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In this research work, we present a synthesis of silver and cobalt bimetal nanoparticles stabilized by a carboxymethyl cellulose biopolymer (CMC-AgCo) and its coating on a cellulose filter paper (CFP) to prepare the dip-catalyst. All the prepared samples were subjected to characterization by scanning electron microscopy for surface morphology, EDX, XRD and thermogravimetric analysis. The catalytic properties of the CFP/CMC-AgCo as dip-catalysts were evaluated in the reduction of organic nitroaromatic pollutants of 2,6-dinitrophenol to 2,6-diaminophenol as well as the 4-nitrophenol to 4-aminophenol. It was found that the reduction reaction advanced with the pseudo-first-order kinetics. The CFP/CMC-AgCo catalyzed the 2,6-diaminophenol and 4-nitrophenol with a reaction rate constant of 0.1244 and 0.177 min− 1, respectively. The separation of the CFP/CMC-AgCo was easy as it required a simple pulling of the strip from the reaction medium. Importantly, the catalytic reaction rates and conversion percentages of the two nitroaromatics were well-maintained for multiple times during recycling experiments.

Background B-cell tumors and plasma cell malignancies have been identified in persons living with the human immunodeficiency virus (PLHIV). The literature review has revealed numerous reports of solitary plasmacytomas with metastasis in PLHIV. Case report A young patient with no prior medical or surgical history presented with tumor lysis syndrome secondary to metastatic plasma cell Epstein-Baer virus (EBV) related malignancy with peritoneal carcinomatosis. The history and clinical picture promptly led to the diagnosis of HIV. The subsequent hospital course was dismal, and lifespan was cut short by multi-organ failure. Conclusion This case is being reported to highlight the suspicion of HIV in patients presenting acutely with aggressive plasma cell malignancies.

The main aims of this investigation were the isolation of dimeric naphthoquinones, a new class of dinaphthodiospyrols (1-7), from chloroform fractions and screening them for antibacterial, antifungal, and antioxidant potential. The susceptibility of the isolated compounds, namely, dinaphthodiospyrol A (1), dinaphthodiospyrol B (2), dinaphthodiospyrol C (3), dinaphthodiospyrol D (4), dinaphthodiospyrol E (5), dinaphthodiospyrol F (6), and dinaphthodiospyrol G (7) was assessed for antibacterial potential using well diffusion methods. The isolated compounds showed excellent antibacterial activity against selected bacterial strains, including Gram-positive Bacillus subtilis, Streptococcus epidermis, and Bacillus subtilis, and Gram-negative bacteria Klebsiella pneumonia with the zones of inhibition 6 to 26 nm. The standard drug Imipenem showed a maximum inhibitory zone 30 to 35 nm. Similarly, the isolated compounds were screened for antifungal properties, which showed an excellent reduction in the growth of selected fungal strain including Candida albicans, Aspergillus flavus, Fusarium solani, Trichyton logifusus, Microsporum canis , and Candida glabrata. Among all the screened compounds, 7 exhibited good activity (30-49 mm), followed by compounds 5 and 6, (35-46 mm), while compounds 1-4 showed a moderate effect (8-28 mm) against the selected fungal strain against miconazole which showed potent effects (101-110.98 mm). The isolated compounds were also screened for 1, 1-diphenyl-2-picrylhydrazyl (DPPH) activity. In vitro-based free radical was employed using ascorbic acid as a standard antioxidant. The tested compounds (1-7) exhibited significant antioxidant activity in a concentration-dependent manner. The dinaphthodiospyrol 7 exhibited 97.32% scavenging activity, followed by dinaphthodiospyrol 6, 92.01%, and compounds 5 and 4 with 89.90 and 88.43% scavenging activity at 100 μg/mL, respectively; ascorbic acid showed 96.45% scavenging effect. Furthermore, docking analysis was performed to know the exact binding mode of the tetra-substituted derivatives of dinaphthodiospyrols to the selected target proteins. From the docking analysis, it was found that the docking results are well correlated with the experimental observations. In conclusion, the dinaphthodiospyrols exhibited excellent antibacterial, antifungal, and free radical scavenging potential.

CAR T cell therapy is an innovative approach to treat cancers in the modern era. It utilizes the application of chimeric antigen receptors targeted against specific antigens expressed by the tumor cells. Although its efficacy is established in hematological malignancies, the safety and efficacy of this therapy in solid tumors, especially pancreaticobiliary cancers, is a highly investigated aspect. A focused review of clinical data was conducted to examine the outcomes of this therapy in pancreaticobiliary cancers. A comprehensive literature search was done on Medline and Embase databases through April 24, 2020 for studies that evaluated the outcomes of CAR T cell therapy in pancreaticobiliary cancers. There were six phase 1 trials, while one was phase 1/2. Some of these trials were specifically done for pancreaticobiliary cancers, while others included patients of various solid organ cancers, including pancreatic and biliary tract cancers. The target antigens for therapy in these trials included mesothelin, CD133, prostate stem cell antigen, claudin 18.2, epidermal growth factor receptor, and human epidermal growth factor receptor 2. CAR T cell therapy has shown very few grade 3 and 4 side effects. Most of the adverse events are associated with cytokine release syndrome. CAR T cell therapy has a manageable safety profile based on phase 1 studies, and efficacy assessments are currently ongoing in dose expansion and phase 2 studies.

This study was focused to synthesize silver nanoparticles (AgNps) from the aqueous extract of Bistorta amplexicaule and to evaluate their antimicrobial, antifungal, and 4-nitrophenol (4-NP) degradation potential. The AgNps from B. amplexicaule were characterized by field emission scanning electron microscopy, energy dispersive X-ray spectrometry, X-ray diffraction, and X-ray photoelectron spectroscopy studies. The biological activity of the AgNps was checked against the three bacterial and two fungal strains. The inhibition activities of the synthesized nanoparticles on pathogenic bacteria and fungi were equally studied using the colony-forming unit method. The AgNps synthesized showed excellent bactericidal and fungicidal activities against pathogenic Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Candida albicans, and Candida tropicalis. The removal of nitrophenols is one of the most demanding tasks, due to their injurious impact on the health of the living organisms. The AgNps showed superior performance compared with the pure plant extract. The AgNps also displayed efficient catalytic ability in reducing toxic 4-NP into harmless 4-aminophenol in the presence of NaBH4 solution. Hence, the synthesized AgNps can be effectively used against bacterial and fungal infections and in the decontamination of 4-NP polluted water.

Photorhabdus spp. has a high molecular weight Tc toxin with insecticidal activity. These toxins have been suggested as an alternative to BT toxin from Bacillus thuringiensis. Herein, we constructed a cosmid library with the genome of M1021 and screened the Escherichia coli clones showing insect toxicity by injecting each clone into Galleria mellonella larvae. In a total of 1020 clones, one clone with high insecticidal activity was selected and the nucleotide sequence of the cosmid of the clone was determined. In cosmid PtC28, a gene with 87% homology to the tccB gene of Photorhabdus temperata was found. Consequently, we have isolated the tccB gene cassette from the M1021 and expressed in E. coli expression vectors. The toxin was produced in the form of inclusion bodies but the denatured and refolded recombinant TccB showed strong mortality to the G. mellonella larvae.

Cadmium (Cd) is a toxic heavy metal and an abiotic stressor to plants; however, inoculation of endophytic bacteria can raise resistance in plants against Cd, as well as improve plant growth. In the present study, two endophytic bacterial strains were isolated from Solanum nigrum, identified as Serratia sp. IU01 and Enterobacter sp. IU02 by 16S DNA sequencing. Both IU01 and IU02 were tolerant up to 9.0 mM of Cd in culture broth and successive increase in Cd concentration from 0 mM to 9.0 mM, led to an increase in the SOD enzyme activity of the isolates. Both strains were capable of indole-3-acetic acid (IAA) synthesis and phosphate solubilization, detected through gas spectrometry-mass chromatography (GC-MS) and Pikovskaya agar medium respectively. Brassica juncea plants stressed with 0–25 mg/kg Cd showed retardation in all growth attributes, however, inoculation of strain IU01 and IU02 significantly promoted the plant growth attributes as compared to control. Moreover, antioxidant enzymes and metabolites against reactive oxygen species (ROS) including polyphenol oxidase (PPO), peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), alcohol dehydrogenase (ADH), reduced glutathione (GSH), malondialdehyde (MDA), flavonoid and polyphenolic contents were also significantly relieved by inoculation of IU01 and IU02 in plant exposed to different concentration of Cd stress as compared to control plants. Phytohormone production, phosphate solubilization, and/or antioxidative support of IU01 and IU02 might be responsible for growth promotion and Cd resistance in the plant.

Background Hepatic veno-occlusive disease (VOD), also termed as sinusoidal obstruction syndrome (SOS), is a lethal complication after hematopoietic stem cell transplantation (HSCT). Various factors put patients undergoing allogeneic HSCT at an increased risk for VOD. Thrombomodulin (TM) is an important factor which has a wide range of effects, including anticoagulant, anti-inflammatory, angiogenic, and protective effect, on endothelial cells. It plays a role in preventing excessive coagulation and thrombosis by binding with thrombin and inhibiting the coagulation cascade. There are a limited number of options for the prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, as prophylactic therapy might be able to prevent veno-occlusive complications after stem cell transplantation. Methods A literature search was performed on PubMed, Embase, and Web of Science. We used the following Mesh terms and Emtree terms, "Hepatic Veno-Occlusive Diseases" OR "Sinusoidal Obstruction" OR "Stem Cell Transplantations" AND "Thrombomodulin" from the inception of data up to April 1, 2021. The PICO (Patient/Population, Intervention, Comparison and Outcomes) framework was used for the literature search. Results For the VOD incidence after HSCTstem cell transplantation, the result was in favor of rTM with a risk ratio (RR) of 0.53 (I2 = 0%, 95% confidence interval [CI] = 0.32-0.89). The incidence of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT was reduced in rTM group. The RR for incidence of TA-TMA was 0.48 (I2 = 62%, 95% CI = 0.20-1.17) favoring rTM. The RR for incidence of graft-versus-host disease (GvHD) was also lower in rTM group, 0.48 (I2 = 64%, 95% CI = 0.32-0.72). Conclusion In our meta-analysis, we evaluate the efficacy and safety of rTM in the prevention of SOS after HSCT. According to our results, rTM use led to a significant reduction in SOS episodes, TA-TMA, and GvHD after HSCT.

Globally, drought and salinity stress critically constrain potato (Solanum tuberosum L.) production. Considering the impact of these stresses on crops and increasing food demand, insight into both tolerance and susceptibility is essential. The present study screens two potato cultivars, BARI-401 and Spunta, for their tolerance to simulated salinity and drought by in vitro LiCl and mannitol exposure. Plantlets treated with a range of LiCl (0, 10, 30, and 40 mM) and mannitol (0, 50, 100, 200, and 250 mM) concentrations were biochemically and physiologically characterized to assess their tolerance capacity. Shoot number, shoot length, root number, and root length were affected in both cultivars under higher LiCl and mannitol concentrations, even though Spunta was able to better maintain a higher shoot length under the 40 mM of LiCl and 250 mM of mannitol compared to BARI-401. The total phenol contents (TPC) in both cultivars were increased at the highest treatment concentration and the total flavonoids content (TFC) was decreased in BARI-401 as compared to Spunta. Higher free radical scavenging capacity (FRSC, low IC50 value) was recorded in Spunta as compared to BARI-401 with increasing treatment concentrations, which supports the high antioxidant capacity of Spunta. An inverse correlation between polyphenol oxidase (PPO) and TPC was noted in both cultivars. Peroxidase dismutase (POD) activity was increased significantly in both cultivars for all treatments, but activity was highest overall in Spunta. These physiological and biochemical analyses of both cultivars suggest that cultivar Spunta is more tolerant to salinity and drought stress. Further open-field experiments are required to confirm these results.

Acute lymphoblastic leukemia (ALL) typically responds better when treated with multiagent chemotherapy in the pediatric and young adolescent populations. Treatment of relapsed/refractory (RR) ALL remains a challenge. Even after stem-cell transplantation and intensive chemotherapy, the prognosis of RR-ALL remains grave. The advent of chimeric antigen receptors has demonstrated promising results in RR-ALL. Chimeric antigen receptor-modified T cells (CAR-T) and engineered T cells are used to target cancer cells. In 2017, the US Food and Drug Administration approved CD19-specific CAR-T (tisagenlecleucel) therapy for RR-B-cell ALL in patients under 25 years old. In this systematic review, we discuss the efficacy and safety of CD19-specific CAR-T therapy in RR-B-cell ALL in the pediatric and young adult population. We searched the PubMed, Embase, Web of Science, Cochrane Library, and clinical trials databases. A total of 448 patients received a CD19-specific CAR-T product, and 446 patients had evaluable data. The age range was 0 to 30 years. The incidence rate of complete remission was 82%. The cumulative incidence of relapse after CD19-specific CAR-T therapy is 36%. Similarly, the incidence rate of grade 3 or higher adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections, and cytokine release syndrome were 38%, 23%, 18%, 29%, and 19%, respectively. Our subgroup analysis shows the incidence rate of minimal residual negative complete remission was 69% with the CD28z costimulatory domain, 81% with the 4-1BB domain, and 77% with fourth-generation CD19-specific CAR-T therapy.

Crocus sativus, a medicinally important herbaceous plant, has been traditionally used to cure coughs, colds, insomnia, cramps, asthma, and pain. Moreover, the therapeutic applications of saffron include its immunomodulatory and anticancer properties. The current experimental analysis was performed to explore the potential nutraceutical efficacy of corm, leaf, petal, and stigma of saffron ethanolic extracts as analgesic, anti-inflammatory, anticoagulant, and antidepressant using hot plate, carrageenan-induced paw edema, capillary tube and forced swim test, respectively in mice. The results indicated that among all the extracts, stigma ethanolic extract (SEE) represented maximum latency activity (72.85%) and edema inhibition (77.33%) followed by petal ethanolic extract (PEE) with latency activity and edema inhibition of 64.06 and 70.50%, respectively. Corm ethanolic extract (CEE) and leaf ethanolic extract (LEE) displayed mild analgesic activity of 22.40% and 29.07%, respectively. Additionally, LEE (53.29%) and CEE (47.47%) exhibited mild to moderate response against inflammation. The coagulation time of SEE (101.66 s) was almost equivalent to the standard drug, aspirin (101.66 s), suggesting a strong anticoagulant effect followed by PEE (86.5 s). LEE (66.83 s) represented moderate inhibitory effect on coagulation activity while CEE (42.83 s) showed neutral effect. Additionally, PEE and SEE also expressed itself as potential antidepressants with immobility time &le, 76.66 s, while CEE (96.50 s) and LEE (106.83 s) indicated moderate to mild antidepressant efficacy. Based on the in vivo activities, saffron extract, particularly SEE and PEE, can be used as a potential nutraceutical and therapeutic agent due to its significant pharmacological activities.

Sickle cell disease is prevalent in several parts of the world. Most hospitalizations of these patients are related to pain crisis episodes. Moreover, levels of hemoglobin are lower in sickle cell disease patients as compared with the general population. Complications related to sickle cell disease are managed with blood transfusions, hydroxyurea, and opioids. Despite these therapies, patients with sickle cell disease experience multiple pain crisis episodes leading to hospitalizations and end-organ damage. The US Food and Drug Administration has approved three new drugs-L-glutamine, voxelotor, and crizanlizumab-for the prophylaxis and treatment of complications related to sickle cell disease. This review was aimed at assessing the efficacy and safety of recently approved drugs for the treatment of sickle cell disease. A comprehensive search was made on PubMed and clinicaltrials.gov to look for clinical trials reporting the efficacy and safety of recently approved drugs for sickle cell disease. Based on the results of clinical trials, L-glutamine, voxelotor, and crizanlizumab were well tolerated by sickle cell disease patients. L-Glutamine and crizanlizumab reduced the number of sickle cell crisis episodes, while voxelotor improved the level of hemoglobin in sickle cell disease patients. These drugs were effective alone and in combination with hydroxyurea.

The purpose of this study is to check out the spread rate of Hepatitis B Virus in the districts of Mardan and Charsadda, KPK Pakistan. As we know that Hepatitis results in damaging liver tissues, so it is one of the serious threats to the human health across the world. Hepatitis can give rise to acute and chronic infection which give rise to Liver cancer or Liver cirrhosis. It may be transfer from one person to another. Its transmission routs are oral, fecal and parental. The purpose of this paper is to check and judge health condition. Blood serum was collected from Mardan Medical Complex, Mardan and District Head Quarter, Charsadda. The paper was design to calculate anti-HBV antibody positive patients with ICT(immune-chromatography technique)based detection among various patients in MMC Mardan and DHQ hospital Charsada and from various regions of Mardan and Charsadda, KPK Pakistan. Total of 10852 patients of HBV in Charsadda and 14168 patients of HBV in Mardan. The blood samples were collected from Oct 2017 to May 2018 from both districts of KPK. The method for testing blood sample was ICT (immune chromatography technique). Our study about 10852 patients in district Charsadda who were at the risk of HBV infection, 103 were screened positive with the prevalence ratio of 0.949%. On the other hand, 14168 patients`s samples were collected in district Mardan, among them 149 were detected positive and ratio of prevalence is 1.051%. According to the above study the ratio of prevalence is lower in Charsadda as compare to Mardan

The study concentrate on the biosynthesis of silver nanoparticles (AgNps) from the leaves extract of Guiera senegalensis with focus on its; antiproliferation effect on prostate (PC3), breast (MCF7) and liver (HepG2) cancer cell lines, antibacterial effect on Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) and the degradation on 4-nitrophenol (4-NP) and congo red dye (CR). The synthesized AgNps were characterized by FTIR, TEM, FESEM, XRD and EDX analysis. The EDS spectrum revealed that the synthesized nanoparticles (Nps) were composed of 55.45% Ag atoms of spherical shape with approximately 50nm size, identified from TEM and FESEM data. The antiproliferation effect of the AgNps varies with cell lines in a concentration dependent manner. The result showed that the AgNps were more effective on PC3 (IC50 23.48μg/mL) than MCF7 (29.25μg/mL) and HepG2 (33.25μg/mL) by the virtue of their IC50 values. The AgNps were highly effective against E. coli and S. aureus by killing 99% colonies. The AgNps also shows a good catalytic reduction of the toxic organic pollutants in which only 3mg of the AgNps degraded 95% of both CR dye and 4-NP in 22 and 36min respectively. Therefore, the green synthesis of AgNps may have potential applications in pharmacology and industries for the treatment of cancers, bacterial infections and in degrading toxic organic pollutants in water.

Background: Amyloidosis is characterized by the deposition of misfolded lambda or kappa light chain (AL) proteins in tissue. It commonly affects the heart, which correlates with poor prognosis. Disease-modifying therapies aim to suppress the production of abnormal light chains. Daratumumab (Dara) use is associated with a reduction in light chain protein production. Dara is a human anti-CD38 monoclonal antibody approved for the treatment of newly diagnosed and Relapsed & Refractory Multiple Myeloma. AL amyloidosis plasma cells express CD38, and therefore, Dara is an attractive alternative in this setting. This review aims to assess the efficacy and safety of daratumumab in pre-treated AL amyloidosis patients. Methods: We conducted a comprehensive literature search in PubMed, Embase, Medline using MeSH terms and keywords "AL amyloidosis," "daratumumab", and "darzalex" to incorporate the studies published up to July 2020. We included studies assessing the efficacy and safety of daratumumab alone or in combination with other therapies in pretreated AL amyloidosis. After excluding duplicates, non-relevant, and review articles, we selected four prospective and twelve retrospective studies. RESULTS: In our review, data on 482 patients were included. The ages ranged from 35-88 years. The median number of prior therapies was 3 (ranges:2-6), and the most common therapy was bortezomib in 90% of patients followed by immunomodulators in 55% and stem cell transplant in 35%. A total of 260 (54%) patients received Dara monotherapy, 126 (26%) received Dara plus Dexamethasone (d), and 96 (20%) patients received other Dara containing two or three-drug regimens. The time from the diagnosis to the start of Dara therapy varied from 1 to 137 months. 71 % of patients had cardiac, and 62 % had renal involvement. There was a greater than 30 % reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) in cardiac patients responsive to therapy. 1. Daratumumab monotherapy: Dara monotherapy achieved an overall response rate (ORR) of 76% (191/249), complete response (CR) of 30% (69/224), very good partial response (VGPR) of 41% (79/192) and partial response (PR) of 14% (19/140). The overall survival (OS) ranges from 59-100% at 10-12 months were noted. Table 1. 2. Daratumumab+ Dexamethasone: Dara plus d achieved ORR of 81% (86/106), CR of 51% (53/102), VGPR of 29% (18/62), PR of 15% (15/102), and OS of 87% at 24 months. Table 1. 3. Daratumumab with combination regimens: The use of Dara based combination regimens of Dara+pomalidomide (P)+d (36% of patients), Dara+lenalidomide (R)+d (32%) and Dara+bortezomib (V)+d (18%), reported by Abeykoon et al., showed an ORR of 88% (14/16), CR of 19 % (3/16), VGPR of 63% (10/16), PR of 6 %(1/16), OS of 89 % at 10 months and progression-free survival (PFS) of 83% at 10 months. Godara et al. reported an ORR of 100% (9/9) using a combination of Dara and birtamimab. The combination of D+cyclophosphamide (c)+V+d reported by Palladini et al. achieved an ORR of 96 % (27/28), CR of 36 % (11/28), VGPR of 29 % (8/28) and PR of 14 % (4/28).Table 1. The most reported adverse event was infusion-related reactions; grade 3-4 adverse were less than 10 % and mostly related to the heart (heart failure & atrial fibrillation). The most-reported hematological adverse effects were anemia, thrombocytopenia, neutropenia, infections, and sepsis. The most common non-hematological adverse events were heart failure, bronchitis, pneumonia, fatigue, nausea, and diarrhea. Table 2. Conclusion: Dara therapy is associated with promising efficacy with a response rate of more than 70% when used alone and more than 80% when used in combination. These regimens are well tolerated in advanced cardiac disease patients with a tolerable risk of volume overload and infusion-related complications. Additional multicenter randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Background: Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the US. Lenalidomide (Len), an immunomodulator, is used in the treatment of multiple hematological malignancies. This systematic review and meta-analysis aimed to assess the efficacy and safety of Lenalidomide based regimens in Newly Diagnosed (ND) and Relapsed/Refractory (R/R) DLBCL. Methods : A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, "Lenalidomide" OR "Revlimid" AND "diffuse large B cell lymphoma" from the inception of literature till 06/20/2020. We screened 1640 articles and included 2 randomized clinical trials (N=72) and 21 single-arm clinical trials (N=860) in this meta-analysis. We excluded case reports, case series, preclinical trials, review articles, meta-analysis, observational studies, and clinical trials not providing any information about the lenalidomide efficacy or safety in DLBCL. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results : In 23 studies (N=932), Len based regimens were used in patients with age 19-92 years (range) Table 1. In 5 trials on R/R patients (N=252), Len was used as a maintenance therapy. Cumulative overall response rate (ORR) and cumulative complete response (CR) were 0.27 (95% CI 0.21; 0.33, I2=0%) (Fig1) and 0.10 (95% CI 0.07; 0.16, 8%) (Fig2), respectively. In one phase III trial, the ORR and CR were significantly improved in the Len arm vs investigator's choice drug. In 4 trials on R/R patients (N=207), Len with monoclonal antibodies (MoAb) was used. Cumulative ORR and CR were 0.40 (95% CI 0.28; 0.54, I2=71%) and 0.28 (95% CI 0.17; 0.42, I2=72%), respectively. In a trial on R/R patients (N=33), Len with Gemcitabine, Rituximab, and Oxaliplatin was used. Cumulative ORR and CR were 0.61 (95% CI 0.43; 0.76, I2=0%) and 0.39 (95% CI 0.24; 0.57, I2=0%), respectively. In a trial on R/R patients (N=15), Len with RICE was used with ORR and CR of 0.73 (95% CI 0.47; 0.90, I2=0%) and 0.60 (95% CI 0.35; 0.81, I2=0%), respectively. In a trial on R/R patients(N=55), Len with Everolimus was used. ORR and CR were 0.27 (95% CI 0.17; 0.40, I2=0%) and 0.07 (95% CI 0.03; 0.18, I2=0%), respectively. In a trial on R/R patients (N=19), Len with R-ESHAP was used. ORR and CR were 0.79 (95% CI 0.55; 0.92, I2=0%) and 0.47 (95% CI 0.27; 0.69, I2=0%), respectively. In a phase III trial on R/R patients (N=21), Len with Gemcitabine and Rituximab was used vs. placebo The ORR and CR were significantly improved in the Len arm vs placebo. In 4 trials on ND patients (N=158), Len with R-CHOP was used and the cumulative ORR and CR were 0.94 (95% CI 0.88; 0.97, I2=12%) and 0.81 (0.75; 0.87, I2=0%), respectively. In a trial on ND patients (N=15), Len with R-EPOCH was used with ORR and CR of 0.93 (95% CI 0.65; 0.99, I2=0%) and 0.87 (95% CI 0.59; 0.97, I2=0%), respectively. In 2 trials (N=103), Len with Ibrutinib and Rituximab was used. In R/R patients (N=45), cumulative ORR and CR were 0.38 (95% CI 0.25; 0.53, I2=0%) and 0.24 (95% CI 0.14; 0.39, I2=0%), respectively. In ND patients (N=58) has ORR and CR 0.86 (95% CI 0.75; 0.93, I2=0%), respectively. In 2 trials with a combination of ND and R/R patients (N=54), Len with Rituximab and Bendamustine was used. Cumulative ORR and CR were 0.63 (95% CI 0.49; 0.75, I2=0%) and 0.39 (95% CI 0.27; 0.52, I2=0%), respectively. The most common serious treatment-related adverse events (TRAE) were infection, thromboembolism, fatigue, sepsis, respiratory, neurological, cardiac (arrhythmias), gastrointestinal, rash, seizures, and hematological side effects (Table 1). Conclusion : Based on early phase trials, Len based regimens are well tolerated and effective in the treatment of both ND and R/R DLBCL patients. Combinations of lenalidomide with Tafasitamab and R-ESHAP have shown the highest response in R/R patients and combination with R-CHOP has shown the best response in ND patients. In randomized trials, lenalidomide has shown significant improvement in the survival of DLBCL patients as compared to placebo or physician's choice drug. Additional double-blind multicenter randomized clinical trials are needed to compare the efficacy and safety of lenalidomide based regimens in DLBCL patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Background: Multiple myeloma (MM) is an incurable disease, and clinical trials with newer agents have shown improved patient outcomes. There is a need for effective and tolerable treatment for patients with relapsed/refractory MM (RRMM). Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) remain an integral part of regimens used in RRMM or newly diagnosed (ND) MM. This meta-analysis aims to assess the efficacy and safety of ixazomib (Ixa) based regimens in RRMM. Methods: A comprehensive literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used MeSH and Emtree terms, "ixazomib" AND "multiple myeloma" from the inception of literature till 06/01/2020. We screened 1529 articles and included 3 randomized clinical trials (RCT, N=907) and 8 non-randomized clinical trials (NRCT, N=321). We excluded case reports, case series, review articles, meta-analysis, observational studies, and clinical trials that didn't provide data about the efficacy and safety of Ixa in RRMM. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 11 clinical trials (N=1228), the age range of patients was 30-91 years. In Phase III RCTs (N=837) comparing Ixa + Lenalidomide (Len) + dexamethasone (Dex) vs. placebo + Len + Dex, risk ratio of overall response rate (ORR), complete response (CR), and very good partial response (VGPR) were 1.14 (95% CI=1.05-1.24, I2=80%), 1.87 (95% CI=1.17-2.99, I2=0), and 1.15 (95% CI=0.95-1.40, I2=0), respectively in favor of Ixa + Len + Dex. (Fig 1-3) Grade 3 or higher treatment-related adverse events (TRAEs) thrombocytopenia, diarrhea, and rash were reported in 20%, 5.7% and 6.4% of the patients in the Ixa group vs. 10%, 2.1%, and 2.8% in the placebo group, respectively. In a Phase II RCT by Kumar et al (N=70) comparing the Ixa dosage, 4 mg Ixa + Dex yielded an ORR of 31%, CR 2.8%, and VGPR 17.1%, while 5.5 mg Ixa yielded improved ORR of 54%, CR 2.8%, and VGPR 25.7%. In a NRCT by Costello et al. (N=6), Ixa + daratumumab (Dara) + Pom + Dex yielded 100% ORR, CR 5% (95% CI=0.17-0.83), and VGPR 50% (95% CI=0.17-0.83). ≥Grade 3 TRAEs were hypertension (16%), and hematological (33%). Among 417 patients from two RCT in single arm who received Ixa + Len + Dex, pooled ORR was 70% (95% CI=0.53-0.82, I2=84%), pooled CR 11% (95% CI=0.8-0.14, I2=0), and pooled VGPR was 29% (95% CI=0.18-0.43, I2=66%). In a NRCT by Dhakal et al. (N=19), Ixa + bendamustine + Dex yielded an ORR 58% (95% CI=0.36-0.77), CR 0, and VGPR 11% (95% CI =0.03-0.34). ≥Grade 3 TRAEs were neutropenia 31%, thrombocytopenia 52%, and diarrhea 10%. In 2 NRCT (N=106), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR 52% (95% CI=0.42-0.61, I2=0), CR 4% (95% CI=0.01-0.10, I2=0), and VGPR 17% (95% CI=0.11-0.25, I2=0). ≥Grade 3 TRAEs were thrombocytopenia (15%), and upper abdominal pain (4%). In a NRCT by Ludwig et al. (N=90), Ixa + thalidomide (Thal) + Dex yielded an ORR 51% (95% CI=0.41-0.61), CR 9% (95% CI=0.5-0.17), and VGPR 14% (95% CI=0.09-0.23). ≥Grade 3 TRAEs were anemia (17.8%), and infections (16.1%). In a NRCT by Krishnan et al. (N=31), Ixa + Pomalidomide (Pom) + Dex yielded an ORR 48% (95% CI=0.32-0.65) and VGPR 16% (95% CI=0.07-0.33). (Fig 4-6) ≥Grade 3 TRAEs were neutropenia (10%), and lymphopenia (35%). In 2 NRCT by Kumar et al. (N=70) of two drugs combination, Ixa + Dex yielded a pooled ORR 43% (95% CI=0.28-0.59, I2=47%), pooled CR 1% (95% CI=0-0.09, I2=0), and pooled VGPR 24% (95% CI=0.16-0.36, I2=0). ≥Grade 3 TRAEs were hematological (28%), and non-hematological (22.8%). In 2 NRCT of Ixa monotherapy (N=69), pooled ORR was 17% (95% CI=0.10-0.28, I2=0), and pooled CR 6% (95% CI=0.2-0.22, I2=0). (Fig 4-6) ≥Grade 3 TRAEs were anemia (11%), thrombocytopenia (5.4%), and neutropenia (2.7%). Conclusion: Our study provides useful insight into relative efficacy of various Ixa regimens for the treatment of RRMM. The pooled analysis of RCT showed that the combination of Ixa + Len + Dex yielded better response as compared to placebo. In the pooled analysis of outcomes in single arm NRCT, Ixa + Dara + Pom + Dex and Ixa + Len + Dex showed better efficacy outcomes as compared to Ixa + Dex in combination with Thal, Cyc, or Bendamustin. Three drugs Ixa combination regimens had better efficacy as compared to two drugs combination of Ixa + Dex and Ixa monotherapy. Ixa was well tolerated with acceptable safety profile. Additional multicenter, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Background: Hepatic veno-occlusive disease (VOD) also termed as sinusoidal obstruction syndrome (SOS) is a lethal complication seen after haematopoietic stem cell transplantation (HSCT). There are a limited number of options for prevention of this fatal complication. Recombinant thrombomodulin (rTM), an endothelial anticoagulant co-factor, has been shown to help prevent veno-occlusive complications after stem cell transplantation. Various trials have shown safety and efficacy of recombinant thrombomodulin in preventing SOS. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "thrombomodulin" AND "stem cell transplantation" from the inception of literature till June 2020. Out of 239 articles, we screened and included nine trials (N=850) in the systematic review and meta-analysis. We extracted the data for VOD episodes, graft vs host disease (GVHD) episodes and survival after stem cell transplantation. We excluded case reports, preclinical trials, review articles, meta-analysis, and trials not providing any information about the above-mentioned. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: Total number of patients tested was 356 in thrombomodulin group and 494 in control group. The age range was 16 to 74 years. Thrombomodulin group had 254 males and control group had 190 (Table 1.). For VOD, risk ratio (RR) was 0.53 (I2= 0%, 95% CI=0.32-0.89) in favor of rTM vs heparin or no therapy for prevention of VOD after stem cell transplantation (Fig 1.). rTM was effective in prevention of transplant-associated thrombotic microangiopathy (TA-TMA) after HSCT. RR was 0.48 (I2= 62%, 95% CI=0.20-1.17) with significant lower incidence of TMA in rTM group (Fig 2.). In a trial, seven of nine patients recovered from TA-TMA in the rTM group, but none recovered in the control group who received various therapies including fresh frozen plasma, therapeutic plasma exchange(TPE) or others (p=0.003) (Fujiwara et al). The risk of GVHD was also significantly lower in rTM group and RR was 0.48 (I2= 64%, 95% CI=0.32-0.72) which again favours rTM vs heparin or no therapy (Fig 3.). Ishii et al showed that stepwise multivariate logistic regression analyses revealed that anti-coagulation therapy without rTM was an independent risk factor for aGVHD (p=0.000, odds ratio=3.006) and VOD (p=0.015, odds ratio=2.65). Yakushijin et al compared rTM with Defibrotide and found similar complete remission (CR) rate and the overall survival (OS) at day 100 in both the groups. Therefore, rhTM could be one of the potential novel candidate for SOS treatment. Use of rTM improved the survival rate of patients with disseminated intravascular coagulation (DIC), diagnosed according to the criteria established by the Ministry of Health, Labor and Welfare of Japan, at day 100 (83% vs. 50%, P = 0.026) and significantly prolonged the OS of these patients (P = 0.044). The Kaplan-Meier curves clearly showed the improved non-relapse-related mortality of patients who received rTM after HSCT (Ikezoe et al). Mean DIC scores improved significantly with the use of rhTM (p = 0.003; DIC withdrawal rate 91.7%). FDP and CRP levels were also significantly decreased (p = 0.042 and p = 0.001). The recovery rate from DIC at 28 days was significantly better in rTM than in antithrombin or heparin group (p = 0.011) (Inoue et al). The mean peak plasminogen activator inhibitor type one (PAI- 1) level was significantly lower in the rTM group vs heparin and ursodiol group (P = 0.04), and the mean peak activated protein C (APC) level was significantly higher in the rTM group (P = 0.01) (Yamamoto et al). No serious grade 3 or 4 adverse events were reported by trials. Conclusion: This systematic review and meta-analysis shows that prophylactic rTM (380 units/kg) has a beneficial role in the prevention of post- HSCT SOS complication in patients that are at high risk of developing the condition. It appears to help improve treatment-related mortality and overcome the poor survival rates. Additional randomized clinical trials are needed to establish efficacy and safety of rTM to prevent VOD and to confirm these results. Disclosures Anwer: Celgene: Research Funding; Millennium Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau.

Introduction The ability of the neoplastic cells to escape from immune surveillance has been considered as a hallmark of cancer. The upregulation of programmed death-1 (PD-1) and programmed death ligand-1/2 (PDL-1) axis is a major immune escape pathway in multiple malignancies including classical hodgkin lymphoma (cHL). Disruption of PD1-PDL1/2 pathway using checkpoint inhibitors (CPIs) leads to reactivation of immune cells to attack malignant cells. CPIs have been studied in cHL in different settings. Here in, we did a systematic review and meta-analysis of phase II and III clinical trials that looked at the efficacy of CPIs in cHL Methods We did a comprehensive literature search, using 4 major databases (pubmed, embase, chocrane, and clinialtrials.gov). We used MeSH terms and related keywords that included all CPIs in generic and trade names, and cHL. We included phase II and III prospective clinical trials in patients > 18 year-old. We excluded case reports, case series, review articles, retrospective and observational studies, and phase I clinical trials. Initial search resulted in 1647 articles. After applying the inclusion and exclusion criteria, we had 13 articles that we explored in details. We stratified the articles according to CPIs and did a pooled-analysis of the complete response (CR) rate. Medcalc was used to do the statistical analysis. Results Of those 13 clinical trials, we had 12 phase II trials and 1 phase III trial. Nivolumab was studied in 7 trials (n=568), pembrolizumab in 5 trials (n=427), and camrelizumab in 1 trial (n=86). Table 1 shows the characteristics of these trials. (table 1) Four studies evaluated the efficacy of nivolumab in the relapsed/refractory (RR) setting. Armand et al (2018) evaluated the efficacy of nivolumab after autologous hematopoietic stem cell transplantation (auto-HSCT), the cohort in this study was divided into 3 groups: patients who received brentuximab vedotin (BV) after auto-HSCT, patients who are BV naïve, and patients who received BV before and/or after auto-HSCT. Overall response rate (ORR) and CR were 68% and 13%, 65% and 29%, 73% and 12%, respectively. Maruyama et al (2017) reported ORR and CR of 81.3% and 25%, in 16 Japanese patients received nivolumab in combination with BV. The ORR and CR in the remaining 2 trials were: 82% and 59%, and 85% and 67%. In the frontline setting, nivolumab showed ORR and CR of 84% and 67% (Ramchandren et al, 2019), 96%-100% and 53-85% (Brockelmann et al, 2019 in 2 different dosing regimens), and 100% and 72% (Yasenchack et al, 2019). Pooled analysis of all nivolumab trials showed CR rate of 47.4 % (95% CI 29.0-66.1) (figure 1) Pembrolizumab was evaluated in 4 clinical trials in the RR setting. Armand et el (2019) reported CR rate of 83% in 25 patients. Chen et al (2019) reported ORR and CR of 76.8 % and 26.1% in patients who relapsed after auto-HSCT and BV, 66.7% and 25.9% in patients ineligible for HSCT, and 73.3% and 31.7% in patients who relapsed after auto-HSCT with no prior exposure to BV. In combination with gemcitabine, vinorelbone , and doxorubicin, pembrolizumab showed ORR and CR of 100% and 93%, respectively. The only phase III clinical trial compared pembrolizumab vs BV in the RR setting showed ORR of 65.6% vs 54% and CR of 24.5% vs 24%, respectively. Only one study evaluated pembrolizumab in the frontline setting, ORR and CR of 100% in 30 patients received 3 cycles of pembolizumab followed by 4-6 cycles of doxorubicin, vinblastine, and dacarbazine. Pooled analysis of all pembrolizumab trials showed CR rate of 54.4% (95% CI 32.6-77.2) (figure 2) Only one trial evaluated the role of camrelizumab as monotherapy or in combination with decitabine. The combination regimen showed ORR and CR of 95% and 71% in CPIs naïve patients, and 52% and 28% in patients previously received CPIs. Camrelizumab monotherapy showed ORR and CR of 90% and 32% in CPIs naïve patients. Conclusion CPIs in cHL have showed high rates of response in the frontline and RR settings, with fairly acceptable toxicity profile. Their efficacy was studied post HSCT and BV, in BV naïve patients, and in HSCT-ineligible patients. Pembrolizumab and nivolumab were the 2 most studied CPIs. Future direction should focus on more studies in the frontline setting, the role of combined CPIs with other CPIs or with novel agents, to spare this relatively young population the long term toxicity of chemotherapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.Fazal:Jansen:Speakers Bureau;Jazz Pharma:Consultancy, Speakers Bureau;Stemline:Consultancy, Speakers Bureau;Glaxosmith Kline:Consultancy, Speakers Bureau;Gilead/Kite:Consultancy, Speakers Bureau;Amgen:Consultancy, Speakers Bureau;Novartis:Consultancy, Speakers Bureau;Agios:Consultancy, Speakers Bureau;BMS:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene:Speakers Bureau;Karyopham:Speakers Bureau;Incyte Corporation:Consultancy, Honoraria, Speakers Bureau;Takeda:Consultancy, Speakers Bureau.

BACKGROUND: Acute Lymphoblastic leukemia (ALL) has good prognosis when treated with multiagent chemotherapy in pediatrics and young adolescents. Treatment of relapsed/refractory (R/R) ALL remains a challenge. Even after stem cell transplantation (SCT), the prognosis of R/R ALL is still grave. Chimeric antigen receptor- T cell (CAR-T) therapy, uses T cells engineered for cancer therapy. CD-19 specific Car-T cell is a recent advancement, FDA approved use of tisagenlecleucel in 2017 for R/R- B cell ALL in patients under 25years of age. In this systematic review we will discuss efficacy and safety of CD-19 specific CAR-T cell therapy in R/R B-ALL in pediatrics and young adults. There are still 30 clinical trials that are going on the CD-19 CAR-T cell therapy in R/R ALL in pediatrics and adults MATERIALS and METHODS: We searched PubMed, Embase, Clinical Trials, Web of Science and Cochrane. We searched without any filters and used Mesh Terms for "ALL" and "Chimeric antigen receptor". After screening of 2381 articles, we included 12 clinical trial and 3 prospective studies evaluating the role of CD-19 specific CAR-T cell in Relapsed/ Refractory ALL in pediatrics and young adults under 30years only. We followed PRISMA guidelines in literature search and selection of studies. We used "R" for meta-analysis. RESULTS: A total of 448 patients received a CD-19 specific CAR-T cell product and 446 patients were evaluable. The age range was 0-30 years. The female population in reported studies was 42.8% (n=111/259). Fludarabine and cyclophosphamide lymphodepleting therapy was used as a conditioning regimen followed by a single infusion of CAR-T cell product. Second generation CAR-T cell with a 4-1BB signaling domain was used in 66.7% of studies (n=10/15). High Risk cytogenetics was seen range from 4%-32% (n=53/220) and CNS disease in 66.9% (n=73/109) of the population. Median number of prior therapies ranges from 1 to 8 and 43.5%(n=186/247) had previous allo-HSCT. The median follow-up ranges from 3 to 14.4months. [Table 1] Complete remission (CR) and complete remission with incomplete count recovery (CRi) range from 50%-95% of the total participants. CR with minimal residual disease (MRD) negative status was reported in 50% to 86% of total participants. The Relapse rate range from 26%-100% of the total participants. Of 82 cases of relapse, 27 had CD19 positive disease, 42 had CD19 negative, 10 had unknown status. There were 3 AML transformations. Median overall survival at 12months ranges from 63%-84%. Median event free survival ranges from 46%-76%. [Table 1] The cumulative incidence of complete remission is 82% (heterogeneity,I2=27%) (95%CI; 0.82[0.76; 0.87]). Cumulative incidence of relapse after CD19 CAR-T cell therapy is 36% (heterogeneity,I2=10%), (95%CI; 0.36[0.29;0.43]). Similarly pooled cumulative incidence of ≥Grade 3 adverse events of neutropenia, thrombocytopenia, neurotoxicity, infections and cytokine release syndrome was 38%(95%CI; 0.38[0.09; 0.72]), 23%(95%CI; 0.23 [0.09; 0.39]), 18%(95%CI; 0.18[0.10; 0.26]) , 29%(95%CI; 0.29[0.16; 0.46]),19%(95%CI; 0.19[0.08;0.33]) respectively. [Table 2, Fig 1] CONCLUSION: CAR-T cell therapy against R/R B-ALL can achieve CR in significant pediatric patient population. The relapse rate is also high, about 36% pooled cumulative incidence. Being a bridging therapy, there is a need for additional therapy such as HSCT or maintenance targeted chemotherapy after CAR-T cell therapy while the patient is in remission. While most studies are phase-1 and there are still 30 ongoing clinical trials, we will be in a better position in near future to evaluate the effect of CAR-T cell therapy on overall survival and relapse rate after CAR-T cell therapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Background: Low-risk Myelodysplastic Syndromes (MDS) patients commonly present with anemia and may become blood transfusions dependent upon progression. Luspatercept, a targeted drug for an activin receptor ligand has emerged as new anemia treatment in MDS for patients with ring sideroblasts and the patients with SF3B1 mutation. This systemic review highlights the efficacy of luspatercept in MDS patients whom erythropoietin stimulating agents (ESA) are not effective. Methods: We conducted a comprehensive literature search using PubMed, Clinical trial.gov, Embase, Cochrane, and Web of science. Our search strategy included MeSH (Medical Subject Headings) terms and keywords for MDS and luspatercept including trade names and generic names from inception to 29 April 2020. Studies were selected according to PRISMA guidelines. The initial screening revealed 240 articles. After excluding review articles, duplicates, and non-relevant articles, finally we included two clinical trials, which reported transfusion independence (TI), an erythroid response (HI-E) in MDS patients with luspatercept. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.0.2) to report the efficacy of luspatercept. We pooled the results of the experimental arms of the two trials using the inverse variance method and logit transformation. Between studies, variance was calculated using DerSimonian-Laird Estimator. Results: A total of 287 patients were enrolled and evaluated in two phases II/III trials. Platzbecker et al and Fenaux et al reported Erythropoietin stimulating agents (ESA) with one median prior line of therapy (n= 148, n=46). Fenaux et al. also reported iron chelation therapy (n=71) as a prior line of therapy. Patients having ring sideroblast positive 500: n=57 for both studies. The baseline means hemoglobin (Hb) levels were eight before therapy. TI for more than eight weeks was observed in 38% of patients in both the MEDALIST trial and PACE trial. The erythroid response was 53% and 63% in both trials respectively. In a Phase II study, for LR-MDS patients, the overall erythroid response was higher among patients (n= 69%) having ringed sideroblast status (>15% ring sideroblast) and SF3B mutation (n=77%). The mean increase of Hb was observed in 29 out of 46 and 32 out of 41 pts in MEDALIST and PACE trial, respectively. Luspatercept proved to be efficacious in the pooled analysis i.e transfusion independence (TI): 38%, 95% CI 0.31-0.45; p =0.98, I2 = 0%), and erythroid response (HI-E): 54%, 95% CI 0.48-0.62; p=0.22, I2 = 32%) with an increase in mean Hb of 70% 95%: CI 0.59-0.78; I2 = 56%) (Figure 1). CONCLUSION: In patients with low risk MDS positive ringed sideroblast or SF3B1 mutation status shows good responses with luspatercept treatment, with reduced transfusion dependence, and higher erythroid response. Disclosures Anwer: Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Millennium Pharmaceuticals: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; AbbVie Pharmaceuticals: Research Funding.

Background: Conditioning regimen given before allogeneic hematopoietic stem cell transplantation (allo-HSCT) contributes significantly to the outcomes following transplant for myelodysplastic syndrome (MDS). Myeloablative conditioning (MAC) regimens are often associated with a lower risk of relapse; however, their use is often limited by toxicity and a higher risk of non-relapse mortality (NRM). Reduced-intensity conditioning (RIC) regimens are associated with a higher risk of relapse, a lower NRM, a lower incidence of graft versus host disease (GVHD), and hence is feasible in patients with advanced age or comorbidities. This study highlights the importance of the difference between the two interventions used in allo-HSCT for myelodysplastic syndrome (MDS). Methods: We conducted a comprehensive literature search using PubMed, Clinicaltrial.gov, Embase, Cochrane, and Web of Science on 5th May 2020 with no restriction of language or period. Initial research revealed 1698 articles. After excluding review articles, duplicates, and non-relevant articles, we included two randomized clinical trials and three cohort studies, which reported overall survival (OS), relapse-free survival (RFS), relapse incidence (RI), and incidence of acute and chronic (GVHD). Based on inclusion criteria, two randomized clinical trials (BMT CTN 0901 Trial Scott et al. 2017 & EBMT RICMAC Trial Kroger et al. 2017) and three cohort studies (BBMT 55226 Park et al. 2018, BBMT Orozco et al. 2019, BMT Alatrash et al. 2019) were included. Results: Among combined MDS and acute myeloid leukemia (AML) patients (n=1188) enrolled in 5 studies, 651 patients had MDS. Patients underwent MAC (n=484) or RIC (n=692) followed by either a matched related donor (MRD), n=236, or matched unrelated donor (MUD), n=236, allo-HCT. The median age range at the time of transplant was 50-54 years The use of RIC causes statistically non-significant trend of improved overall survival (OS) (OR 1.11: 95% CI: 0.74-1.67, p-value= 0.61) along with more risk of relapse incidence (RI) (R 1.34: 95% CI: 0.56-3.18, p value= 0.51), and reduced relapse free survival (RFS) (OR 0.88, 95% CI: 0.55-1.44: p value= 0.59). Differences were found in terms of safety of both conditioning regimens. MAC allo-HCT have more acute GVHD, grade 3 and 4 (OR 0.66: 95% CI: 0.29-1.52, p value= 0.33) and chronic GVHD, grade 3 and 4 (OR 0.72: 95% CI: 0.41-1.27: p value= 0.26) and treatment-related mortality (TRM) (OR 0.83, 95% CI: 0.37-1.86, p value= 0.65). The meta-analysis results are shown in figure-1. Conclusion: In adult MDS patients undergoing allo-HSCT, RIC is associated with improved overall survival, but at the cost of reduced RFS, and a higher risk of relapse. MAC, on the other hand, is associated with more treatment-related mortality and GVHD. Results of our analysis point out these trends but these are not statistically significant Figure 1 Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Background: Phosphatidylinositol-3-Kinase (PI3K)-oncogenic protein kinase is ubiquitously expressed in cells, however, PI3Kδ and PI3Kγ are selectively expressed in hematopoietic cells predominantly in leucocytes. Suppression of the PI3K pathway has emerged as a therapeutic strategy for non-Hodgkin lymphoma (NHL) and 3 PI3K inhibitors are already approved for therapeutic use with many others under exploration. The application of these agents in terms of risk and benefit remains scarcely explored. Therefore, a systematic review and meta-analysis was conducted to assess the efficacy and safety of PI3K inhibitors in non-Hodgkin lymphoma. Methods: A comprehensive literature search was conducted from inception to the 4th of April 2020, following PRISMA guidelines on 4 databases (PubMed, Cochrane library, clinicaltrials.gov, web of science, and Embase). A search was performed without the use of filters and the MeSH terms used were "lymphoma, non-Hodgkin" and "phosphoinositide-kinase inhibitors". Only studies with available data that were either completed or still recruiting were included. Trials with no reported efficacy or safety data were excluded. A pooled analysis of the extracted data was performed using the "meta" package by Schwarzer et al. in the R programming language (version 4.0.2). For data analysis purposes, in the case of multi-arm studies, only those cohorts where PI3K was administered were included. The event rates were pooled using the inverse variance method and logit transformation. The between-studies variance was calculated using the DerSimonian-Laird estimator. The random-effects model was used for the analysis. Results: Initial search revealed 391 articles. After a thorough screening, 22 studies involving 1123 patients with relapsed or refractory NHL that fulfilled the inclusion criteria were included (Table 1). The median age ranged from 58-70 years. The median number of prior therapies ranged from 2 to 4. Twenty studies used a selective PI3K inhibitor including voxtalisib, pilaralisib, umbralisib, duvelisib, idelalisib, copanlisib, buparlisib, and parsaclisib. The pooled overall response rate (ORR) was 50% [95% CI: 42%; 58%] with pooled complete response of 15% [95% CI: 12%; 20%]. A subgroup analysis was performed on complete responses (CR) of patients with diffuse large B cell lymphoma (DLBCL), and follicular lymphoma (FL). The CR in FL and DLBCL were 20% [95% CI: 15%-20%] and 14% [95% CI 8%-25%] respectively, and the difference between the two subgroups was statistically non-significant with the Cochran Q test yielding the p-value of 0.34. The overall survival (OS) was extractable in only 3 studies with the highest OS reported as 28.9 months. The progression-free survival (PFS) ranged from 1.9 to 37.1 months and was reported in 16 studies. In terms of safety, the most common ≥ grade 3 hematologic abnormality was neutropenia with a pooled incidence rate of 24% [18%; 32%] while the pooled incidence rates of anemia and thrombocytopenia were 11% [7%; 17%], and 10% [7%; 13%]. Diarrhea was the most common ≥ grade 3 non-hematological adverse event, which was seen in 14.85% [12%;18%] patients. Conclusion: PI3K pathway inhibitors have shown promising efficacy. However, the therapeutic applicability is hindered by the off-target adverse events especially gastrointestinal as well as the consequences of neutropenia. Overcoming these limitations would involve exploring the selectivity of novel agents, optimizing sequencing, use in combination regimens, and varying of the doses. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Introduction: Hematopoietic stem cell transplantation (HSCT) is used for the treatment of multiple hematologic diseases. The donor cells kill the host malignant cells, but unfortunately, the immune response can cause graft vs. host disease (GvHD). Anti-thymocyte globulin (ATG) is an antibody derived from rabbits or horses. It targets antigens expressed on T-cells, B-cells, macrophages, natural killer cells, and dendritic cells, and used for the prevention of GvHD. We conducted a meta-analysis to assess the efficacy of ATG in preventing high-grade GvHD after hematopoietic stem cell transplant. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following mesh terms and Emtree terms, "antilymphocyte globulin" OR "antithymocyte globulin" AND "graft vs. host disease" from the inception of literature till 06/01/2020. We screened 5767 articles and included 10 randomized clinical trials (N=1,227) and 31 observational studies (N=14,895) in this meta-analysis. We extracted data for severe acute GvHD (grade III-IV or grade II-IV) and severe chronic GvHD (an extensive disease by Seattle criteria or moderate to severe disease according to NIH criteria). We excluded case reports, case series, preclinical trials, single-arm studies, review articles, meta-analysis, and controlled studies not providing any information about high-grade GvHD. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 41 included studies (N=16,122), the median age was ≥40 years in 22 studies (N=12,099), ≤40 years in 16 studies (N=3536), and ≤18 years in 3 studies (N=487). 2986 patients had at least one HLA allele mismatch. Out of 41 studies, data for high-grade acute GvHD was available in 40 studies (N=16,047), and data for high-grade chronic GvHD was available in 33 studies (N=14,206), see Figure 1, 2. For high-grade acute GvHD, risk ratio (RR) was 0.68 (I2=24%, 95% CI=0.61-0.75) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 9 RCTs (N=1,152), RR was 0.59 (I2=38%, CI=0.42-0.82) in favor of ATG use. High-grade acute GvHD significantly improved in all subgroups, i-e., peripheral blood (PB) /bone marrow (BM) HSCT from related donors (RR=0.73; 95% CI=0.61-0.88), PB/BM transplant from unrelated donors (RR=0.62; CI=0.52-0.72) and umbilical cord blood (UC) HSCT (RR=0.61; CI=0.43-0.88). For high-grade chronic GvHD, RR was 0.47 (I2=49%, 95% CI=0.40-0.55) in favor of the use of ATG vs. no use of ATG in the prophylaxis of GvHD with HSCT. In 6 RCTs (N=714), RR was 0.40 (I2=58%, 95% CI=0.27-0.61) in favor of ATG use. High-grade chronic GvHD significantly improved with the use of ATG in both related donors (RR=0.44; 95% CI=0.34-0.58) and unrelated donors (RR=0.46; 95% CI=0.38-0.55) subgroups for BM / PB HSCT. However, there was no significant improvement in the risk of high-grade chronic GvHD with the use of ATG with cord blood HSCT (RR=0.98; 95% CI=0.73-1.31). Conclusion: ATG is effective in the prophylaxis of severe acute GvHD irrespective of donor relationship or type of HSCT. ATG is also effective in the prophylaxis of severe chronic GvHD with bone marrow or peripheral blood HSCT except for cord blood HSCT. Additional multicenter randomized double-blinded clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Introduction: Stem cell transplantation (SCT) is used to treat multiple malignancies, but a major complication of the procedure is graft versus host disease (GvHD), which is a significant cause of morbidity and death in SCT patients. Methylprednisolone is the first-line therapy of GvHD. Ruxolitinib is a Janus kinase (JAK) inhibitor that can dampen the effect of inflammatory cytokines involved in GvHD and may be used in patients refractory to steroid treatment. In this systematic review and meta-analysis, we assessed the safety and efficacy of Ruxolitinib in steroid-resistant (SR) acute (a) and chronic (c) GvHD. Methods: We performed a search on PubMed, Cochrane, Embase, and Web of Science. We used the keywords, "Ruxolitinib" AND "Graft vs Host Disease" from the inception of literature till 7/10/2020. We screened 694 articles and included 1 randomized clinical trial (RCT) (N=309), 4 non-randomized trials (NRCT) (N=232), and 13 observational studies (N=481) in this meta-analysis. We extracted data for efficacy (i-e, OS, CR, ORR) and safety (≥grade 3 treatment related adverse events (TRAE). We excluded case reports, case series, review articles, meta-analysis, and preclinical trials. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In the 18 included studies (N=1022), Ruxolitinib was used in patients with the age range of 6 months to 70 years. 417 participants had grade III-IV acute GvHD, and 272 participants had moderate to severe chronic GvHD (Table 1). In an RCT (N=309), patients aged between 12-73 years with SR aGVHD were randomized 1:1 to receive either Ruxolitinib or physician's choice drug. Overall response rate (ORR) and complete response (CR) were significantly higher in the Ruxolitinib group as compared to the physician's choice drug. The results were consistent for all grades of GvHD. Grade 3 or higher treatment-related adverse events (TRAEs) were 78% in the two groups. 22% of the patients died of GvHD related adverse events in the Ruxolitinib group vs. 25% of the patients in the control group. In 12 clinical trials and observational studies, among SR GvHD patients (N=443), pooled ORR was 0.74 (CI=0.65-0.81, I2=61%) with Ruxolitinib treatment. Similarly, pooled CR was 0.45 (CI=0.34-0.68, I2=81%). The most common adverse events were cytopenias, viral reactivation, and infections. (Fig 1, 2) In 9 early phase trials and observational studies (N=282) in SR- chronic GvHD patients, pooled ORR and pooled CR were 0.75 (CI=0.64-0.83, I2=64%) and 0.11 (CI=0.08-0.16, I2=0), respectively. The most common adverse events were cytopenias and viral reactivation (Fig 3, 4). In a non-randomized trial (N=64), Ruxolitinib was used in combination with Etanercept for SR- acute GvHD patients. The ORR and CR were 87.5% and 72%, respectively. High rates of hematological adverse events and infections were reported in these patients. In an observational study (N=18), Ruxolitinib was used in combination with Extracorporeal Photopheresis (ECP). The combination was well-tolerated, and ORR and CR were 55% and 44%, respectively (Table 1). Conclusion: Ruxolitinib was well tolerated by patients with acute or chronic SR-GvHD. Ruxolitinib showed a higher efficacy compared to the physician's choice drug in SR acute GvHD. Ruxolitinib was also effective in SR cGvHD patients. The addition of etanercept to Ruxolitinib increased the efficacy in SR-acute GvHD patients but resulted in an increased incidence of infections. Ruxolitinib with ECP was effective and well tolerated in SR-acute GvHD. Additional multicenter, randomized, double-blind clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

This study concentrates on biosynthesis of Silver Nanoparticles (AgNPs) from stem extract of Acacia nilotica (A. nilotica). The reaction was completed at a temperature ~40–45 °C and time duration of 5 h. AgNPs were thoroughly investigated via advanced characterization techniques such as UV–Vis spectrophotometry (UV–Vis), Fourier Transform Infrared spectroscopy (FTIR), X-ray Diffractometry (XRD), Field Emission Scanning Electron Microscopy (FESEM), High Resolution Transmission Electron Microscopy (HRTEM), X-ray Photoelectron Spectroscopy (XPS), Thermo Gravimetric Analysis (TGA), Diffuse Reflectance Spectroscopy (DRS), Brunner-Emmett-Teller (BET), Dynamic Light Scattering (DLS), and Zeta potential analysis. AgNPs with average size below 50 nm were revealed by all the measuring techniques. Maximum surface area ~5.69 m2/g was reported for the as synthesized NPs with total pore volume ~0.0191 mL/g and average pore size ~1.13 nm. Physical properties such as size and shape have changed the surface plasmon resonance peak in UV–visible spectrum. Antimicrobial activity was reported due to denaturation of microbial ribosome's sulphur and phosphorus bond by silver ions against bacterium Methicillin Resistant Staphylococcus aureus (MRSA) and fungus Candida Albican (CA). Furthermore, AgNPs degraded toxic pollutants such as 4-nitrophenol (4-NP), 2-nitrophenol (2-NP) and various hazardous dyes such as Congo Red (CR), Methylene Blue (MB) and Methyl Orange (MO) up to 95%. The present work provided low cost, green and an effective way for synthesis of AgNPs which were utilized as potential antimicrobial agents as well as effective catalyst for detoxification of various pollutants and dyes.

In this study the production of high surface area silver nanoparticles (AgNPs) are reported from the Dodonaea viscosa plant species under controlled condition. The reaction was completed at 40 °C within 5 h and the product was characterized by several advanced techniques such as PXRD, FTIR, TGA, FESEM, XPS, DRS, BET, and UV–Vis. The prepared AgNPs were also evaluated for antimicrobial activities against pathogenic bacteria and fungi such as multi-drug resistant Staphylococcus aureus (MRSA) and Candida albican at a minimum inhibitory concentration (1 μg/mL) with 9 mL of liquid medium (Nutrient Broth). AgNPs were also found to speed up the reduction of organic pollutants such as 2-nitrophenol (2-NP), 4-nitrophenol (4-NP) and azo dyes included Methyl orange (MO), Congo red (CR) and Rhodamine B (RB) which causes pollution. The highest surface area is found for Ag-25 (7.38 m2/g) as compared to others NPs might be the highest catalytic potential of Ag-25.

Background: Immune checkpoints, by interacting with their ligands, modify the actions of immune cells. By inhibiting or manipulating this interaction by using checkpoint inhibitors (CPIs), we can harness the powers of the immune system to treat malignancies. CPI targets include PD1, PD-L1, or CTLA-4. CPIs have traditionally been used to treat solid malignancies like melanoma and lung cancer, but recently many trials established efficacy for hematological malignancies. CPIs can cause various immune-related adverse events, and the most significant ones are related to the endocrine system. In this meta-analysis, we will assess the risk of thyroid dysfunctions with CPIs in the light of data from randomized controlled trials (RCTs). Methods: We performed a comprehensive literature search on PubMed, Embase, clinicaltrials.gov, and Cochrane databases from inception till July 12, 2020. We used keywords for different checkpoint inhibitors. We used the filter for randomized controlled trials. We screened 9859 articles and selected 48 randomized clinical trials (N=27, 275), that reported the incidence of hyperthyroidism, hypothyroidism, or thyroiditis in CPIs vs. placebo/chemotherapy. Case reports, case series, observational studies, review articles, meta-analysis, single-arm trials, RCTs not reporting data on thyrotoxicity, and RCTs with thyrotoxic drugs in the control group were excluded. Screening and data extraction were done according to PRISMA guidelines. Meta-analysis was performed using the R programming language (version 4.0.2). Results: Our literature search yielded 9859 articles. After excluding the articles based on the predefined criteria described above, we included 48 articles and found the incidence of hypothyroidism, hyperthyroidism, and thyroiditis reported in 48, 31, and 18 RCTs, respectively. In 48 RCTs (n=27,275), 14 RCTs (n=7151) had patients with median age ≤ 60 years, while 34 RCTs (n=20,125) had patients with median age > 60 years. 27 RCTs (n= 13,582) used PD-1 targeting CPIs, 8 RCTs (n=5,589) studied CTLA-4 targeting CPIs, 9 RCTs (n= 6,020) involved PD-L1 targeting CPIs and 4 RCTs (n= 2084) used a combination of two CPIs. In RCTs reporting treatment related hypothyroidism, the total number of patients were 27,275 (CPI arm = 14,771, Control arm = 12, 504). For all grade treatment related hypothyroidism, the risk ratio (RR) was 7.04 [5.47; 9.05, p < 0.0001, I2 = 20%] in favor of control group. Upon subgroup analysis, the maximum RR of 12.25 [5.38; 27.89, I2 = 0%] was seen in RCTs using two CPIs vs. placebo/chemotherapy. For ≥ grade 3 treatment related hypothyroidism, risk ratio was 1.56 [0.94; 2.58, p= 0.09, I2 = 0%] in favor of control group. In the 31 RCTs (n= 17,257; CPIs = 9495; Control= 7762) reporting hyperthyroidism, the risk ratio for all grade hyperthyroidism was 6.39 [4.71; 8.68, p In the 18 RCTs (n= 10,846; CPIs = 6082; Control= 4764) reporting the incidence of thyroiditis, the RR was 3.12 [1.58; 6.15, p = 0.001, I2= 0%] in favor of control group. The highest risk ratio for thyroiditis was seen in PD-1 targeting checkpoint inhibitors (RR= 3.82 [1.73; 8.43, I2= 0%]). Conclusion: Although checkpoint inhibitors significantly increase the incidence of hypothyroidism, hyperthyroidism, and thyroiditis, most of the reported effect was grade 1 or 2 category. CPIs also increased the risk of treatment-related grade ≥ 3 thyroid dysfunctions, but the results were not statistically significant. We recommend that clinicians should be vigilant about autoimmune disorders and routinely monitor patients for thyroid disorders while using CPIs. Disclosures Anwer: Millennium Pharmaceuticals: Research Funding; AbbVie Pharmaceuticals: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Acetylon Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Incyte Pharmaceuticals: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau.

Introduction: Sickle cell disease (SCD) is caused by mutation of beta-globin chain alleles, with the involvement of at least one sickle mutation. Sickling of red cells leads to hemolytic anemia, vaso-occlusions, and inflammation. Voxelotor (GBT440) is a hemoglobin modulator that prevents polymerization by increasing the affinity of hemoglobin with oxygen. We performed a systematic review to evaluate the efficacy and safety of voxelotor in SCD patients. Methods: PRISMA guidelines were followed to perform the literature search and selection of articles for this systematic review. A search was performed using databases including PubMed, Cochrane, Web of Science, Embase, and clinicaltrials.gov. We used the following keywords, "Voxelotor" OR "Benzaldehydes" OR "GBT440" AND "Sickle Cell Anemia" from the inception of literature till 04/25/2020. Out of 475 articles, we screened and included three clinical trials and a case series measuring the efficacy (i-e, change in Hemoglobin (Hb), Hb modification, etc.) and safety (adverse events) in clinical terms (N=359). We excluded case reports, pre-clinical studies, review articles, and meta-analysis. RESULTS: We included data on 359 patients, with 12-67 years of age. In Blyden et al. 2018, authors presented a case series of 7 patients with advanced SCD treated with 700 mg-1500 mg voxelotor. With treatment, vaso-occlusive episodes related hospitalizations decreased by 67%, hemoglobin levels, and markers of hemolysis improved in all patients. Authors in Hutchaleelaha et al. 2019 randomly assigned 24 participants to a once-daily dose of 900 mg, 600 mg, 300 mg voxelotor, and placebo for 15 days. With treatment, hemoglobin modification was maximum in the 900 mg voxelotor group. Headache and diarrhea were the only adverse events related to voxelotor treatment. No grade 3 adverse events were reported. In phase I/II trial by Howard et al. 2019, (n=54) 38 patients were followed for 28 days, and 16 patients were followed for >90 days. The compliance for study drug was 91%. In the 28-day cohort, treatment with 1000 mg of voxelotor showed maximum improvement in hemoglobin level, reticulocyte count, and unconjugated bilirubin. In >90-day cohort, the improvement in hemoglobin, unconjugated bilirubin, and reticulocyte count were statistically significant in favor of 900 mg voxelotor treatment as compared to placebo (p In a randomized placebo-controlled phase III clinical trial by Vichinsky et al. 2019, two doses of voxelotor 1500 mg (N=90) and 900 mg (N=92) were compared with placebo (N=92). 12-65 years old SCD patients were followed for 24 weeks. After treatment, improvement in hemoglobin was statistically significant in favor of 1500 mg voxelotor vs. placebo. Moreover, markers of hemolysis, reticulocyte count, and indirect bilirubin levels were also significantly improved in favor of 1500mg voxelotor treatment vs. placebo. The incidence of vaso-occlusive crisis episodes was similar in 1500 mg, 700 mg, and placebo groups (p>0.05). Treatment-related adverse events were seen in 94%, 93%, and 89% of participants in 1500mg, 700mg, and placebo groups, respectively. (Table 1) There are 6 ongoing clinical trials registered on clinicaltrials.gov (n=665) to determine the efficacy and safety of high doses of voxelotor and its use in children below 12 years. (Table 2) Conclusion: Voxelotor has an acceptable safety profile in sickle cell disease patients of 12 years or older. Voxelotor has shown a dose-dependent improvement in hemoglobin levels and markers of hemolysis, which is associated with a reduction in end-organ damage. Moreover, the increase in hemoglobin was not associated with an increase in vaso-occlusive crisis episodes, in contrast to the other hemoglobin modulator (senicapoc). Additional large prospective multicenter randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Introduction: Multiple myeloma (MM) is an incurable malignancy, and clinical trials with newer agents have shown improved patient outcomes. Ixazomib (Ixa) is a proteasome inhibitor and induces apoptosis in cancer cells. It is commonly used with immunomodulators for the treatment of MM. We conducted a systematic review and meta-analysis to assess the efficacy of Ixazomib alone and in combination with other drugs for the treatment of newly diagnosed multiple myeloma (NDMM). Methods: A literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used the following MeSH and Emtree terms; "ixazomib" AND "Multiple Myeloma" from inception till 06/05/2020. We screened 1,558 articles and included 3 randomized clinical trials (RCTs) (N=901) and 12 non-randomized clinical trials (NRCT) (N=632). We excluded case reports, case series, preclinical trials, review articles, observational studies, meta-analysis, and ongoing clinical trials that did not report interim efficacy outcomes. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 15 clinical trials (N=1533), Ixa based regimens were used in patients with age range of 39-92 years. (Table 1) In 3 clinical trials (N=170), Ixa with Lenalidomide (Len) and dexamethasone (Dex) yielded a pooled overall response rate (ORR) of 90% (95% CI=0.82-0.94, I2=32%), a pooled complete response (CR) of 23% (95% CI=0.16-0.32, I2=24%) and a pooled ≥very good partial response and better (≥VGPR) of 39% (95% CI=0.24-0.57, I2 =76%) when used as induction therapy for NDMM patients. As consolidation therapy (N=88), pooled ORR was 91% (95% CI=0.79-0.97, I2=0), pooled CR was 36% (95% CI=0.27-0.47, I2=0) and pooled ≥VGPR was 70% (95% CI=0.53-0.84, I2=60%). (Fig 1-3) In 5 clinical trials (N=233), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR, CR, and ≥VGPR of 76% (95% CI=0.70-0.81, I2 =0), 12% (95% CI=0.07-0.20, I2=44%), and 25% (95% CI=0.14-0.39, I2=78%), respectively. (Fig 1-3) The lower dose of Cyc 300mg/m2 had similar efficacy as 400mg/m2 with better safety profile in elderly patients. In a RCT (N=175) of Ixa with multiple combinations, Ixa + Dex yielded ORR 55% (95% CI=0.40-0.69), CR 14% (95% CI=0.07-0.28) and ≥VGPR 24% (95% CI=0.13-0.39). Ixa+ thalidomide (Thal) + Dex fostered ORR 82% (95% CI=0.70-0.90), CR 15% (95% CI=0.08-0.26), and VGPR 43% (95% CI=0.31-0.55). Ixa + bendamustine + Dex yielded ORR of 73% (95% CI=0.41-0.91), CR 9% (95% CI=0.01-0.44), and ≥VGPR 27% (95% CI=0.09-0.59). In one clinical trial (N=53), Ixa + melphalan (Mel) + prednisone (Pred) combination yielded pooled ORR, CR, and ≥VGPR of 66% (95% CI=0.52-0.77), 13% (95% CI=0.06-0.25), and 30% (95% CI=0.19-0.44), respectively. In a phase II trial (N=40), Ixa + daratumumab (Dara) + Len + Dex yielded an ORR, CR and ≥VGPR of 97% (95% CI=0.84-1), 15% (95% CI=0.07-0.28), and 35% (95% CI=0.22-0.51) respectively. (Fig 1-3) In a phase III RCT by Dimopholous et al. (N=656), Ixa maintenance therapy after stem cell transplant (SCT) yielded an ORR, CR, and ≥VGPR of 76%, 15%, and 54%, respectively. They observed 28% reduction in the risk of progression or death with Ixa vs. placebo, median progression free survival (mPFS) was 26.5 months (95% CI 23·7-33·8) vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). Second malignancies were 3% in both ixazomib and placebo group. 27% of the patients in ixazomib group and 20% patients in placebo group experienced serious adverse events. In a clinical trial on unfit and frail patients (N=46) treated with Ixa + daratumumab (Dara) + Dex, pooled ORR and ≥VGPR were 83% (95% CI=0.69-0.91, I2=0), and 33% (95% CI=0.21-0.47, I2=0), respectively. (Fig 1-3) In the phase II trial, ORR, CR, and VGPR with ixazomib and lenalidomide were 64%, 26%, and 53%, respectively. Conclusion: Ixa in combination with Len, Dex, Cyc, Dara, Mel, Pred is effective in the treatment of NDMM patients. In early phase trials, Ixa with Dara, Len, and Dexa showed the highest overall response as induction therapy. Ixazomib maintainance therapy prolongs PFS after SCT as compared to placebo and represents an additional option for post SCT maintainace therapy in NDMM patiens. The safety profile of Ixa was acceptable with most commonly encountered adverse events were hematological including neutropenia and thrombocytopenia. Additional multicenter, double-blind, randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Introduction: Five year overall survival for acute myeloid leukemia (AML) is estimated to be less than 30%. Encouraging results seen with the tyrosine kinase inhibitors (TKIs), midostaurin and gilteritinib resulted in the approval of these molecular targeted therapies for patients with FLT3 Mutated AML. Other TKIs like sorafenib and quizartinib, have ongoing clinical trials. In this systematic review and meta-analysis, we assessed the efficacy and safety of TKIs for the treatment of newly diagnosed (ND) and relapsed refractory (R/R) AML. Methods: A search was performed on PubMed, Cochrane, Embase, and clinicaltrials.gov. We used the keywords "tyrosine kinase inhibitors" AND "acute myeloid leukemia" from the inception of literature till 07/10/2020. We screened 3245 articles and included 5 randomized clinical trials (RCTs) (N=1919) in this meta-analysis. We extracted data for efficacy (i-e, OS, CR, ORR, EFS) and safety (≥grade 3 treatment related adverse events (TRAE). We excluded case reports, case series, preclinical studies, review articles, meta-analysis, observational studies, and controlled clinical studies not providing any information about the efficacy or safety of TKI. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In the 5 RCTs (n=1919), the age range was 18-85 years. 1675 participants had FLT-3 mutation (Table 1). In 2 RCTs (N=738), two TKIs (gilteritinib and quizartinib) (N=492) were compared with salvage chemotherapy (N=246). Risk ratio (RR) of overall response rate (ORR) and complete remission (CR) was 2.43 (95% CI=1.97-3.00, I2=0) and 2.09 (95% CI=1.5-2.90, I2=48%), respectively in favor of TKIs. The hazard ratio (HR) for overall survival (OS) was 0.70 (95% CI=0.58-0.84, I2=0) in favor of TKIs. (Fig 1-3). The median OS was 6.2 months in the quizartinib group vs. 4.7 months in the chemotherapy group. Similarly, median OS was 9.3 months in the gilteritinib group vs. 5.6 months in the chemotherapy group. Grade 3 or higher TRAEs (anemia, infections, sepsis, febrile neutropenia, and liver toxicity) were reported more often in the TKI group vs. salvage chemotherapy group. (Fig 4-6). In 3 RCTs (N=1181), two TKIs (midostaurin and sorafenib) (N=597) were compared with placebo (N=582). In the RCT evaluating role of sorafenib in older patients (>60 years) (N=197), RR of CR was 0.75 (95% CI=0.58-0.96) in favor of placebo. Although more patients died in the sorafenib group than the placebo group (23 vs 10 within 60-day period), TRAEs were similar in the two groups. In the remaining 2 RCTs, sorafenib and midostaurin were compared with placebo in younger patients ( Conclusion: Gilteritinib and quizartinib were not only better tolerated but also more effective than salvage chemotherapy in patients with FLT-3 mutated AML. In older patients, sorafenib appeared to have lower efficacy and higher toxicity when compared with placebo. In contrast, for younger patients, sorafenib and midostaurin had better efficacy and lower toxicity than placebo. Additional multicenter double-blind randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

Background: Lenalidomide is an immune modulator, approved for use since 2005 for the treatment of multiple myeloma (MM) patients. Its use is associated with an increased risk of infections. Combination of lenalidomide with other drugs, monoclonal antibodies, proteasome inhibitors, dexamethasone, and alkylators, can enhance the risk of serious infections. We conducted a network meta-analysis to compare the incidence of ≥Grade 3 infections among lenalidomide based regimens used in MM that can help clinicians to monitor patients for the risk of infections. Methods: A search was performed on PubMed, Cochrane, Embase, and Web of Science. We used the following keywords, "lenalidomide" AND "multiple myeloma" from the inception of literature till 06/10/2020. We screened 14,684 articles and included 23 randomized clinical trials (RCT) (N=11,174) in network meta-analysis. We extracted the data for serious (≥Grade 3) infections in lenalidomide based regimens. We excluded case reports, case series, preclinical trials, non-randomized clinical trials, observational studies, review articles, meta-analysis, and RCTs not providing any information about ≥Grade 3 infections. We used the "netmeta" package by Rucker et al. in the R programming language (version 4.0.2) to conduct frequentist network meta-analysis. Results: In 23 RCTs, the median age was ≥65years in 11 RCTs (N=5585) and ≤65 in 12 RCTs (5589). 9 RCTs were performed on relapsed/refractory multiple myeloma (RRMM) patients (N=4254), while 13 RCTs were performed on newly diagnosed multiple myeloma (NDMM) patients (N=6920). Lenalidomide regimen was used as maintenance therapy in 8 RCT (N=4255). Table 1 reviews the baseline characteristics. The pooled incidence of high-grade infections in trials with a median age of ≥65 and ≤65 years is 1010/5585 and 634/5589, respectively. The incidence of high-grade infections is 693/4254 in RRMM patients, 951/6920 in NDMM patients, and 466/4255 in NDMM patients with maintenance therapy. P-score in table 2 represents the mean extent of certainty with which a regimen is better in terms of the incidence of high-grade infections, i.e., higher P-score means a lower risk of serious infections. According to P-score, lenalidomide with carfilzomib and dexamethasone is worst in terms of the incidence of infections. Indirect comparison of placebo with lenalidomide shows a risk ratio of high-grade infections of 2.87 (95% CI: 1.96; 4.23) in favor of placebo. Fig 1 outlines the indirect comparison of the incidence of high-grade infections with different lenalidomide based regimens vs. placebo. Table 3. shows the calculated indirect comparison of high-grade infections in each lenalidomide based regimen. Heterogeneity was not statistically significant. For serious infections, lenalidomide dexamethasone showed a risk ratio of 0.86, 0.70*, 0.76*, 0.78*, 0.77, and 0.77 in comparison with the combination of lenalidomide dexamethasone with bortezomib, carfilzomib, daratumumab, elotuzumab, ixazomib, and pembrolizumab respectively (*statistically significant). Conclusion: This network meta-analysis suggests an increase in the risk of high-grade infections with the addition of bortezomib, monoclonal antibodies, ixazomib, and carfilzomib to lenalidomide in multiple myeloma patients with the highest increase in risk with the addition of carfilzomib. Additional randomized clinical trials are needed on the toxicity of lenalidomide based regimens to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium that is resistant to a large group of beta-lactam antibiotics. Rhazya stricta is a local shrub that grows naturally as a normal flora and is used as a medicinal plant by several nations for a lot of infectious diseases, caused by microorganisms. Therefore, the effect of the plant against different genotypes of methicillin-resistant S. aureus was tested in the present study. Molecular identification was done for the medical sampling of 44 MRSA and biodiversity approaches were applied to detect the mecA gene. The 16S rRNA genes analysis was performed for the construction of a phylogenetic tree. Later on, the antimicrobial effect of the plant leaves’ water extract was tested on different genotypes. MecA gene appeared in all isolates, except in methicillin-susceptible Staphylococcus aureus. The selected MRSA 16S rRNA sequences were sent to GenBank and six accession numbers (KM893010, KM893011, KP091274, KP091275, KP137513 and KP137514) were acquired. Also, an evolutionary analysis of these strains was done and a phylogenetic tree was constructed. Plant extracts showed that the interaction between pathogens and drugs is more efficient in a liquid environment than in a solid one.

The eco-friendly biosynthesis of silver nanoparticles (AgNps) from bark extract of Albizia chevalier are reported here for their anti-proliferative, antibacterial and pollutant degradation potentials. The synthesized AgNps were characterized by FTIR spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), energy dispersive X-rays spectrometry (EDS) and X-ray diffraction studies. The TEM and FESEM images show a monodispersed spherical shaped particles of approximately 30 nm. Crystalline peaks were obtained for the synthesized AgNps in XRD spectrum. The AgNps were investigated for in vitro anticancer and antibacterial activities and its potential to degrade 4-nitrophenol (4-NP) and congo red dye (CR). The MTT results shows a significant dose-dependent antiproliferation effect of the AgNps on the cell lines HepG2, MDA-MB-231 and MFC7. The effect was found more pronounced in MDA-MB-231 as compared to MFC-7 cell lines. The antibacterial results indicated 99 and 95% killing of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) respectively, after 24 h of incubation with the AgNps. The AgNps were found to speed up the reductive degradation of 4-NP and CR dye, which give an alternative route for the removal of toxic organic pollutants from the wastewater. The synthesized AgNps were not only used as a bactericidal and anticancer agent, but also effectively used for the reductive degradation of carcinogenic compounds which are listed as the priority pollutants. Therefore, AgNps have the potential for the treatment of various cancers, bacterial infections and for industrial detoxification of wastewater.

Introduction FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM. Methods Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript. Results Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor. KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts. AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%. Conclusion Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Four brands of commercially milk samples and unpasteurized milk, produced by farmers collected from Peshawar City (NWFP). These samples and samples of sterilized milk treated with ultra-high temperature (UHT) process, were microbiallly examined. The average minimum TPC of raw milk were 7.05 x 10 cfu/ml and maximum were 3.5 x 10 cfu/ml, minimum average coliforms were 16.65MPN/ml and average 4 5 maximum 132MPN/ml, maximum fecal coliforms were 7.65MPN/ml and minimum value =0.3MPN/ml, E. coli O157:H7 were isolated from all samples except S7, Salmonella were also isolates from all raw milk samples, average maximum yeast and mould were 4.3 x 10 cfu/ml and minimum were 3 x 10 cfu/ml. Storage 6 4 life study of branded milk at t 4 C, 25 C and 35 C for TPC were indicate that after 45 days TPC were o o o increases and at the end of 90 days TPC were decreases, but in some cases it increases. All above microbes can have a hazardous effect on human body, unpasteurized milk sold by farmers showed a very high total viable count which indicates serious faults in production hygiene, unsatisfactory sanitation and unsuitable storage temperature. On contrast, the UHT milk produced by modern dairies showed a very high quality of microbial standard with a very delicate flavor.

5-Lipoxygenase (5-LO) is the key enzyme involved in the synthesis of pro-inflammatory leukotrienes (LTs) and has become a prime target for new drug discovery research and development efforts by the pharmaceutical and biotech industry. The pathophysiological effects of LTs can be modulated by the selective inhibition of 5-LO. In this review, we summarize the established dogma and recent progress on the biochemical and pharmacological regulation of 5-LO and its diverse cellular partners. In the last decade, significant research efforts have led to the exploitation of 5-LO pathway for developing new drugs against inflammatory diseases. Despite few setbacks, a number of promising molecules have moved into clinical development. These fundamental discoveries and proof-of-concept studies will ultimately be helpful in delineating how 5-LO pathway participates in the development of disease phenotype and what are possible key biomarkers of disease progression and regression. Elucidation of molecular mechanism-of-action of 5-LO in individual cell types will pave the way for improving efficacy parameters. Taken together, this combined knowledge about the 5-LO pathway would be helpful in planning collaborative and targeted R&D efforts, by the academic laboratories and pharmaceutical/ biotech industry, for the discovery and development of novel, efficacious and safer drugs against multiple diseases.