IR arm. Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. Figure 1 Figure 1. Disclosures Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; SOBI: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria; Janssen: Honoraria; AbbVie; Takeda: Other: Conference support; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ROCHE: Research Funding; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria.

Abstract Abstract 2951 Introduction: Everolimus (RAD001) is an inhibitor of MTORC1, a component of the Akt-MTOR pathway which regulates growth and survival of lymphoplasmacytic cells in Waldenstrom's Macroglobulinemia (WM). Everolimus also exhibits activity in WM patients with relapsed/refractory disease (Ghobrial et al, JCO 2010; 28 :1408–14). We therefore initiated this multicenter, prospective study to delineate the efficacy and tolerability of Everolimus as primary therapy in WM. Patients and Methods: WM patients with symptomatic disease, adequate organ function, who were not previously treated, and who did not have symptomatic hyperviscosity were eligible for this study. Intended therapy consisted of 10 mg of oral Everolimus administered daily, with sequential dose de-escalation to 7.5 mg daily, 5 mg daily, and 5 mg every other day permitted for toxicity. Patients were treated until progression or unacceptable toxicity. Patients were encouraged to use 5 mL of an oral dexamethasone solution (0.5 mg/5mL) to swish and spit up to 4 times daily for prevention of oral ulcerations associated with Everolimus. Study participants were assessed monthly for the first 3 months, and thereafter every 3 months which included a physical examination, complete blood counts, chemistries, and serum IgM monitoring. Bone marrow biopsies and aspirations were performed at baseline, at months 6 and 12, and as required for response assessment. Results: Thirty-three patients were enrolled on this prospective, multicenter study and are evaluable for response. Median baseline characteristics for all patients are as follows: Age 62 (range 41–80 years); Hematocrit 31.3% (range 24.5–45.7%); Hemoglobin 10.8 (range 7.8–15.7 g/dL); serum IgM 4, 440 (range 959–10, 256 mg/dL), with 23 (69.7%) patients demonstrating an IgM level ≥3, 000 mg/dL; serum M-protein 2.60 g/dL (range 0.31–5.31 g/dL), B2M 3.0 mg/L (1.6–6.7 mg/L). The median baseline bone marrow disease burden was 70% (range 7.5–95%), and 21 patients (63.6%) demonstrated adenopathy or splenomegaly by CT scans at baseline. At best response, serum IgM levels declined from 4, 440 to 1, 925 (p<0.0001), and serum M-protein decreased from 2.60 to 1.50 g/dL (p<0.0001). The median time to best serum IgM response was 3 months (range 0.6–15 months). Median hematocrit and hemoglobin levels declined modestly from 31.3% to 30.6% (p=0.057) and 10.8 to 10.4 g/dL (p= 0.1059), respectively. Twenty-two patients are evaluable for response by both bone marrow biopsy and IgM level at 6 months, at which time bone marrow disease burden remained unchanged with a median of 65% involvement (range 10–95%; p=0.3595). The best overall response rate utilizing consensus criteria was 66.7% (14 Partial Responses, 8 Minor Responses, and 11 Stable Disease), for a major response rate of 42.4%. However, discordance between serum IgM levels upon which consensus criteria for response are based, and bone marrow disease response were common and complicated response assessment. At 6 month assessments, 10 of 22 (45.5%) patients for whom both serum IgM and bone marrow assessments were performed, discordance between serum IgM levels and bone marrow disease involvement were observed. Among these patients, 2 had no change, and 8 had increased bone marrow disease involvement despite decreases in serum IgM levels. Grade ≥2 hematologic and non-hematologic toxicities possibly, probably or definitively associated with Everolimus included anemia (n=8, 24%), thrombocytopenia (n=5, 15%), neutropenia (n=5, 15%), hyperglycemia (n=2, 6%), oral ulcerations (n=7, 21%), pneumonitis (n=5, 15%), fatigue (n=4, 12%), rash (n=2, 6%), and cellulitis (n=2, 6%). With a median follow-up of 9 months (range 0–18 months), 15 patients remain on study. Reasons for study discontinuation included non-response or disease progression (n=11), unacceptable toxicity (n=6, including 5 for pneumonitis and 1 for neutropenia), and loss of follow-up (n=1). Conclusions: Everolimus is active in the primary therapy of WM, with rapid reductions observed in serum IgM levels in most patients. Serum IgM discordance to underlying bone marrow disease burden is common, and serial bone marrow assessments are important for response monitoring in WM patients receiving Everolimus. Disclosures: Treon: Millennium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria. Eradat:Millennium: Speakers Bureau; Genentech, A Roche Company: Speakers Bureau. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Speakers Bureau; Cephalon: Speakers Bureau; Millennium: Speakers Bureau. Anderson:Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Equity Ownership. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction Internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations (m) in FLT3 occur in about 30% of the patients (pts) with newly diagnosed AML. FLT3m are associated with a higher risk of relapse and inferior overall survival (OS). Outcomes remain poor in older/unfit pts with FLT3m AML; with expected median OS of 8-12 months with combinations of low intensity chemotherapy (LIC) with FLT3 inhibitors (FLT3i) or with venetoclax (VEN) [Ohanian et al. AJH, 2018; Konopleva et. al. ASH, 2020). In this current study, our goal was to analyze outcomes in newly diagnosed older/unfit pts with FLT3m AML treated with LIC + FLT3i (doublet regimen) vs. LIC + VEN + FLT3i (triplet regimen) on clinical trials at our institution. Methods We identified 87 older or unfit adult pts with newly diagnosed FLT3-m (ITD and/or TKD) AML treated on FLT3i-based LIC clinical trials between 6/2012-3/2021 (Figure 1). All pts had at least two or more bone marrow (BM) assessments including at baseline, end of the first cycle of therapy, and/or later during therapy. MRD assessments were performed by in-house multicolor flow cytometry (MFC) (sensitivity of 10 -4) and multiplex polymerase chain reaction (PCR) (sensitivity of 10 -2-10 -3) for ITD and D835. Results Of the 87 pts with newly diagnosed FLT3m AML, 60 (69%) and 27 (31%) received doublet and triplet regimens, respectively. Baseline clinical characteristics, including age, WBC, organ function, cytogenetics, ECOG PS and molecular aberrations, were generally similar between patients treated with doublet vs triplet (Table 1). Of the 60 pts who received LIC (HMA 83%, LDAC-based 17%) + FLT3i doublets, 44 (73%) received a first-generation FLT3i (36 sorafenib, 8 midostaurin) and 16 (27%) second-generation FLT3i (quizartinib). Our analysis showed no statistically significant difference in CR/CRi and FLT3-PCR or MFC negativity rates in patients treated with first or second-generation FLT3i based LIC doublets (Figure 2A). There was no statistically significant OS difference between patients treated with first- vs. second-generation FLT3i doublet regimens (P=0.19). In the triplet group, 12 (44%), 10 (37%), 4 (15%) and 1 (4%) pts received gilteritinib, sorafenib, quizartinib and midostaurin combined with HMA-VEN, respectively. Triplet HMA-VEN-FLT3i was associated with significantly higher CR/CRi (93% vs 70%, P=0.02), FLT3-PCR (96% vs 54%, P&lt;0.01), and MFC negativity (83% vs 38%, P&lt;0.01) rates than doublet regimens (Figure 2B). The 60-day mortality was similar between triplet vs doublet; 7% (n=2) vs 10% (n=6), respectively. The median follow-up time was shorter in the triplet arm than in the doublet arm: 12 vs. 63 months (p&lt;0.01). The median OS was better with the HMA-VEN-FLT3i triplets compared with the HMA-FLT3i doublets (not reached (NR) vs 9.5 months, P&lt;0.01). The median OS in patients treated with triplets vs second-generation FLT3i doublets vs first-generation FLT3i doublets was NR vs 15.7 vs 8.7 months (P&lt;0.01) (Figure 3). 8 (29%) and 6 (10%) pts went to SCT after triplet vs doublet, respectively. A landmark analysis at 4-month (n=50) demonstrated that pts who received ASCT in CR1 had superior OS than patients who did not receive ASCT in CR1 ( NR vs 19 months, P=0.01). Conclusions First- and second-generation FLT3i-based doublet regimens were associated with comparable response rates and survival of 9-16 months in older adults with newly diagnosed FLT3 mutated AML. The HMA-VEN-FLT3i combination significantly improved CR/CRi rates, FLT3-PCR and MFC MRD rates as well as OS, without increasing early mortality in this retrospective analysis. These findings suggest the need for prospective validation of HMA-VEN-FLT3i triplets in older/unfit AML. Figure 1 Figure 1. Disclosures Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Kantarjian: AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Aptitude Health: Honoraria; Astellas Health: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Precision Biosciences: Honoraria; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Short: AstraZeneca: Consultancy; Astellas: Research Funding; NGMBio: Consultancy; Takeda Oncology: Consultancy, Research Funding; Novartis: Honoraria; Jazz Pharmaceuticals: Consultancy; Amgen: Consultancy, Honoraria. Konopleva: Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; KisoJi: Research Funding; Stemline Therapeutics: Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Cellectis: Other: grant support; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; AstraZeneca: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support. Kadia: AstraZeneca: Other; Astellas: 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. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Foghorn: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding. Borthakur: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Protagonist: Consultancy; University of Texas MD Anderson Cancer Center: Current Employment; Astex: Research Funding; GSK: Consultancy. Pemmaraju: LFB Biotechnologies: Consultancy; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Clearview Healthcare Partners: Consultancy; Affymetrix: Consultancy, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Samus: Other, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Sager Strong Foundation: Other; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; Roche Diagnostics: Consultancy; DAVA Oncology: Consultancy; MustangBio: Consultancy, Other; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Issa: Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding. Jain: Bristol Myers Squibb: Honoraria, Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; Beigene: Honoraria; Incyte: Research Funding; Aprea Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Janssen: Honoraria; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Loghavi: Abbvie: Current equity holder in publicly-traded company; Curio Sciences: Honoraria; Gerson Lehrman Group: Consultancy; Guidepoint: Consultancy; Peerview: Honoraria; Qualworld: Consultancy. Andreeff: Medicxi: Consultancy; Senti-Bio: Consultancy; Amgen: Research Funding; Syndax: Consultancy; Oxford Biomedica UK: Research Funding; ONO Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Aptose: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Breast Cancer Research Foundation: Research Funding; Glycomimetics: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company. Ravandi: AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Xencor: Honoraria, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Daver: Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Novimmune: Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Astellas: Consultancy, Research Funding; Hanmi: Research Funding; 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.

Abstract Background: The innate capacity of natural killer (NK) cells to kill tumor targets has been translated into cancer immunotherapy. GDA-201 represents a novel class of metabolically enhanced ex-vivo expanded allogeneic NK cells with acquired capacity for improved organ trafficking, augmented resistance against exhaustion and in vivo proliferation. We conducted a phase 1 study of GDA-201 in combination with rituximab (NCT03019666) in patients (pts) with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) and report 2-year outcomes and cytokine biomarkers associated with survival. Methods: Following donor apheresis, CD3-depleted mononuclear cells were cultured for 14-16 days with NAM (5mM) and IL-15 (20ng/ml), resulting in a 40-fold increase in NK cells and increased expression of CD62L from 2.9% to 21%. GDA-201 contained ~98% NK cells, and CD3 content was low at &lt;0.5% (&lt;5x10 5/kg/dose). Pts with R/R B-cell NHL received lymphodepleting (LD) chemotherapy with cyclophosphamide (400mg/m 2 IV x 3d) and fludarabine (30 mg/m 2 /d IV x 3d), followed by GDA-201 (days 0 and 2) and low-dose IL-2 (6 million units sc x 3 doses at days 0,2,4). Pts also received rituximab (375 mg/m 2) x 3 weekly infusions (days -8,+1 and +11). Results: 20 NHL pts were enrolled: 1 mantle cell, 10 follicular [FL], 9 diffuse large cell lymphoma [DLBCL]) 16 pts received the maximum target dose (median dose 12.4 (range 2.0-26.0) x 10 7 GDA cells/kg. The most common grade 3/4 adverse events were thrombocytopenia (n=9), hypertension (n=9), neutropenia (n=4), febrile neutropenia (n=4), and anemia (n=3). There were no CRS, neurotoxic events, GVHD or marrow aplasia. One patient died of E-coli sepsis. Among 19 NHL pts evaluable for response, the median age 64 (range 48-83 years), most were multiply relapsed (median lines of therapy 3 (range 1-8) or refractory (n=3) and 87% had advanced stage. Thirteen patients (65%) had complete response (CR), 1 pt had partial response (PR) with the best overall response rate of 74%. Two of these patients underwent allogeneic hematopoietic stem cell transplantation and are doing well at 3 years post GDA-201. One patient underwent autologous HSCT and is well at 18 months. Four NHL patients underwent re-treatment with GDA-201 without LD chemotherapy; 2 patients (FL and transformed DLBCL) had further deepening of response from PR to CR. Median duration of response was 16 months (range 5-36 months). At median follow-up of 11 months (range 1-36 months), progression-free survival (PFS) at 1 and 2 years was estimated at 50% (95% CI 27-69%) and 35% (95% CI 14-58%). OS at 2 years was 78% (95%CI 51-91%). Flow cytometry confirmed the persistence of donor NAM-NK in peripheral blood up to day 7-14 (day 7 range 2-92% GDA 201 cells), as well as enhanced in vivo proliferation (median Ki67 99%). Lymphopenia following LD chemotherapy is known to result in a surge of endogenous cytokines IL7 and IL15. The median IL-7 plasma levels at baseline, day 7 and 14 were 5.12pg/dl (range 1.7-16), 11.7pg/dl (range 3.5-20) and 9.66 pg/dl (5.4-18.5). Increased delta of IL7 between days 14 and day 0 positively correlated with survival. Delta IL7 serum level increase by each 1 pg/dl was associated with improved 1-year PFS with HR 0.63 (95% CI; 0.41-0.96); p=0.03) and 1-year OS with HR 0.42 (95%CI 0.40-0.85; p=0.02). Conclusions: Cellular therapy using GDA-201 with rituximab is well-tolerated, and demonstrated significant clinical activity in heavily pre-treated pts with advanced NHL. A cytokine surge following LD chemotherapy appears to be associated with clinical activity. Phase II studies in aggressive and indolent NHL cohorts are planned. Disclosures Bachanova: FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; KaryoPharma: Membership on an entity's Board of Directors or advisory committees. Cichocki: Fate Therapeutics, Inc: Patents & Royalties, Research Funding; Gamida Cell: Research Funding. McKenna: Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Other: all manufacturing of cell therapy products for clinical trials; Intima: Other: all manufacturing of cell therapy products for clinical trials; Gamida: Other: all manufacturing of cell therapy products for clinical trials; Magenta: Other: all manufacturing of cell therapy products for clinical trials. Janakiram: FATE, Nektar Therapeutics: Research Funding; Bristol Meyer Squibb, Kyowa Kirin, ADCT Therapeutics: Honoraria. Grzywacz: Gamida: Research Funding. Simantov: Gamida: Current Employment. Lodie: Gamida Cell: Current holder of stock options in a privately-held company, Ended employment in the past 24 months. Miller: Fate Therapeutics, Inc: Consultancy, Patents & Royalties, Research Funding; GT Biopharma: Consultancy, Patents & Royalties, Research Funding; Vycellix: Consultancy; ONK Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Magenta: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Wugen: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: IL-2, Rituximab both in combination with GDA-201

The pandemic of COVID-19 has afflicted every individual and has initiated a cascade of directly or indirectly involved events in precipitating mental health issues. The human species is a wanderer and hunter-gatherer by nature, and physical social distancing and nationwide lockdown have confined an individual to physical isolation. The present review article was conceived to address psychosocial and other issues and their aetiology related to the current pandemic of COVID-19. The elderly age group has most suffered the wrath of SARS-CoV-2, and social isolation as a preventive measure may further induce mental health issues. Animal model studies have demonstrated an inappropriate interacting endogenous neurotransmitter milieu of dopamine, serotonin, glutamate, and opioids, induced by social isolation that could probably lead to observable phenomena of deviant psychosocial behavior. Conflicting and manipulated information related to COVID-19 on social media has also been recognized as a global threat. Psychological stress during the current pandemic in frontline health care workers, migrant workers, children, and adolescents is also a serious concern. Mental health issues in the current situation could also be induced by being quarantined, uncertainty in business, jobs, economy, hampered academic activities, increased screen time on social media, and domestic violence incidences. The gravity of mental health issues associated with the pandemic of COVID-19 should be identified at the earliest. Mental health organization dedicated to current and future pandemics should be established along with Government policies addressing psychological issues to prevent and treat mental health issues need to be developed. References World Health Organization (WHO) Coronavirus Disease (COVID-19) Dashboard. 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Abstract 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 & Objective: Residual insulin secretion (IS) from surviving beta cells (BC) can be hampered by a stressful T1D islet microenvironment (e.g. cytokines - Cyt, increased glucose - G). We evaluated the effects of Cyt and Cyt+G on isolated human islet (HI) IS, assessed if BC dysfunction is reversible, and explored the associated molecular mechanisms. Methods: HI from five nondiabetic organ donors (age, 78±15 yrs; BMI, 24.4±3.8 kg/m2) were exposed to Cyt (50 U/ml IL-1β + 1000 U/ml IFN-γ) at 5.5 or 11.1 mM G for 24h, followed by 72h culture in normal medium (wash-out, WO). IS at 3.3 and 16.7 mM G was assessed, and HI transcriptome evaluated by RNA sequencing. Results: Cyt increased IS by 2-fold at 3.3 and 16.7 mM G, with an insulin stimulation index (ISI) of 5.3±2.3 (similar to that of control HI: 5.0±2.7). After WO, no change in IS was observed. Combined Cyt+G decreased ISI by &gt; 50% (2.1±0.6); it improved after WO (4.0±1.1), due to better IS at 16.7 mM glucose. Transcriptome of Cyt+G washed-out vs exposed HI showed 3,137 differentially expressed genes (padj&lt;0.01, log2FC≥1, ≤-1, 1,443 up- and 1,694 down-regulated). By GSEA, 10 pathways were positively enriched (including Glycolysis/Gluconeogenesis, AMPK signaling and Metabolic pathways) and 65 negatively enriched (including Cytokine-cytokine receptor interaction, signaling by IL-17, TNF, JAK-STAT and NF-kB, Spliceosome, Protein processing in ER). Conclusion: Short-term exposure to Cyt increased HI IS, which persisted after WO. Combined Cyt+G impaired BC function, which recovered after WO. The improvement was associated with transcriptomic changes in metabolic processes, inflammatory pathways and the innate immune system. These data suggest that human BC function can be rescued in a T1D-like environment by alleviating the insult and/or targeting underlying molecular mechanisms. Disclosure M. Tesi: None. M. Suleiman: None. R. Semeraro: None. C. De Luca: None. E. Bosi: None. S. Del Guerra: None. A. Magi: None. M. Cnop: None. D.L. Eizirik: None. L. Marselli: None. P. Marchetti: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk. Funding Innovative Medicines Initiative 2 (115,797 and 945,268), European Commission and Italian Ministry of University and Research within the PNRR Project (M4C2-I1.3 PE_00000019 HEAL ITALIA)

Consumption of hazelnuts has been associated with reduced cardiovascular risk and improved metabolic outcomes. Furthermore, the Bone Marrow Fat (BMF) might contribute to skeletal as well as systemic metabolism, modulating insulin sensitivity and, consequently, cardiovascular risk. Previously, we demonstrated a beneficial effect of hazelnuts and cocoa integration on vascular reactivity and metabolic profile in healthy individuals. Aim of this randomized controlled interventional study with 3 parallel groups was to investigate the effects of a daily supplementation with 30 g of hazelnuts, with or without aerobic physical activity (PA), throughout 8 weeks, on insulin sensitivity and resistance, lipid profile, and on BMF content (evaluated by proton magnetic resonance spectroscopy) in healthy individuals. Twenty-five adults (age 18-50 yrs; BMI 18-28 Kg/m2) were randomized in 3 groups: 9 subjects (5F/4M, age 25.6±8.8 yrs, BMI 23.3±2.5) received 30 g of hazelnuts associated with diet (Group 1); 9 subjects (6F/3M, age 26.3±6.3 yrs, BMI 22.0±2.1) received 30 g of hazelnuts associated with diet and aerobic PA (Group 2); 7 subjects (4 F/3 M, age 29.7±6.4 yrs, BMI 23.3±4.2) received only diet (Group 3). After the 8 weeks-intervention, an improvement in LDL-Cholesterol was found in Groups 1 and 2 [-9.3±11.5% (Group 1) vs -5.0±13.6% (Group 2) vs +21.9±35.7% (Group 3); p=0.02]. BMF content variation negatively correlated with LDL-Cholesterol change in Group 1 (r=-0.802, p=0.054); variations in BMF content and in HDL-Cholesterol positively correlated in Group 2 (r=+0.8687, p=0.011). This study confirms the beneficial effects of hazelnuts, in association with PA in improving lipid profile. The correlations between HDL- and LDL-cholesterol and BFM changes suggest an impact of bone homeostasis on whole-body lipid metabolism, through a rapid utilization of lipids, drawing them out of the circulation and decreasing their deposition in the organ tissues. Disclosure A.Ferrulli: None. S.Massarini: None. C.Macrì: None. P.Senesi: None. I.Terruzzi: None. G.Rosso: Employee; Soremartec Italia Srl, Ferrero Group. M.Charron: Employee; Soremartec Italia Srl, Ferrero Group. R.Menta: Employee; Soremartec Italia Srl, Ferrero Group. L.Luzi: Advisory Panel; Eli Lilly and Company, Medtronic, Research Support; Gelesis, Speaker's Bureau; A. Menarini Diagnostics, Amgen Inc., Boehringer Ingelheim and Eli Lilly Alliance, Eli Lilly and Company, Novo Nordisk, Novartis. Funding IRCCS MultiMedica (Ricerca Corrente)

Introduction: Transformation of white adipocytes into beige adipocytes, known as adipocyte browning, holds great promise for development of new therapeutics. Our previous studies have demonstrated nanoparticle-based delivery of dibenzazepine (ADPO-002), a γ-secretase inhibitor, induces browning of white adipose tissue in obese mice and in pigs. The current study aims to investigate the browning efficacy of ADPO-002 in human adipose tissue organ culture. Methods: Abdominal subcutaneous and omental adipose tissue samples were collected from 24 subjects undergoing bariatric surgery (BMI 47.5±3.2 kg/m2, age 44.8±3.0 yr). The study was approved by the Ascension St. Vincent hospital IRB and all subjects provided informed consent. Tissues were cut into small pieces (~5-10 mg) using surgical scissors and cultured in medium M199 supplemented with 0.7 nM insulin and 10 nM dexamethasone. The treatment groups were DMSO (negative control), 50 µM forskolin (positive control), and 3, 10 and 30 µM ADPO-002. After 7-days treatment, total RNA was isolated, and RT-qPCR performed for the browning marker genes PRDM16 and PGC1A. Statistical significance was determined using Wilcoxon non-parametric paired t-test. Results: In omental adipose tissue, 30 µM ADPO-002 significantly increased PRDM16 (429.1±149.3 vs 10.6±4.9 relative units, p=0.0020) and PGC1A (117.4±58.7 vs 58.5±30.2 relative units, p=0.0273) expression compared to the control group. In subcutaneous adipose tissue, 30 µM ADPO-002 significantly upregulated PRDM16 expression compared to control group (398.9±198.6 vs 22.06±6.28 relative units, p=0.0039). Conclusion: These findings suggest that ADPO-002 treatment increases the expression of genes associated with increased mitochondrial expression. This finding supports the hypothesis that inhibition of γ-secretase can increase browning in human adipose tissue. Disclosure M. Abedin: Employee; Adipo Therapeutics LLC. W. Freije: None. M.A. Oswalt: None. A.J. Acton: None. C.B. Crawford: None. M.M. Inman: None. R.V. Considine: Research Support; Eli Lilly and Company, Adipo Therapeutics. M. Deng: Other Relationship; Adipo Therapeutics. Funding Indiana Innovation Voucher

Photo by Robina Weermeijer on Unsplash INTRODUCTION Geographic inequities in access to donor lungs have persisted since the first successful lung transplant in 1983.[1] With unanswered questions regarding organ preservation and transport in the early days of transplantation, the United Network of Organ Sharing (UNOS) understandably incorporated geography in the allocation algorithm. Today, geography is still the most influential criterion in the lung allocation algorithm.[2] As a result, patients in urban centers often receive transplants before patients in less-resourced rural areas. Ex vivo machine perfusion can significantly improve lung procurement and transport, offering longer preservation times before, after, or during transportation. Out-of-hospital perfusion centers, a recent addition to the healthcare field, may increase both the number of lungs available and potentially the distance they can travel. Before the adoption of machine perfusion becomes commonplace, UNOS should direct how to integrate machine perfusion into procurement networks best and shed the antiquated geographical confines that govern allocation today and compromise the ethical standards on which the field was founded. ANALYSIS l. The Past: A History of Geographic Disparities in Lung Transplantation Since the founding of UNOS in 1986, patient geography has been the first filter for all lung procurements. In the early days of the field, implementing these so-called donor service areas, while arbitrarily formed, made sense given the unknowns pertaining to lung preservation and transportation. For almost two decades, donor service areas and time on the waitlist governed lung allocation. In 1998, after physician protest and advocacy, the U.S. Department of Health and Human Services (HHS) delivered the Final Rule on Organ Transplantation to create a more equitable organ allocation system. Even then, it was not until 2005 that UNOS developed the lung allocation score, a quantitative metric that considered predicted waitlist survival and transplant benefit. The implementation of the lung allocation score in the U.S. and abroad by Eurotransplant was a success by multiple standards, most importantly reducing waitlist mortality to record lows.[3] However, a glaring problem remained: the donor service area criterion remained, and arbitrary geographical boundaries continued to govern the distribution of all procured lungs. Despite the improvements in waitlist mortality, regions with low rates of lung donation, primarily rural areas, have suffered disproportionately. Areas in the lowest quartile of lung availability had an 84 percent increased risk of waitlist death and a 57 percent lower transplantation rate than the top quartile.[4] In fact, simply moving to an adjacent donor service area a few miles away might double a patient’s chances of receiving a lung transplant, significantly more than that patient being bumped into a higher lung allocation score bracket.[5] That is, driving across an arbitrary border might increase one’s chances of receiving a new set of lungs. Unsurprisingly, analysis of data over the last decade shows that donor service areas are independently associated with disparities in access to lung transplants significantly more than any other factor, including gender, ethnicity, diagnosis group, or age. ll. The Future: Machine Perfusion and Equity in Organ Allocation Farther allocation distances are associated with sharper drops in waitlist mortality. A model from Stanford University demonstrates that expanding the existing 250-mile threshold to a 500-mile threshold would decrease waitlist mortality by 21.3 percent; an expansion of 1000 miles would lower it by 31.8 percent.[6] Since lungs are already more delicate than other solid organs,[7] an expansion would require better and longer preservation. The answer is already here: machine perfusion. Ex vivo machine perfusion of organs prior to transplantation has grown remarkably over the past two decades, with recent clinical trial results demonstrating the ability of machine perfusion to resuscitate and assess “marginal” organs prior to transplantation.[8] Many centers around the U.S. already apply machine perfusion to expand the donor pool, and the adoption of machine perfusion as common practice is burgeoning. While the availability of more organs will decrease waiting list mortality, it alone will not address the longstanding geographical disparities. In fact, unless there is deliberate preparation by UNOS, this new biotechnology could very easily exacerbate geographic disparities. It is currently an expensive technology that is exclusive to urban centers with an already high organ availability. Proper foresight before widespread adoption is critical. As machine perfusion will extend the preservation of all solid organs, discussions must start taking place now regarding larger allocation boundaries or even a boundless system altogether. One concern is that organs resuscitated in this manner will have lower efficacy than organs preserved on ice and rapidly transplanted. Yet, a recent retrospective study from the Toronto group showed that longer perfusion times over 12 hours do not impact patient outcomes,[9] and some groups have had success with preservation times over 20 hours.[10] In addition to longer preservation times, machine perfusion can easily be made portable. Data from a recent international pivotal trial using the Organ Care System (OCS) from the Massachusetts-based company TransMedics showed the promising ability of portable machine perfusion to preserve and resuscitate marginal lungs. Indeed, while much of the attention around machine perfusion has been about its capability to resuscitate marginal organs, its secondary ability, allowing farther transport of lungs, could end geographic disparities in organ allocation. Before it is universally adopted into clinical practice, it is imperative that UNOS acts now to direct hospitals on how to integrate machine perfusion into procurement networks. There also must be preemptive policies regarding out-of-hospital perfusion centers. The first and only example thus far is the private corporation Lung Bioengineering, located in Silver Spring, Maryland. This standalone center aims to resuscitate and analyze declined lungs via machine perfusion, shipping viable ones to nearby U.S. transplant centers. The company is currently finishing a phase 2 clinical trial assessing the safety of extending lung preservation times with it. Unless decisive action is taken now, these centers will continue to open exclusively in urban areas surrounded by high-volume centers. To engage in the UNOS organ allocation system, private corporations should be required to distribute to rural and previously under-resourced areas. This could be accomplished by setting up satellite campuses or investing in the necessary infrastructure to preserve and deliver organs far distances portably. CONCLUSION We finally have the tools to extinguish the perennial problem of geographic disparities in organ allocation. Within the next five to ten years, there will be widespread adoption of machine perfusion, both in hospitals and in out-of-hospital perfusion centers. In an already convoluted organ allocation system, it will further complicate organ allocation and will potentially worsen disparities if action is not taken upfront. Establishing regulations to ensure machine perfusion is leveraged in a way that is equitable to all who need solid organ transplants, not only those who live within 250 miles of transplant centers, is crucial. It is necessary for UNOS to be ahead of the curve, mitigate these potential consequences, and reprioritize the ethical principles on which the field was founded. This example should serve as a model for how biotechnology can ameliorate disparities – geographic or otherwise – in scarce resource allocation in healthcare. [1] Lynch, R. J., and R. E. Patzer. 2019. "Geographic inequity in transplant access." Curr Opin Organ Transplant 24 (3): 337-342. https://doi.org/10.1097/MOT.0000000000000643. [2] Goff, R. R., E. D. Lease, S. Sweet, A. Robinson, and D. Stewart. 2020. “Measuring and Monitoring Equity in Access to Deceased Donor Lung Transplants among Waitlisted Candidates.” J Hear Lung Transplant 39 (4): S216. https://doi.org/10.1016/j.healun.2020.01.847. [3] Egan, T. M. 2018. "From 6 years to 5 days for organ allocation policy change." J Heart Lung Transplant 37 (5): 675-677. https://doi.org/10.1016/j.healun.2017.12.010. [4] Benvenuto, L. J., D. R. Anderson, H. P. Kim, J. L. Hook, L. Shah, H. Y. Robbins, F. D'Ovidio, M. Bacchetta, J. R. Sonett, S. M. Arcasoy, and Program From the Columbia University Lung Transplant. 2018. "Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study." Am J Transplant 18 (6): 1471-1480. https://doi.org/10.1111/ajt.14630. [5] Kosztowski, M., S. Zhou, E. Bush, R. S. Higgins, D. L. Segev, and S. E. Gentry. 2019. "Geographic disparities in lung transplant rates." Am J Transplant 19 (5): 1491-1497. https://doi.org/10.1111/ajt.15182. [6] Mooney, J. J., J. Bhattacharya, and G. S. Dhillon. 2019. "Effect of broader geographic sharing of donor lungs on lung transplant waitlist outcomes." J Heart Lung Transplant 38 (2): 136-144. https://doi.org/10.1016/j.healun.2018.09.007. [7] Possoz, J., A. Neyrinck, and D. Van Raemdonck. 2019. "Ex vivo lung perfusion prior to transplantation: an overview of current clinical practice worldwide." J Thorac Dis 11 (4): 1635-1650. https://doi.org/10.21037/jtd.2019.04.33. [8] Noah, C. V., P. Tratnig-frankl, S. Raigani, C. Cetrulo, K. Uygun, and H. Yeh. 2020. “Moving the Margins: Updates on the Renaissance in Machine Perfusion for Organ Transplantation.” Curr Transplant Reports 7 (2): 1-10. https://doi.org/10.1007/s40472-020-00277-z. [9] Yeung, J. C., T. Krueger, K. Yasufuku, M. de Perrot, A. F. Pierre, T. K. Waddell, L. G. Singer, S. Keshavjee, and M. Cypel. 2017. "Outcomes after transplantation of lungs preserved for more than 12 h: a retrospective study." Lancet Respir Med 5 (2): 119-124. https://doi.org/10.1016/S2213-2600(16)30323-X. [10] Cypel, M., A. Neyrinck, and T. N. Machuca. 2019. "Ex vivo perfusion techniques: state of the art and potential applications." Intensive Care Med 45 (3): 354-356. https://doi.org/10.1007/s00134-019-05568-3.

Abstract Introduction Sex hormone profile evaluation is commonly used in male infertility assessment to identify potential hormonal imbalances and underlying issues that can impact sperm production, sperm quality, or reproductive organ function. Objective To evaluate the likelihood of having a child in subfertile and infertile men within five years based on their serum hormone levels on their initial encounter for infertility evaluation/treatment. Methods We identified a retrospective cohort from the Subfertility, Health, and Assisted Reproduction (SHARE) study (compiled 1996-2017) linked with familial information from the Utah Population Database (UPDB) including all men with a measured value of albumin, follicle-stimulating hormone (FSH), luteinizing hormone (LH), Free testosterone (T), total, and bioavailable T, sex hormone binding globulin (SHBG), and estradiol (E). We included men who had a semen analysis (SA) within 1 year of their hormone measurement. The primary outcome of the study was any evidence of childbirth, and the secondary outcome was the time from baseline hormone evaluation to childbirth. All men were followed for 60 months after their recorded hormone value for evidence of childbirth. Using Cox proportional hazards models, we modeled the likelihood of having a child and the time to childbirth (using linear regression) against the quintile of hormone distribution. Results A total number of 1298 men who underwent hormone profile evaluation and SA were included in this study. The mean age for the total cohort was 33 (29-37) years old. Men who had a child at the end of the study period (31 (28-36)) were significantly younger than men without a child at the end of the study with a mean age of (35.5 (32-40.25)) (p &lt; 0.001). The mean sperm concentration for the total cohort was 7.6 (1-27.4) (M/ml) and the mean total progressive motile count was 9 (0.9-47) (M). Overall, semen parameters showed no significant differences between men who had a child at the end of the study follow-up versus men who did not. Our models showed that prolactin serum levels in quantile 7 have the highest ratio (2.236 (0.919-5.44) p=0.076) for the likelihood of having a child. Total testosterone in quantiles 3 and 5 showed an increased likelihood of having a child (2.119 (1.176-3.821) (p=0.012), (2.518 (1.412-4.491)) (p=0.002), respectively. Albumin in quantiles 5-9 followed a similar pattern with the highest ratio in quantile 8 (3.551 (1.486-8.487)) (p=0.004). Our results did not show meaningful patterns between semen parameters, serum hormone levels, and time to having a child. Conclusions The outcomes of this study indicate that prolactin, total testosterone, and albumin serum levels on the first visit in men with infertility concerns are associated with an increased likelihood of having a child. Abnormal semen analysis outcomes are not well associated with hypoandrogenism in infertile men. Our study shows that baseline serum prolactin, total testosterone, and albumin levels can be used to estimate the likelihood of having a child in subfertile and infertile men. These findings can provide the basis for further studies to determine an optimal screening method for male-factor infertility related to abnormal hormone levels. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Equity/salary/officer in company: Paterna bio, firmtech; Consulting: Turtle health, maximus, carrot; inherent bio.

Pentingnya membangun OCB tidak lepas dari komitmen karyawan dalam organisasi. Komitmen karyawan akan mendorong terciptanya OCB dan tanpa adanya kontrol yang baik dalam pemberian kompensasi yang sesuai dengan hasil kerja tentunya memperlambat kerja pegawai. Penelitian ini bertujuan untuk menguji dan menganalisis pengaruh kompensasi dan komitmen organisasi terhadap kepuasan kerja dan OCB. Jumlah responden dalam penelitian ini berjumlah 86 orang. Pengumpulan data diperoleh dengan kuesioner menggunakan skala likert. Metode analisis data menggunakan Path Analysis. Hasil penelitian diperoleh bahwa kompensasi berpengaruh positif dan signifikan terhadap kepuasan kerja dan Kepuasan kerja berpengaruh positif dan signifikan terhadap OCB. Kata Kunci : Komitmen Organisasi, Kompensasi, Kepuasan kerja dan OCBDAFTAR PUSTAKA Bangun, Wilson. (2012). Manajemen Sumber Daya Manusia. Erlangga. Jakarta. Bernardin, H. John, & Joyce E.A Russel. (2003). 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Photo ID 158378414 © Eduard Muzhevskyi | Dreamstime.com ABSTRACT There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities. INTRODUCTION Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve. BACKGROUND Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes.[1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research.[2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.”[3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops.[4] Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture. I. Global Cultural Perspective of Embryonic Stem Cells Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense,[5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research.[6] Consequently, global engagement in ESC research depends on social-cultural acceptability. a. US and Rights-Based Cultures In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism,[7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.”[8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed.[9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field.[10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture.[11] b. Ubuntu and Collective Cultures African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama, which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,”[12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth.[13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole. Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value.[14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society. Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.”[15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail. Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable.[16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus[17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines.[18] Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim.[19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research.[20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF. Their use is conditioned on consent, and available only to married couples.[21] The community's receptiveness to stem cell research depends on including communitarian African ethics. c. Asia Some Asian countries also have a collective model of ethics and decision making.[22] In China, the ethics model promotes a sincere respect for life or human dignity,[23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life.[25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research.[26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions.[27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency.[28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021.[29] However, issues still need to be addressed in implementing effective IRB review and approval procedures. The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy,[30] research ethics should also adapt to ensure respect for the values of its represented peoples. Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies.[31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells.[32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval,[33] and in another instance, the oocyte source was unclear and possibly violated ethical standards.[34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust. d. Middle East Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells,[35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research.[36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors.[37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so.[38] Jordan has a positive research ethics culture.[39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial.[40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation.[41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.”[42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes. e. Europe In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected.[43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44] For example, in Germany, Lebenzusammenhang, or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.”[45] Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount.[46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007.[47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization.[48] Spain’s approach differs still, with a comprehensive regulatory framework.[49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility.[50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices.[51] II. Religious Perspectives on ESC Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives. The Qur'an states: “And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.”[52] Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception.[53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible.[54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research.[55] In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided.[56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden.[57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all.[58] Acceptance varies on applied beliefs and interpretations. Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero,[59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all.[60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime.[61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit.[62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets.[63] Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life.[64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception:[65] “If she is found pregnant, until the fortieth day it is mere fluid,”[66] Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation.[67] Stem cell research is accepted due to application of these religious laws. We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory, which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions.[68] We only wish to show that the interaction with morality varies between cultures and countries. III. A Flexible Ethical Approach The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities. While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe.[69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation. For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent.[70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context,[71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders. This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research. Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values.[72] An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions.[73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion. IV. Concerns Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values.[74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions. Other concerns include medical tourism, which may promote health inequities.[75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments.[76] For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.”[77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices.[78] The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.”[79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds.[80] CONCLUSION While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research. For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society. This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model. - [1] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice. 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International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk [5] Concerning the moral philosophies of stem cell research, our paper does not posit a personal moral stance nor delve into the “when” of human life begins. To read further about the philosophical debate, consider the following sources: Sandel M. J. (2004). Embryo ethics--the moral logic of stem-cell research. The New England journal of medicine, 351(3), 207–209. https://doi.org/10.1056/NEJMp048145; George, R. P., & Lee, P. (2020, September 26). Acorns and Embryos. The New Atlantis. https://www.thenewatlantis.com/publications/acorns-and-embryos; Sagan, A., & Singer, P. (2007). The moral status of stem cells. Metaphilosophy, 38(2/3), 264–284. http://www.jstor.org/stable/24439776; McHugh P. R. (2004). Zygote and "clonote"--the ethical use of embryonic stem cells. 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[14] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324 [15] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324 [16] Jackson, C.S., Pepper, M.S. Opportunities and barriers to establishing a cell therapy programme in South Africa. Stem Cell Res Ther 4, 54 (2013). https://doi.org/10.1186/scrt204; Pew Research Center. (2014, May 1). Public health a major priority in African nations. Pew Research Center’s Global Attitudes Project. https://www.pewresearch.org/global/2014/05/01/public-health-a-major-priority-in-african-nations/ [17] Department of Health Republic of South Africa. (2021). Health Research Priorities (revised) for South Africa 2021-2024. National Health Research Strategy. https://www.health.gov.za/wp-content/uploads/2022/05/National-Health-Research-Priorities-2021-2024.pdf [18] Oosthuizen, H. (2013). Legal and Ethical Issues in Stem Cell Research in South Africa. In: Beran, R. (eds) Legal and Forensic Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32338-6_80, see also: Gaobotse G (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [19] United States Bureau of Citizenship and Immigration Services. (1998). Tunisia: Information on the status of Christian conversions in Tunisia. UNHCR Web Archive. https://webarchive.archive.unhcr.org/20230522142618/https://www.refworld.org/docid/3df0be9a2.html [20] Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [21] Kooli, C. Review of assisted reproduction techniques, laws, and regulations in Muslim countries. Middle East Fertil Soc J 24, 8 (2020). https://doi.org/10.1186/s43043-019-0011-0; Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142 [22] Pang M. C. (1999). Protective truthfulness: the Chinese way of safeguarding patients in informed treatment decisions. Journal of medical ethics, 25(3), 247–253. https://doi.org/10.1136/jme.25.3.247 [23] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences, 8(1). https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199 [24] Wang, Y., Xue, Y., & Guo, H. D. (2022). Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction. Frontiers in pharmacology, 13, 1013740. https://doi.org/10.3389/fphar.2022.1013740 [25] Li, X.-T., & Zhao, J. (2012). Chapter 4: An Approach to the Nature of Qi in TCM- Qi and Bioenergy. In Recent Advances in Theories and Practice of Chinese Medicine (p. 79). InTech. [26] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students. Stem cells international, 2021, 6667743. https://doi.org/10.1155/2021/6667743 [27] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students. Stem cells international, 2021, 6667743. https://doi.org/10.1155/2021/6667743 [28] Zhang, J. Y. (2017). Lost in translation? accountability and governance of Clinical Stem Cell Research in China. Regenerative Medicine, 12(6), 647–656. https://doi.org/10.2217/rme-2017-0035 [29] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences, 8(1). https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199 [30] Chen, H., Wei, T., Wang, H. et al. Association of China’s two-child policy with changes in number of births and birth defects rate, 2008–2017. BMC Public Health 22, 434 (2022). https://doi.org/10.1186/s12889-022-12839-0 [31] Azuma, K. Regulatory Landscape of Regenerative Medicine in Japan. Curr Stem Cell Rep 1, 118–128 (2015). https://doi.org/10.1007/s40778-015-0012-6 [32] Harris, R. (2005, May 19). Researchers Report Advance in Stem Cell Production. NPR. https://www.npr.org/2005/05/19/4658967/researchers-report-advance-in-stem-cell-production [33] Park, S. (2012). South Korea steps up stem-cell work. Nature. https://doi.org/10.1038/nature.2012.10565 [34] Resnik, D. B., Shamoo, A. E., & Krimsky, S. (2006). Fraudulent human embryonic stem cell research in South Korea: lessons learned. Accountability in research, 13(1), 101–109. https://doi.org/10.1080/08989620600634193. [35] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 [36]Association for the Advancement of Blood and Biotherapies. https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia [37] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 [38] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6 Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics, 23(3), 260–268. https://doi.org/10.1111/dewb.12355; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know. Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know [39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics. Research Ethics, 17(2), 228-241. https://doi.org/10.1177/1747016120966779 [40] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics. Research Ethics, 17(2), 228-241. https://doi.org/10.1177/1747016120966779 [41] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East. Nature 510, 189. https://doi.org/10.1038/510189a [42] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East. Nature 510, 189. https://doi.org/10.1038/510189a [43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3 [44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France. Biotechnology Law Report, 32(6), 349–356. https://doi.org/10.1089/blr.2013.9865 [45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3 [46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf [47] Regulation of Stem Cell Research in Germany. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany [48] Regulation of Stem Cell Research in Finland. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland [49] Regulation of Stem Cell Research in Spain. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain [50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered: Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110. Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ... Revista do Colegio Brasileiro de Cirurgioes, 41(5), 374–377. https://doi.org/10.1590/0100-69912014005013 Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India. Routledge. For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe. Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe [51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights. Cultura (Iasi, Romania), 14(2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent? Research Ethics, 13(1), 23-41. https://doi.org/10.1177/1747016116650235 [52] The Qur'an (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23 [53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life. Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/ [54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics, 31:399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386 [55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association, 12(4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf. [56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52. https://doi.org/10.5372/1905-7415.0801.260 [57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.), Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues (pp. 79-94). Berkeley: University of California Press. https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005 [58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation. Journal of Religion and Health, 30(1), 35–41. http://www.jstor.org/stable/27510629; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva. A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm [59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. ((King James Bible. (1999). Oxford University Press. (original work published 1769)) Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…” In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David. Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…” These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth. [60] It should be noted that abortion is not supported as well. [61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day. Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html [62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells. Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology. Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf. [63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed. Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/ [64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. 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Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.), Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues (pp. 79-94). Berkeley: University of California Press. https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005 [68] Gert, B. (2007). Common morality: Deciding what to do. Oxford Univ. Press. [69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA, 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association.; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). The Belmont report: Ethical principles and guidelines for the protection of human subjects of research. 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I was born illegitimate. Born on an existential precipice. My unwed mother was 36 years old when she relinquished me. I was the fourth baby she was required to give away. After I emerged blood stained and blue tinged – abject, liminal – not only did the nurses refuse me my mother’s touch, I also lost the sound of her voice. Her smell. Her heart beat. Her taste. Her gaze. The silence was multi-sensory. When they told her I was dead, I also lost, within her memory and imagination, my life. I was adopted soon after but not told for over four decades. It was too shameful for even me to know. Imprinted at birth with a psychological ‘death’, I fell, as a Late Discovery Adoptee (LDA), into a socio-cultural and psychological abyss, frozen at birth at the bottom of a parturitive void from where, invisible within family, society, and self I was unable to form an undamaged sense of being.Throughout the 20th century (and for centuries before) this kind of ‘social abortion’ was the dominant script. An adoptee was regarded as a bastard, born of sin, the mother blamed, the father exonerated, and silence demanded (Lynch 28-74). My adoptive mother also sinned. She was infertile. But, in taking me on, she assumed the role of a womb worthy woman, good wife, and, in her case, reluctant mother (she secretly didn’t want children and was privately overwhelmed by the task). In this way, my mother, my adoptive mother, and myself are all the daughters of bereavement, all of us sacrificed on the altar of prejudice and fear that infertility, sex outside of marriage, and illegitimacy were unspeakable crimes for which a price must be paid and against which redemptive protection must be arranged. If, as Thomas Keneally (5) writes, “original sin is the mother fluid of history” then perhaps all three of us all lie in its abject waters. Grotevant, Dunbar, Kohler and Lash Esau (379) point out that adoption was used to ‘shield’ children from their illegitimacy, women from their ‘sexual indiscretions’, and adoptive parents from their infertility in the belief that “severing ties with birth family members would promote attachment between adopted children and parents”. For the adoptee in the closed record system, the socio/political/economic vortex that orchestrated their illegitimacy is born out of a deeply, self incriminating primal fear that reaches right back into the recesses of survival – the act of procreation is infested with easily transgressed life and death taboos within the ‘troop’ that require silence and the burial of many bodies (see Amanda Gardiner’s “Sex, Death and Desperation: Infanticide, Neonaticide, and Concealment of Birth in Colonial Western Australia” for a palpable, moving, and comprehensive exposition on the links between 'illegitimacy', the unmarried mother and child murder). As Nancy Verrier (24) states in Coming Home to Self, “what has to be understood is that separation trauma is an insidious experience, because, as a society, we fail to see this experience as a trauma”. Indeed, relinquishment/adoption for the baby and subsequent adult can be acutely and chronically painful. While I was never told the truth of my origins, of course, my body knew. It had been there. Sentient, aware, sane, sensually, organically articulate, it messaged me (and anyone who may have been interested) over the decades via the language of trauma, its lexicon and grammar cellular, hormonal, muscular (Howard & Crandall, 1-17; Pert, 72), the truth of my birth, of who I was an “unthought known” (Bollas 4). I have lived out my secret fatality in a miasmic nebula of what I know now to be the sequelae of adoption psychopathology: nausea, physical and psychological pain, agoraphobia, panic attacks, shame, internalised anger, depression, self-harm, genetic bewilderment, and generalised anxiety (Brodzinsky 25-47; Brodzinsky, Smith, & Brodzinsky 74; Kenny, Higgins, Soloff, & Sweid xiv; Levy-Shiff 97-98; Lifton 210-212; Verrier The Primal Wound 42-44; Wierzbicki 447-451) – including an all pervading sense of unreality experienced as dissociation (the experience of depersonalisation – where the self feels unreal – and derealisation – where the world feels unreal), disembodiment, and existential elision – all characteristics of Post Traumatic Stress Disorder (PTSD). In these ways, my body intervened, acted out, groaned in answer to the social overlay, and from beyond “the dermal veil” tried to procure access, as Vicky Kirby (77) writes, to “the body’s opaque ocean depths” through its illnesses, its eloquent, and incessantly aching and silent verbosities deepened and made impossibly fraught because I was not told. The aim of this paper is to discuss one aspect of how my body tried to channel the trauma of my secret fatality and liminality: my pre-disclosure art work (the cellular memory of my trauma also expressed itself, pre-disclosure, through my writings – poetry, journal entries – and also through post-coital glossolalia, all discussed at length in my Honours research “Womb Tongues” and my Doctoral Dissertation “The Womb Artist – A Novel: Translating Pre-verbal Late Discovery Adoption Trauma into Narrative”). From the age of thirty onwards I spent twelve years in therapy where the cause of my childhood and adult psychopathology remained a mystery. During this time, my embodied grief and memories found their way into my art work, a series of 5’ x 3’ acrylic paintings, some of which I offer now for discussion (figures 1-4). These paintings map and express what my body knew but could not verbalise (without language to express my grief, my body found other ways to vent). They are symptom and sign of my pre-verbal adoption trauma, evidence that my body ‘knew’ and laboured ceaselessly and silently to find creative ways to express the incarcerated trauma. Post disclosure, I have used my paintings as artefacts to inform, underpin, and nourish the writing of a collection of poetry “Womb Tongues” and a literary novel/memoir “The Womb Artist” (TWA) in an ongoing autoethnographical, performative, and critical inquiry. My practice-led research as a now conscious and creative witness, fashions the recontextualisation of my ‘self’ into my ‘self’ and society, this time with cognisant and reparative knowledge and facilitates the translation of my body’s psychopathology and memory (explicit and implicit) into a healing testimony that explores the traumatised body as text and politicizes the issues surrounding LDAs (Riley 205). If I use these paintings as a memoirist, I use them second hand, after the fact, after they have served their initial purpose, as the tangible art works of a baby buried beneath a culture’s prejudice, shame, and judgement and the personal cries from the illegitimate body/self. I use them now to explore and explain my subclinical and subterranean life as a LDA.My pre-disclosure paintings (Figures 1-4) – filled with vaginal, fetal, uterine, and umbilical references – provide some kind of ‘evidence’ that my body knew what had happened to me as if, with the tenacity of a poltergeist, my ‘spectral self’ found ways to communicate. Not simply clues, but the body’s translation of the intra-psychic landscape, a pictorial and artistic séance into the world, as if my amygdala – as quasar and signal, homing device and history lesson (a measure, container, and memoir) – knew how to paint a snap shot or an x-ray of the psyche, of my cellular marrow memories (a term formulated from fellow LDA Sandy McCutcheon’s (76) memoir, The Magician’s Son when he says, “What I really wanted was the history of my marrow”). If, as Salveet Talwar suggests, “trauma is processed from the body up”, then for the LDA pre-discovery, non-verbal somatic signage is one’s ‘mother tongue’(25). Talwar writes, “non-verbal expressive therapies such as art, dance, music, poetry and drama all activate the sub-cortical regions of the brain and access pre-verbal memories” (26). In these paintings, eerily divinatory and pointed traumatic, memories are made visible and access, as Gussie Klorer (213) explains in regard to brain function and art therapy, the limbic (emotional) system and the prefrontal cortex in sensorimotor integration. In this way, as Marie Angel and Anna Gibbs (168) suggest, “the visual image may serve as a kind of transitional mode in thought”. Ruth Skilbeck in her paper First Things: Reflections on Single-lens Reflex Digital Photography with a Wide-angled Lens, also discusses (with reference to her photographic record and artistic expression of her mother’s death) what she calls the “dark matter” – what has been overlooked, “left out”, and/or is inexplicable (55) – and the idea of art work as the “transitional object” as “a means that some artists use, conceptually and yet also viscerally, in response to the extreme ‘separation anxiety’ of losing a loved one, to the void of the Unknown” (57). In my case, non-disclosure prevented my literacy and the evolution of the image into language, prevented me from fully understanding the coded messages left for me in my art work. However, each of my paintings is now, with the benefit of full disclosure, a powerful, penetrating, and comprehensible intra and extra sensory cry from the body in kinaesthetic translation (Lusebrink, 125; Klorer, 217). In Figure 1, ‘Embrace’, the reference to the umbilical is palpable, described in my novel “The Womb Artist” (184) this way; “two ropes tightly entwine as one, like a dark and dirty umbilical cord snaking its way across a nether world of smudged umbers”. There is an ‘abject’ void surrounding it. The cord sapped of its colour, its blood, nutrients – the baby starved of oxygen, breath; the LDA starved of words and conscious understanding. It has two parts entwined that may be seen in many ways (without wanting to reduce these to static binaries): mother/baby; conscious/unconscious; first person/third person; child/adult; semiotic/symbolic – numerous dualities could be spun from this embrace – but in terms of my novel and of the adoptive experience, it reeks of need, life and death, a text choking on the poetic while at the same time nourished by it; a text made ‘available’ to the reader while at the same narrowing, limiting, and obscuring the indefinable nature of pre-verbal trauma. Figure 1. Embrace. 1993. Acrylic on canvas.The painting ‘Womb Tongues’ (Figure 2) is perhaps the last (and, obviously, lasting) memory of the infinite inchoate universe within the womb, the umbilical this time wrapped around in a phallic/clitorial embrace as the baby-self emerges into the constrictions of a Foucauldian world, where the adoptive script smothers the ‘body’ encased beneath the ‘coils’ of Judeo-Christian prejudice and centuries old taboo. In this way, the reassigned adoptee is an acute example of power (authority) controlling and defining the self and what knowledge of the self may be allowed. The baby in this painting is now a suffocated clitoris, a bound subject, a phallic representation, a gagged ‘tongue’ in the shape of the personally absent (but socially imposing) omni-present and punitive patriarchy. Figure 2. Womb Tongues. 1997. Acrylic on canvas.‘Germination’ (Figure 3) depicts an umbilical again, but this time as emerging from a seething underworld and is present in TWA (174) this way, “a colony of night crawlers that writhe and slither on the canvas, moving as one, dozens of them as thin as a finger, as long as a dream”. The rhizomic nature of this painting (and Figure 4), becomes a heaving horde of psychosomatic and psychopathological influences and experiences, a multitude of closely packed, intense, and dendridic compulsions and symptoms, a mass of interconnected (and by nature of the silence and lie) subterranean knowledges that force the germination of a ‘ghost baby/child/adult’ indicated by the pale and ashen seedling that emerges above ground. The umbilical is ghosted, pale and devoid of life. It is in the air now, reaching up, as if in germination to a psychological photosynthesis. There is the knot and swarm within the unconscious; something has, in true alien fashion, been incubated and is now emerging. In some ways, these paintings are hardly cryptic.Figure 3. Germination.1993. Acrylic on canvas.In Figure 4 ‘The Birthing Tree’, the overt symbolism reaches ‘clairvoyant status’. This could be read as the family ‘tree’ with its four faces screaming out of the ‘branches’. Do these represent the four babies relinquished by our mother (the larger of these ‘beings’ as myself, giving birth to the illegitimate, silenced, and abject self)? Are we all depicted in anguish and as wraithlike, grotesquely simplified into pure affect? This illegitimate self is painted as gestating a ‘blue’ baby, near full-term in a meld of tree and ‘self’, a blue umbilical cord, again, devoid of blood, ghosted, lifeless and yet still living, once again suffocated by the representation of the umbilical in the ‘bowels’ of the self, the abject part of the body, where refuse is stored and eliminated: The duodenum of the damned. The Devil may be seen as Christopher Bollas’s “shadow of the object”, or the Jungian archetypal shadow, not simply a Judeo-Christian fear-based spectre and curmudgeon, but a site of unprocessed and, therefore, feared psychological material, material that must be brought to consciousness and integrated. Perhaps the Devil also is the antithesis to ‘God’ as mother. The hell of ‘not mother’, no mother, not the right mother, the reluctant adoptive mother – the Devil as icon for the rich underbelly of the psyche and apophatic to the adopted/artificial/socially scripted self.Figure 4. The Birthing Tree. 1995. Acrylic on canvas.These paintings ache with the trauma of my relinquishment and LDA experience. They ache with my body’s truth, where the cellular and psychological, flesh and blood and feeling, leak from my wounds in unspeakable confluence (the two genital lips as the site of relinquishment, my speaking lips that have been sealed through non-disclosure and shame, the psychological trauma as Verrier’s ‘primal wound’) just as I leaked from my mother (and society) at birth, as blood and muck, and ooze and pus and death (Grosz 195) only to be quickly and silently mopped up and cleansed through adoption and life-long secrecy. Where I, as translator, fluent in both silence and signs, disclose the baby’s trauma, asking for legitimacy. My experience as a LDA sets up an interesting experiment, one that allows an examination of the pre-verbal/pre-disclosure body as a fleshed and breathing Rosetta Stone, as an interface between the language of the body and of the verbalised, painted, and written text. As a constructed body, written upon and invented legally, socially, and psychologically, I am, in Hélène Cixous’s (“To Live the Orange” 83) words, “un-forgetting”, “un-silencing” and “unearthing” my ‘self’ – I am re-writing, re-inventing and, under public scrutiny, legitimising my ‘self’. I am a site of inquiry, discovery, extrapolation, and becoming (Metta 492; Poulus 475) and, as Grosz (vii) suggests, a body with “all the explanatory power” of the mind. I am, as I embroider myself and my LDA experience into literary and critical texts, authoring myself into existence, referencing with particular relevance Peter Carnochan’s (361) suggestion that “analysis...acts as midwife to the birth of being”. I am, as I swim forever amorphous, invisible, and unspoken in my mother’s womb, fashioning a shore, landscaping my mind against the constant wet, my chronic liminality (Rambo 629) providing social landfall for other LDAs and silenced minorities. As Catherine Lynch (3) writes regarding LDAs, “Through the creation of text and theory I can formulate an intimate space for a family of adoptive subjects I might never know via our participation in a new discourse in Australian academia.” I participate through my creative, self-reflexive, process fuelled (Durey 22), practice-led enquiry. I use the intimacy (and also universality and multiplicity) and illegitimacy of my body as an alterative text, as a site of academic and creative augmentation in the understanding of LDA issues. The relinquished and silenced baby and LDA adult needs a voice, a ‘body’, and a ‘tender’ place in the consciousness of society, as Helen Riley (“Confronting the Conspiracy of Silence” 11) suggests, “voice, validation, and vindication”. Judith Herman (3) argues that, “Survivors challenge us to reconnect fragments, to reconstruct history, to make meaning of their present symptoms in the light of past events”. I seek to use the example of my experience – as Judith Durey (31) suggests, in “support of evocative, creative modes of representation as valid forms of research in their own right” – to unfurl the whole, to give impetus and precedence for other researchers into adoption and advocate for future babies who may be bought, sold, arranged, and/or created by various means. The recent controversy over Gammy, the baby boy born with Down Syndrome in Thailand, highlights the urgent and moral need for legislation with regard to surrogacy (see Kajsa Ekis Ekman’s Being and Being Bought: Prostitution, Surrogacy and the Split Self for a comprehensive examination of surrogacy issues). Indeed, Catherine Lynch in her paper Doubting Adoption Legislation links the experiences of LDAs and the children of born of surrogacy, most effectively arguing that, “if the fate that closed record adoptees suffered was a misplaced solution to the question of what to do with children already conceived how can you justify the deliberate conception of a child with the intention even before its creation of cruelly removing that child from their mother?” (6). Cixous (xxii) confesses, “All I want is to illustrate, depict fragments, events of human life and death...each unique and yet at the same time exchangeable. Not the law, the exception”. I, too, am a fragment, an illustration (a painting), and, as every individual always is – paradoxically – a communal and, therefore, deeply recognisable and generally applicable minority and exception. In my illegitimacy, I am some kind of evidence. Evidence of cellular memory. Evidence of embodiment. Evidence that silenced illegitimacies will manifest in symptom and non-verbal narratives, that they will ooze out and await translation, verification, and witness. This paper is offered with reverence and with feminist intention, as a revenant mouthpiece for other LDAs, babies born of surrogacy, and donor assisted offspring (and, indeed, any) who are marginalised, silenced, and obscured. It is also intended to promote discussion in the psychological and psychoanalytic fields and, as Helen Riley (202-207) advocates regarding late discovery offspring, more research within the social sciences and the bio-medical field that may encourage legislators to better understand what the ‘best interests of the child’ are in terms of late discovery of origins and the complexity of adoption/conception practices available today. As I write now (and always) the umbilical from my paintings curve and writhe across my soul, twist and morph into the swollen and throbbing organ of tongues, my throat aching to utter, my hands ready to craft latent affect into language in translation of, and in obedience to, my body’s knowledges. It is the art of mute witness that reverses genesis, that keeps the umbilical fat and supple and full of blood, and allows my conscious conception and creation. 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