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Background and Objectives: The COVID-19 (CO19) pandemic caused by SARS-CoV-2 remains a significant issue for global health, economics, and society. Several reports have shown that African Americans (AA) have been disproportionately affected by the CO19 pandemic. Limited data have suggested that sickle cell disease (SCD) could be one of the several reasons for higher morbidity and mortality related to CO19 among AA. Recent reports have suggested higher-than-average morbidity and mortality related to CO19 among patients with SCD. We conducted a retrospective, single-institution study in adult patients with SCD who were diagnosed with CO19 infection and their outcomes. Methods: After IRB approval, we conducted a chart review of adult patients (greater than 18 years) with SCD who were diagnosed with CO19 infection between March 1st, 2020, and March 31st, 2021. We recorded demographic data including age, gender, social factors (the type of insurance, availability of primary care provider (PCP), living alone/not), clinical parameters (type of SCD, co-morbidities), outpatient management of SCD, and how CO19 infection was managed like inpatient admission and complications. In patients who were admitted or seen in the emergency department (ED), we collected additional data including vitals, labs, the severity of illness, complications, length of stay, and outcomes. Computations were performed using statistical software SAS 9.4 for Windows. Results: We found a total of 51 patients with SCD diagnosed with CO19 infection in the above period. The median age of patients was 30 years. 61% were females and 39 % were males. All of them were AA. 11.76% were living alone, 49.02% were living with family, 1.96% (1 patient) was institutionalized, and the living situation was unknown in 37.25%. Most of the patients had Medicaid Insurance (52.94%), Medicare in 33.3%, private insurance in 13.73 % and 2% were uninsured. Only 64.71% of patients had a PCP. 60% had HbSS disease, 32% had HbSC disease, 4% had HbS-beta thalassemia, one patient each had HbSS with hereditary persistence of HbF and HbS/HbD. Comorbidities and previous history included acute chest syndrome in 65.96%, avascular necrosis in 36.96%, leg ulcers in 8.7%, hypertension in 8.7%, sickle cell retinopathy in 14.57%, cerebrovascular disease in 26.19%, chronic kidney disease in 7.69%, venous thromboembolism (VTE) in 20.41%, 10.41% were on anticoagulation, history of HIV and hepatitis C infection in 6.38%. 28.21% of patients were maintained on partial exchange transfusions as an outpatient for various indications. 72.73% were on hydroxyurea, 7.5% were on crizanlizumab, 5.26% were on voxelotor and 26.83% were on iron chelation. Vitals and pertinent lab values on initial assessment were recorded and many patients had missing data. On presentation, 25.53% were febrile, 29.17% of patients were tachycardic, 31.25% were hypoxic (SpO2 < 95%), 38.46% were tachypneic, 59.18% had a body mass index (BMI) of > 24.9. Median hemoglobin and hematocrit were 8.9/27.4 g/dL. The median white blood cell count was 9490/uL and platelets were 315,000/uL. Median ferritin was 1573 ug/L. Median bilirubin and creatinine were 2.05 mg/dL and 0.86 mg/dL. The patients were further stratified based on the clinical location where CO19 infection was managed (Table 1). 39.3% were diagnosed in the outpatient setting/ED and 60.3% in the inpatient setting. Among 51 patients, 5.71% (n=2) required ICU admission and was mechanically ventilated. 17.5% received dexamethasone, 7.69% received remdesivir, 2.76% received convalescent plasma, 17.07% had infections and 47% received antibiotics. Only one patient received an exchange transfusion during admission. One patient developed a new VTE after CO19 infection. On statistical analysis, the only factor which impacted the clinical location of management was tachycardia (P=0.007). Of the 51 patients, only 3.9% (2 patients) died of complications of CO19 infection, one with hypoxic respiratory failure, disseminated intravascular coagulation, shock, and the other one with pulmonary embolism. 13% were readmitted within a month, one of them was admitted with a new pulmonary embolism and the others were admitted for acute painful episodes. Conclusion: We found a mortality rate of 3.9% in our single-center study of patients with SCD and CO19 infection. This mortality rate is lower than other published experiences in patients with SCD and CO19 infection. Figure 1 Figure 1. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Introduction: Telemedicine can transform the future of medicine, especially in rural settings by improving access to medical care. Here were present the patient satisfaction data from both telemedicine and regular visits in our Hematology & Oncology clinics. In Hematology, we have used tele medicine for sickle cell disease, benign hematology cases like iron deficiency, thrombocytopenia, leukocytosis etc., and in malignant hematology for new patient consults, toxicity checks, follow up of plasma cell disorders, chronic leukemias and low intensity chemotherapies. Methods: We retrospectively collected patient satisfaction survey data from March 2020 to April 2021 for both telemedicine and regular visits. The patients were allowed to give a score from 1 to 99 regarding their experience at visit. We collected data on the following: likelihood of recommending, care provider, access and overall assessment. Results: A total of 53 patient satisfaction survey were available for telemedicine and 462 for regular visits. Over 60 % of tele visits were non cancer related and 40% were cancer related. The average score for likelihood of recommending, care provider, access, and overall assessment for tele visit were 73.5, 41.5, 73.5 and 62 respectively. The average score for likelihood of recommending, care provider, access, and overall assessment for regular visit were 13.75, 7.5, 26.5, and 11 respectively. Conclusion: The patient satisfaction scores for likelihood of recommending, care provider, access and overall assessment were significantly better for tele visits compared to regular visits. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Background: Cardiac and vascular toxicities are known complications on Bruton Tyrosine kinase inhibitor (BTKi)drugs. Ibrutinib, acalibrutinib and zanubrutinib are all approved BTKi drugs. We did a retrospective analysis on adverse effects (AE) of BTKi's that has been made available to public by the FDA. Methods: The FDA has made the data on AEs of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the infectious, cardiac and vascular AEs of various BTKi for the years 2019-2021. Results: The percentage of cardiac AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 12%, 7.3% and 6.2% respectively. The most common cardiac toxicity was atrial fibrillation. The percentage of vascular AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 8.2 %, 5.2 % and 3.9 % respectively. The most common vascular toxicity was hemorrhage. The percentage of infectious AE compared to total AEs reported for ibrutinib, acalibrutinib and zanubrutinib were 18.3%, 13.6% and 35.5% respectively. The most common vascular toxicity was pneumonia. Conclusions: Out of the reported cases of AEs to BTKis approved, ibrutinib have most and acalibrutinib have least cardiac AEs. Zanubrutinib has least vascular AEs. Out of the reported cases of AEs to BTKis approved, zanubrutinib have most infectious AEs. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Background: Phosphatidylinositol 3-kinase inhibitors (PI3KI) are a novel class of drugs that are small molecular inhibitors of various isoforms of phosphatidylinositol 3-kinase (PI3K). Over the past decade, various PI3KI have been approved in follicular lymphoma, marginal zone lymphoma, and chronic lymphocytic leukemia. While Copanlisib inhibits P13K-alpha and P13K-delta isoforms, idelalisib inhibits P13K-delta, duvelisib inhibits PI3K-delta and PI3K-gamma, and the recently approved agent umbralisib targets PI3K-delta and casein kinase 1 epsilon with improved selectivity for the PI3K-delta. All the agents except Copanlisib are given orally. Immune-mediated adverse effects like colitis, marrow suppression with infections, and dermatological toxicities are known complications of PI3KI. We did a retrospective analysis of the adverse effects (AE) of the PI3KI in the FDA Adverse Event Reporting System (FAERS). Methods: FAERS public dashboard is a resource through which information related to AEs of treatments reported to the FDA is made available to the public. We investigated the common immune-mediated, infectious, hepatic, and dermatological toxicities of the three PI3KI, idelalisib, copanlisib, and duvelisib for the years 2018 to March 2021. Umbralisib has not much-reported data in FAERS. Results: The data regarding various adverse effects are summarized in Table 1. Idelalisib has the most reported data. Diarrhea is reported to be most common with duvelisib (21.83% of total AE). Though diarrhea is common, colitis is uncommon and least reported with copanlisib (1.15%). Among the patients with colitis, death occurred in 27.2% with idelalisib, 15.3% with duvelisib and 50% with copanlisib. Pneumonitis is most reported with copanlisib (3.45%). Among the patients with pneumonitis, death occurred in 34.7% with idelalisib, none with duvelisib and 50% with copanlisib. Rash is most reported with copanlisib (6.32%) and the incidence of serious dermatological toxicity is uncommon in all the 3 drugs. Rates of neutropenia and thrombocytopenia are overall similar between the drugs except for a slightly higher rate in copanlisib including febrile neutropenia. Infections including pneumonia, urinary tract infection, PJP pneumonia, and CMV reactivation are overall comparable between the 3 drugs. Among the patients with various infections, death occurred in 24.1% with idelalisib, 14.5% with duvelisib and 16.9% with copanlisib. The rate of hepatotoxicity is also comparable between the drugs. Among the patients with hepatic failure, death occurred in 33.3% with idelalisib, 100% with duvelisib and copanlisib. Conclusion: The overall rates of serious adverse effects are comparable between the 3 PI3KI, though diarrhea is most common with duvelisib, pneumonitis, and rash with copanlisib. As these drugs are mainly used in the relapsed refractory setting, many more years of follow-up are needed to get a better idea of real-world data as we have more experience with these drugs. Figure 1 Figure 1. Disclosures Master: Blue Bird Bio: Current holder of individual stocks in a privately-held company.

Mantle cell lymphoma (MCL) is an aggressive, rare, and difficult to treat subtype of non-Hodgkin's Lymphoma (NHL) that accounts for about 6% of all cases. Although there is no defined standard of care for MCL treatment, some combination of chemo-immunotherapy and rituximab maintenance with or without autologous stem cell transplantation is generally employed depending on the age and fitness of the patient. Despite recent development of novel therapeutics, there is inevitable disease relapse with progressively declining efficacy and increasing frequency of resistance with single agent targeted therapy. Here, we describe the novel multitarget inhibitor SRX3177 which simultaneously hits three oncogenic targets: phosphatidylinositol-3 kinase (PI3K), cyclin-dependent kinases 4 and 6 (CDK4/6), and the epigenetic reader protein BRD4. This in silico designed, thieno-pyranone (TP) scaffold-based small molecule inhibitor orthogonally disrupt three targets within the cancer cell with one agent. Targeting the cell cycle with small molecule inhibitors represents a reasonable attempt to treat MCL, as cell cycle-associated genes like ATM, TP53, CDKN2A, CCND1 and CDK4/6 are most frequently mutated in patients. Palbociclib is a well-known single agent CDK4/6 inhibitor that has been employed in both solid and hematological malignancies. Due to its cytostatic nature, treatment with single agent palbociclib often results in the emergence of treatment-resistant clones. Therefore, a combination strategy would theoretically be more effective and can overcome the development of resistance. Moreover, prolonged G1 arrest by CDK4/6 inhibition sensitizes lymphoma cells to PI3K inhibition, suggesting a synthetic lethality relationship between these two agents. Inhibiting the chromatin reader protein BRD4 causes downregulation of target genes c-MYC and BCL2, further increasing cytotoxic capabilities. Hence, we developed SRX3177 as a potent CDK4/6/PI3K/BRD4 triple inhibitor to synergistically inhibit cell cycle progression and induce cancer cell apoptosis. SRX3177 is an ATP competitive CDK4/6 inhibitor (IC 50: CDK4 = 2.54 nM, CDK6 = 3.26 nM), PI3K inhibitor (IC 50: PI3Kα = 79.3 nM, PI3Kδ = 83.4 nM), and BRD4 inhibitor (IC 50: BD1 = 32.9 nM, BD2 = 88.8 nM). We have tested the efficacy of SRX3177 against a panel of MCL cell lines and report that SRX3177 induces a strong antiproliferative activity with maximal IC 50 0f 340 nM in JeKo-1, 29 nM in Mino cells, and 630 nM for Rec-1 cells while IC 50 values for cell lines Granta and JVM-2 were 1.3 µM and 1.5 µM, respectively. Further, we show that SRX3177 is more potent to tumor cells than the individual PI3K (BKM120), BTK (Ibrutinib), BRD4 (JQ1), and CDK4/6 (palbociclib) inhibitors, and dual PI3K/BRD4 inhibitor SF2523 (backbone for SRX3177) in JeKo-1 cells. Next, we examine the cytotoxic effect of SRX3177 in ibrutinib/palbociclib resistant primary MCL cells. Our results show that SRX3177 triggers cytotoxic response at 500 nM and 1000 nM as compared to the lack of cytotoxicity of combination Ibrutinib and palbociclib at 150 nM and 1000 nM (Fig 1). SRX3177 induces a strong apoptotic response and cell cycle arrest in JeKo-1 and Mino cells at 24hrs. Annexin V/7AAD apoptosis staining confirmed the induction of PCD by SRX3177with increase in c-PARP. Western blot analysis shows SRX3177 treatment blocks both PI3K/AKT signaling and Rb phosphorylation. Moreover, analysis by chromatin immunoprecipitation revealed that SRX3177 effectively blocked BRD4 binding to both the promoter and enhancer of c-MYC (p≤0.01 and p≤0.001) and BCL2 (p≤0.05). SRX3177 also suppresses the c-MYC and BCL2 transcriptional program in both a time- and dose-dependent manner. Our findings also demonstrate a SRX3177-dependent reduction in c-MYC half-life via induction of proteasomal-mediated degradation. This degradation is associated with decreased phosphorylation of c-MYC at Ser62 and increased phosphorylation of c-MYC at Thr58 - indicative of differential regulation of c-MYC stability. Finally, we show that SRX3177 overcomes chronic ibrutinib resistance in Jeko-1 cells with a maximal IC 50 of 150 nM as compared to 64 µM with ibrutinib. Hence, the triple inhibitor SRX3177 has superior potency to ibrutinib in MCL cell lines and succeeds in overcoming ibrutinib-resistance at nanomolar doses. Taken together, our data supports the development of SRX3177 as a novel therapeutic agent for treatment of MCL. Figure 1 Figure 1. Disclosures Martin: ADCT: Consultancy. Park: Takeda: Research Funding; G1 Therapeutics: Consultancy; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding, Speakers Bureau; Gilead: Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Morphosys: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Durden: SignalRx Pharmaceuticals: Current holder of individual stocks in a privately-held company.

Introduction: Amyloidosis is a disease characterized by deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. Although pulmonary involvement in amyloidosis is common, it is rarely symptomatic. The clinical course is considered indolent or benign, however literature available on biology and history of this disease is limited. Sub-typing of pulmonary amyloidosis has been historically difficult. Pulmonary amyloidosis can be a part of an underlying plasma cell dyscrasia or related to an underlying inflammatory systemic disease. Our aim was to identify the further workup done after a biopsy proven diagnosis of pulmonary amyloidosis and the relation to monoclonal gammopathy. We also investigated the frequency of utilization of mass spectrometry for amyloid typing at our institution. Methods: We reviewed medical records of adult patients ≥ 18 years with localized pulmonary amyloidosis from January 1st 2010 to June 30th 2019. The word "amyloidosis" was used to search for cases of localized pulmonary amyloidosis in the hospital's electronic medical records to generate a patient list. We recorded age and gender, medical history, work up for paraproteinemia, renal and hepatic function, pathology results including bone marrow biopsy, imaging studies, treatment and survival. Results: We identified 10 patients with amyloidosis on lung biopsy, out of which 4 were females (40%) and 6 were males (60%). Patient age ranged from 53 to 87 years with a median age of 80 years. (Table - 1) Four out of the 10 patients were found to have kappa light chains. Out of these 4 patients, 3 had kappa light chain restriction on the amyloid deposit of lung biopsy specimen by immunohistochemistry (IHC). One patient had expression of both kappa and lambda light chains. His B-cell polymerase chain reaction (PCR) was negative. Mass spectrometry was done in 1 patient which confirmed Immunoglobulin light chain (AL) amyloidosis. Bone marrow biopsy was performed in 3 out of 4 patients and interestingly, the patient with negative IHC in the amyloid had 19% plasma cells while the other 2 patients had 1.8% and 3%. All the 4 patients had normal renal function, hepatic function, serum albumin. They also had no bone lesions or organomegaly. Out of the 10 patients, 1 patient had a history of hairy cell leukemia and the amyloid nodule showed lambda light chain restriction, likely related to the B-cell Lymphoproliferative disorder. He had no evidence of a monoclonal gammopathy or evidence of organ involvement. The remaining 5 patients were suspected to have amyloid A (AA) amyloidosis and 4 of them had documented underlying systemic disease. None of these patients had evidence of other organ involvement. One patient with suspected AA amyloid nodule had excision of the lesion. All the patients had stable lung nodules and none of them had evidence of progressive systemic amyloidosis. None of the patients were given systemic therapy. Eight out of 10 patients were alive at the time of data cut-off. The 2 deaths were unrelated to amyloidosis were due to hairy cell leukemia in one patient and sepsis secondary to urinary tract infection in the other. Conclusion: Our institutional review of localized pulmonary amyloidosis showed no evidence of disease progression and had good clinical outcome. Interestingly, one of our patients with smoldering myeloma with pulmonary amyloid nodule had negative IHC stain which may point towards the fact that these patients may have amyloid which is unrelated to the paraprotein. Even though mass spectrometry is the gold standard for confirmation of amyloid, it is not widely available and may not be indicated in every case. In our study, we found only 10% rate of utilization of mass spectrometry. The other interesting finding was that patients with B-cell lymphoproliferative disorders can have amyloid with light chain restriction which is a part of the disorder rather than AL amyloidosis. Disclosures No relevant conflicts of interest to declare.

Background: Amyloidosis is the extracellular tissue deposition of small molecular subunits of proteins as fibrils. AL Amyloidosis is a complication of underlying plasma cell dyscrasia with an associated monoclonal paraprotein. It can occur in association with multiple myeloma (MM), Waldenstrom macroglobulinemia (WM) or non-Hodgkin lymphoma. While isolated organ involvement can be seen, many patients (pts) have multiorgan involvement. Our aim was to explore the trend of amyloidosis associated with plasma cell dyscrasia, treatment and outcome at our institution. Methods: After IRB approval, we reviewed medical records of adult pts ≥ 18 years with a histological diagnosis of amyloid and had evidence of monoclonal gammopathy, between January 1st, 2010 and June 30th, 2019. We reviewed age at diagnosis, gender, work up for paraproteinemia, site of biopsy, technique used for identification of amyloid, imaging studies, treatment and outcome. Results: We found a total of 33 pts with biopsy proven amyloid and evidence of a monoclonal paraprotein. 23 (69.6%) were males and 10 (30.3%) were females. Age ranged from 39 to 89 years with a median age of 62; 3 (9%) being Monoclonal paraprotein was IgG Kappa in 10 (30.3%), IgG lambda in 5 (15%), IgA lambda in 3 (9%), IgA kappa in one, IgM lambda in 3 (9%), IgM Kappa in one, kappa light chain in 5 (15.1%), lambda light chain in 3 (9%), one had both IgG lambda and IgM kappa and no paraprotein was documented in one pt. Serum protein electrophoresis with immunofixation was positive in 22 (66.6%), Urine protein electrophoresis and immunofixation was positive in 16 (48.4%). Most common initial site of amyloid identification by biopsy was kidney in 12 (36.3%). Diagnosis was from abdominal fat pad in 8 (24.2%), lung in 4 (12.1%), bone marrow, heart and skin in 2 each (6%) and liver, colon and bone in 1 each (3%). Positive immunohistochemistry (IHC) stain demonstrating light chain restriction was seen in 23 (69.6%) and out of this only 11 (33%) underwent further evaluation with mass spectrometry. One patient with positive IHC had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. IHC was not performed in 8 (24.2%) and identification was only based on Congo red staining. IHC was negative in 2 (6%) despite evidence of a monoclonal paraprotein. Involvement of kidney was identified in 14 (42.4%) with isolated kidney involvement in 2 (6%). Cardiac involvement was identified in 17 (51.5%) either by biopsy, imaging findings and/or pro-BNP and troponin levels and isolated cardiac disease was noted in 3 (9%). 6 (18.1%) had lung involvement, which was the only disease site in 4 (12.1%). Neuropathy was noted in 10 (30.3%). One had only a single bony site involved. 21 (63.6%) were treated with disease related therapy for amyloidosis, one patient underwent radiation to site of isolated bone disease and the remaining patients were either observed or died before therapy was initiated. 7 (21%) underwent Autologous stem cell transplant for amyloidosis. At the time of data cut off, 21 (63.6%) were alive and 12 (36.3%) were deceased. Amyloidosis was the documented cause of death in 10 pts and of this 9 pts had cardiac involvement. Conclusion: AL Amyloidosis is an uncommon disorder and patients should undergo further diagnostic evaluation if suspicious symptoms with an underlying monoclonal gammopathy. In our study, we noted a male predominance and IgG Kappa was the most common monoclonal paraprotein. As immunohistochemistry has a greater chance of false positive and false negative results, mass spectrometry is the preferred method for identification of amyloid. However, this technique is not widely available which restricts it's use in clinical practice. In our study, we identified one patient with positive IHC who had negative mass spectrometry despite high clinical suspicion for AL amyloidosis. We also identified two patients with negative IHC despite evidence of a monoclonal paraprotein and this may be either a false negative IHC or the amyloid being unrelated to the monoclonal paraprotein. 9/10 pts who died of amyloidosis had cardiac involvement. Disclosures No relevant conflicts of interest to declare.

Background: Hemophagocytic lymphohistiocytosis [HLH], is a rare life-threatening syndrome of excessive immune activation. It can be primary due to genetic predisposition or secondary due to infections, immune disorders or malignancies. With nonspecific clinical presentation, a high index of suspicion is required to make the diagnosis. Prompt treatment of underlying etiology and HLH specific therapy is warranted to prevent adverse clinical outcome. Methods: After IRB approval, we conducted a retrospective chart review of adult patients (pts) ≥ 18 years diagnosed with HLH between January 1st, 2010 and June 30th, 2019. We recorded age at diagnosis, gender, cause of HLH, symptoms, laboratory testing, bone marrow pathology, imaging, treatment and outcome. Results: We found a total of 15 patients in the time interval. Pt age ranged from 22 to 64 years with a median of 46 years. 60% were females and 40% were males. 14 pts had secondary HLH and one pt tested positive for HLH gene mutations. Etiology of HLH was malignancy in 6 (40%), infection in 5 (33%), rheumatological disease in 3 (20%) and cause was unclear in one pt but suspected to be an infection. One pt had prior allogenic stem cell transplant and one pt developed HLH even after completion of treatment for lymphoma. On presentation, 14 (93%) had fever, 6 (40%) had respiratory symptoms, 6 (40%) had neurological symptoms, 2 (13%) had a skin rash, 2 (13%) had bleeding manifestations and 3 (20%) required pressor support. Hemoglobin ranged from 5.5 to 13.3 g/dL on presentation, with median of 10.1 g/dL and 14 (93%) had Hb 10,000 ng/ml in 10 (66%) and highest level was 4,57,970 ng/ml. All 15 pts had some degree of hepatic dysfunction and one pt had acute kidney injury. Triglyceride levels were >265 mg/dL in 6 (40%). 10 (66%) had laboratory evidence of disseminated intravascular coagulation (DIC), one pt had clinical DIC. Blood cultures were negative in everyone, except 2 pts who developed infection during the hospital course, one with Candida krusei and the other with methicillin sensitive staphylococcus aureus. Bone marrow biopsy was performed in 14 (93%) and all of them demonstrated hemophagocytosis. 3 (20%) underwent lumbar puncture and 2 had elevated CSF protein. 11 (73%) had immunological testing and all of them had elevated soluble IL-2 receptor alpha (sCD25 or sIL-2R). Of the 3 pts who had HLH genetic testing, one had HLH associated mutations. Organomegaly was noted in 11 (73.3%) (4 had hepatosplenomegaly, 6 had splenomegaly, one had hepatomegaly). 6 (40%) had lung infiltrates. MRI brain was done in 5 (33%) and 2 had patchy hyperintensities. 11 (73.3%) were treated with HLH-94 protocol with etoposide and dexamethasone. One pt had matched unrelated donor Allogenic stem cell transplant. 13 (86.6%) had initial recovery. At the time of data cut off, 10 (66%) were alive. Of the 3 pts who initially recovered, one pt died of relapsed lymphoma, one died of HLH relapse and one developed Clostridium difficile infection with bowel perforation. [Refer to Table 1]. Conclusion: Even though literature suggests that malignancy associated HLH has a worse prognosis, our small series did not suggest that. We also noted that HLH associated with rheumatological diseases leads to a superior outcome if the underlying disease is adequately treated. The most significant finding in our series was a patient with diffuse large B cell lymphoma who was diagnosed to have primary HLH with HLH associated mutations. Typically, primary HLH presents in the first few years of life. This patient case points to the fact that patients with primary HLH can have a late presentation and can also be associated with immunological disorders with a predisposition to malignancy. This finding suggests that all patients diagnosed with HLH should have genetic testing done for HLH associated mutations, as this will impact treatment decisions and these patients will benefit from more intense treatment which may include an allogenic stem cell transplant. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma (MM) is the second most common blood cancer in the United States. Recent breakthroughs in immunotherapy have the potential to transform MM treatment. An immunotherapy target that shows considerable promise in myeloma is the B-cell maturation antigen (BCMA). BCMA is specifically expressed in myeloma cells and plasma cells, making it an ideal target in myeloma. Results from two early-phase clinical trials using anti-BCMA therapy, showed remarkable response in most patients. Although immunotherapy has been promising, recent findings suggest that patients can develop resistance to such therapies by lowering the levels of the target. Here we employ our innovative CRISPR-interference/activation (CRISPRi/a)-based functional genomics platform to identify mechanisms that regulate BCMA expression, which would enable us to design strategies to improve the efficacy of available BCMA immunotherapy agents. Methods: The CRISPRi/a platform utilizes a catalytically dead Cas9 (dCas9) fused to a transcriptional repressor domain to silence genes (CRISPRi) or to activator domains to activate transcription (CRISPRa). The CRISPR machinery is targeted to specific genes using single guide-RNAs (sgRNA). We have engineered a panel of myeloma cell lines to express components of the CRISPRi system. Here we transduced CRISPRi-AMO1 cell line with sgRNAs targeting the human genome. The sgRNA expressing cells were stained with a fluorescent-tagged BCMA antibody and FACS sorted into cells expressing high and low levels of BCMA. The cells were processed for next generation sequencing to determine the frequency of sgRNA in each of these populations. To develop BCMA chimeric antigen receptor-T (CAR-T) cells, CD8+ T cells were transduced with BCMA CAR construct specifically recognizing BCMA. To examine the anti-myeloma activity of the BCMA CAR-T cells, CAR-T cells were co-cultured with MM cell lines at a ratio of 1:2 (Effector:Target) for 24hrs. The cells were analyzed by flow cytometry for expression of CD69, an activation marker on T cells and for apoptosis of cancer cells using propidium iodide. Results: Our FACS-based genome-wide CRISPRi screen identified several genes and pathways regulating BCMA cell surface expression. In addition to previously reported gamma-secretase complex and transcription factor POU2AF1 we identified genes involved in peroxisome biogenesis, subunits of the proteasome, transcription factors and a few druggable targets regulating cell surface expression of BCMA. We are currently validating the novel genes identified from our primary genome-wide screen in a panel of MM cell lines and developing MM cell lines expressing CRISPRa machinery to perform gain-of-function screens that will complement our CRISPRi screen. Furthermore, we have developed active CAR-T cells targeting BCMA and demonstrated its efficacy in MM cell lines expressing different levels of BCMA. We are currently testing the novel genes identified from our CRISPRi screen in combination with BCMA CAR-T cells to identify genes that alter sensitivity to BCMA immunotherapy. Conclusions: Our studies have identified several novel genes and pathways regulating BCMA expression including some druggable targets. Through these studies, we expect to uncover mechanisms regulating expression of BCMA and its impact on sensitivity to BCMA immunotherapy, and pinpoint potential combination therapy targets that pre-empt resistance to BCMA immunotherapy. Disclosures Wiita: Sutro Biopharma: Research Funding; TeneoBio: Research Funding.

Acute leukemia is a life-threatening condition that occurs in MDS, MPD or de novo. Although progress has been made with regard to cytogenetics, little is known about the epigenetic biology of leukemia. MicroRNA (miR) plays a role in regulation of gene expression in many cellular processes, including hematopoiesis. About 19- 25 nucleotides in length, miRs target specific mRNAs and influence their stability, degradation, or translation. miR profiling has begun to contribute to the understanding of the complex regulatory events that occur during normal hematopoiesis and are disrupted during the emergence of the leukemic clone. In particular, miR expression may be useful to understanding normal cytogenetic AMLs and developing novel treatments for AML. Our study was approved by the IRB and informed consent was obtained from patients and controls. We collected peripheral blood samples from 10 patients with newly diagnosed AML, prior to induction therapy, and 8 controls. Two ml of whole blood was collected in Paxgene RNA tubes and frozen for later processing. miRNA was purified using standard Trizol method, followed by RNeasy mini column (Qiagen). Quality of the RNA samples was assessed using the Agilent Bioanalyzer prior to library construction using the Illumina TruSeq Small RNA Sample Prep protocol (Illumina; San Diego, California). Multiplexed samples of RNA that exceeded quality control metrics (RIN > 6.0) were run on an Illumina NextSeq500 instrument at a targeted depth of 10 million reads per sample. After filtering and trimming of index and adapter sequences, whole genome alignment of the miR FASTQ reads was performed using the Homo sapiens/hg19 reference genome in the SHRiMPS aligner included in the miRNAs Analysis application available in BaseSpace (Illumina), as well as the sRNA Toolbox application suite. Quantification and normalization of aligned reads to the miRBase 21 database was performed, and differential expression between AML and control groups performed using DESeq2, NOIseq, and EdgeR algorithms. Consensus changes were seen using all three algorithms after correcting for multiple testing using the Benjamni-Hochberg False Discovery Rate (FDR) algorithm and were examined for use as potential diagnostic markers and for evidence of association with medical/demographic measures. Finally, systems-level analysis of consensus miR findings was performed using the proprietary Core Analysis workflow of the Qiagen Ingenuity® Pathway Analysis (IPA) software to identify leukemia-specific pathways and networks, and to predict the activation or inhibition of specific mRNA targets. We sequenced approximately 800 miRs from our 10 patients with AML and 8 control samples. We identified 44 miRs that showed a statistically significant increase in expression in AML patients versus controls and 33 miRs that showed a statistically significant decrease in expression in AML patients versus controls. Among these 77 differentially expressed miRs, only 10 were previously described in leukemia, including miR 181, miR 199b, miR 10a-5p, miR 22-3p, miR 23b-3p, miR 28-3p, miR 34a-5p, miR 409-3p, miR 500a-3p, miR 744-5p, and miR 126-5p. Finding these 10 miRs confirmed the validity of our approach. The remaining 67 of the miRs that showed differential expression in our study have not been described in relation to AML. Most of these have been found in association with colorectal, breast, cervical, NSCLC. Others have been reported in neurodegerative diseases and cardiac pathologies. Four of the patients with AML also had remission samples sequenced. Comparison of this subset of samples before and after treatment revealed statistically significant differences in three additional miRs. We are currently analyzing our data further to determine possible linkage between specific miRs and subtypes of AML. We are continuing to accrue patients to this study and we are following them over time in order to analyze miR expression as a biomarker that may predict relapse prior to usual indicators, i.e. cbc. Our approach of global sequencing of miRs as opposed to microarray analysis provides an unbiased approach regarding which miRs to assay and has demonstrated discovery of new associations of miRs with AML. We are hopeful that our study will provide further information about the molecular changes that lead to evolution of the leukemic clone and offer new targets for treatments. [ Disclosures No relevant conflicts of interest to declare.