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International audience; Introduction: The risk of inflammatory bowel disease-associated colorectal cancer (IBD-CRC) is known to increase with primary sclerosing cholangitis (PSC) and a family history of CRC. However, the impact of comorbidities such as liver disease, obesity, diabetes, chronic lung, heart, and renal disease, and psychiatric illness on the risk of IBD-CRC remains unclear. We evaluated the effect of these comorbidities on the risk of IBD-CRC.Methods: A retrospective review from 2009 to 2014 was conducted using the National Inpatient Sample data for adults 18 years and older. Patients with IBD (360,892), of whom 2,831 had CRC were identified using the International Classification of Diseases, Ninth Revision codes (ICD-9). Data on comorbidities were also obtained. Adjusted odds ratios (aOR) and confidence intervals (CI) were computed via logistic regression to evaluate the effect of comorbidities on the risk of IBD-CRC; the p-value was set at

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clone of plasma cells in the bone marrow. MM and its therapy increase the risk of complications like anemia, osteolytic lesions, pain, infections, and renal abnormalities in MM patients. Supportive care for MM patients improves the quality of life. Treatment with bisphosphonates decreases skeletal-related events. Vertebroplasty and kyphoplasty are done in cases of vertebral compression fractures. Prophylactic antibiotics and antivirals can decrease infections related to morbidity. Plasmapheresis in patients with renal dysfunctions decreases dialysis dependency and improve quality of life.

Immunoglobulin G4 (IgG4) cholangiopathy is used to describe regional biliary involvement in a systemic fibro-inflammatory and infiltrative disease, IgG4-related disease. Occasionally, it tends to present with localized disease leading to an extensive workup to rule out malignancy and infections, especially since IgG4-related disease is an uncommon entity. Herein, we present a case of a 68-year-old male who presented with pruritus and steatorrhea with imaging studies revealing a biliary hilar mass concerning for malignancy. Subsequent extensive testing was inconclusive of malignancy and finally noted to have elevated IgG4 levels as part of a broader workup. The patient was started on prednisone with the resulting improvement in his symptoms and the imaging findings.

Endoscopic cystogastrostomy using lumen-apposing metal stent (LAMS) is considered the first-line therapy for symptomatic pancreatic fluid collections (PFCs). Routine coaxial placement of a double-pigtail stent (DPS) through LAMS is debated. We report the case of a patient with delayed massive gastrointestinal bleed eight weeks after LAMS placement due to splenic artery pseudoaneurysm leading to a complicated hospitalization. Theoretically, coaxial placement of DPS through LAMS can prevent the relatively sharp LAMS from eroding into the mucosa of the collapsed cavity of PFCs, decreasing the risk of bleeding. Our case adds to the growing need to further explore the utility of this combined intervention.

Introduction: Tracheoesophageal fistulas (TEFs) in adults are uncommon and typically acquired. Traumatic or prolonged intubation account for up to 75% of acquired nonmalignant TEFs.1 No definitive guidelines exist for management of this complication which has poor prognosis without intervention. Case Description/Methods: A 68 year old male presented with SOB and fevers then had prolonged ICU course for COVID-ARDS. The hospital course was complicated by recurrent VAP and unsuccessful attempts to wean the ventilator. He was transitioned to tracheostomy after 34 days. GI was then consulted for PEG placement which was aborted after endoscopy showed what initially appeared to be an ulcer. Further inspection revealed that it was the tracheotomy cuff in the esophagus. (Image 1) PEG placement was deferred and patient underwent tracheostomy exchange for ETT, advanced distal to the site of the fistula, along with esophageal stent placement with CT surgery. Within days patient developed worsening hypoxia refractory to vent adjustments and profound shock then ultimately passed. Discussion: Prognosis for unrepaired TEF is poor with mean survival time 1-6 weeks.1 Risk factors for TEF in the setting of intubation include prolonged ventilation, immunosuppression, malnutrition, episodic hypotension, and NG/OG tube, thus, this patient was the ideal substrate. 2 Symptoms are non specific which delays diagnosis. Evaluation of TEF may include barium esophageal if patient is able to swallow or alternatively CT chest. Definitive diagnosis is made on endoscopy and/or bronchoscopy. Very rarely TEFs may close spontaneously without intervention.3 Strategies for repair include esophageal bypass, direct repair and stenting.2 Studies comparing esophageal stenting with other interventions are lacking. Furthermore, there is no data comparing intervention with esophageal stent by GI vs CT surgery. Approach to repair will depend on the clinical context and physician comfort level. Ideally, patients with TEFs should be extubated, if reasonable, since continued positive airway pressure after repair can increase the risk of dehiscence or stent migration.

Problem-based learning is a learner-centered teaching method, which uses real-world scenarios to promote student learning of concepts and principles. The aim of our study is to analyze the consequence of increased problem difficulty on team-based learning and the analytical skills of medical students. In our prospective descriptive study, two problem-based learning scenarios prepared on the topic of hypercortisolism were given to 197 students in two successive sessions. At the end of two sessions, the perceptions of students about team-based learning were documented using a five-point Likert scale on a standardized questionnaire for both scenarios (simple and complex) simultaneously. A written test consisting of multiple-choice questions (MCQs) and short essay questions (SEQs) was given at the end of a complex scenario to test the problem-solving skills and retention of knowledge. No statistically significant difference (p> 0.05) was noted in team-based learning between the simple and complex problem-based learning scenario. MCQs and SEQs of C-2 (interpretation) level were attempted well than C-1 (recall) level and C3 (problem-solving) level. In conclusion, the understanding of the problem by the medical students was improved; however, there was no significant improvement in the problem-solving skills and knowledge retention of the students.

Biliary cysts are rare cystic dilatations of the biliary tree. Biliary cysts are positively associated with several significant complications, amongst them, cholangiocarcinoma befalls the most dreadful one. The elevated incidence is 20-30% in the unresected cyst and 0.7% in resected cysts. Magnetic resonance imaging (MRI) scan, magnetic resonance cholangiopancreatography (MRCP) or a contrast-enhanced computed tomography (CECT) is applied for the initial diagnostic study but the ultimate diagnosis ordinarily requires the tissue biopsy. Currently, the sole curative option involves the complete surgical resection of the lesion, with standard chemotherapy and active radiation applied as an alternative for the unresectable tumors. Despite the curative surgery the percentage of eternal recurrence of the tumor indefinitely persists, and effective post-surgical surveillance is reasonably demanded. We report a case of 29-year-old female with local recurrence of cholangiocarcinoma in a previously resected biliary cyst type I. The curative resection of the choledochal cyst only minimizes the considerable risk of the possible development of future cholangiocarcinoma but it does not completely prevent it. The appropriate follow-up for potential patients who have been typically treated for a biliary cyst is unclear. The lethal course of cholangiocarcinoma is believed due to its slow asymptomatic growing phase. Therefore, to adequately screen for malignancy, periodic imaging along with annual liver tests represents a reasonable approach to prevent the possible development of this appalling complication.

Enteric fever is a common infectious disease, especially in countries with poor sanitation and in the tropics. It is caused mainly by Salmonella typhi and accounts for nearly 27 million cases worldwide and 200,000 deaths annually. Enteric fever involves the reticuloendothelial system such as bone marrow, spleen, and liver. As it mostly involves the Peyer’s patches of the terminal ileum, enteric perforation occurs commonly. However, gallbladder perforation can also occur, though not very often. Ultrasound as well as computerized tomography (CT) abdomen and pelvis lack specificity for detecting gallbladder perforations in enteric fever. Diagnosis is usually confirmed intraoperatively when the gallbladder is visualized and perforation is seen. Gallbladder perforation is usually seen in acute cholecystitis when the gallbladder becomes necrotic and gangrenous. In acalculous cholecystitis, perforation is rare. Enteric fever is one of the rarest causes of acalculous cholecystitis, leading to perforation. Here, we present the case of a 20-year-old man who presented with fever for 10 days along with loose stools, vomiting, and acute abdomen. Labs showed leukopenia, positive Typhidot test but X-ray erect abdomen and ultrasound abdomen and pelvis were nonspecific. Only after resuscitation and exploration of the abdomen was it found that the gallbladder had multiple perforations. The patient was improved after eight days of postoperative intravenous antibiotics. This is a unique and rare presentation of such a common infectious disease.

Blinatumomab and donor lymphocyte infusion (DLI) combination is a promising cancer therapy, whereby blinatumomab might achieve an initial reduction in leukemic-cell burden using T cells, and after tumor clearance, DLI can potentially stimulate the donor immune system to achieve longer lasting remission. Here, we present a 51-year-old female with mixed phenotype acute leukemia who had a hematologic relapse 3 months after she received total body irradiation-based myeloablative allogeneic hematopoietic stem cell transplantation from an unrelated human leukocyte antigen matched (10/10) donor and achieved complete remission with minimal residual disease negativity by multi-parameter flow cytometry using the combination of blinatumomab and DLI. To the best of our knowledge, this is the first report to describe the use of blinatumomab and DLI combination therapy in the treatment of B/myeloid mixed phenotype acute leukemia.

Introduction: Intracellular signaling cascades including mTOR (mammalian target of rapamycin), MEK (mitogen-activated protein kinase), BCL2 (B-cell lymphoma 2), MET, AKT, and BTK (Bruton's tyrosine kinase) pathways are involved in the growth, proliferation, and survival of tumor cells. Drugs that inhibit these signaling cascades lead to apoptosis and cell cycle arrest making them an important therapeutic modality for treatment of malignancies. The aim of our review is to analyze the published literature on the clinical efficacy of these intracellular signaling cascade inhibitors in patients with relapsed, refractory multiple myeloma (RRMM). Methods: We performed a comprehensive literature search on articles published after 2010. Four hundred and twenty-three articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 11 studies involving 525 RRMM patients. Clinical trials (phase I/II, II and III) with non-FDA approved drugs were included. Results: mTOR inhibitors (Everolimus and Temsirolimus): A total of 157 RRMM patients were included. All trials were early phase (I/II). Everolimus in combination with panobinostat (n=32) achieved an overall response rate (ORR) of 7%. A total of 82 patients received everolimus in combination with sorafenib and achieved a complete response (CR) of 8.5%. Temsirolimus was used in combination with bortezomib (V) (n=43). CR was observed in 5% patients, very good partial response (VGPR) in 9% and stable disease (SD) in 44% patients. AKT Inhibitors (Perifosine and Uprosertib): A total of 153 RRMM patients were included. Eighty-four patients were tested in phase I/II trials while 69 patients were tested in phase III trials. All patients were given perifosine (50 mg) in combination with V with or without dexamethasone (d). In 142 evaluable patients, the pooled ORR was 31%. Uprosertib is currently under phase II evaluation, no clinical data is available while one ongoing phase I/II trial is summarized in Table 2. MEK inhibitor (Selumetinib): A total of 36 RRMM patients were included. All patients were tested in phase II trials. Single-agent selumetinib (75 mg) was given (n= 32). The ORR was 5.6%, VGPR in 3.12%, partial response (PR) in 3.12%, SD in 53.13% and progressive disease (PD) in 40.63% patients. The median progression-free survival (mPFS) was 3.52 months. BCL2 inhibitor (Venetoclax): A total of 66 RRMM patients were included. All patients were tested in phase I/II trials. Single-agent venetoclax (300-1200 mg) was given. The ORR was 21%, CR in 4%, VGPR in 8% and PR in 6% patients. MET inhibitors (Cabozantinib and Tivantinib): A total of 27 RRMM patients were included. Eleven patients were tested in phase I/II trials while 16 patients were tested in phase II trial. Cabozantinib (20-60 mg) and Tivantinib (360 mg) were given to 11 and 16 patients respectively. SD was seen in 54.5% and 36% patients respectively while PD was seen in 18.2% and 63% patients respectively. BTK inhibitor (Ibrutinib): A total of 86 RRMM patients were included. Patients were tested in phase I/II (n=46) and phase II (n=46) clinical trials. Ibrutinib (560-840 mg) was used in combination regimens in all patients. In 85 evaluable patients, the pooled ORR was 35.29%. The best response was seen when ibrutininb was used in combination with carfilzomib (CFZ) with or without dexamethasone (d) i.e. 67%. Conclusion: In RRMM patients, BTK inhibitor (ibrutinib) and AKT inhibitor (perifosine) when used in combination regimens demonstrated a weak efficacy with an ORR of < 40%. The best response was seen when ibrutinib was used in combination with CFZ +/- d i.e. 67%. MET inhibitor (cabozantinib) and MEK inhibitor (selumetinib) showed SD in more than 50% of patients. mTOR inhibitor (temsirolimus) showed SD in more than 40% of patients. Other intracellular signaling cascade inhibitors (venetoclax, selumetinib, everolimus) when used either as single agents or in combination regimens demonstrated a poor efficacy with an ORR of < 25%. However, data on signaling cascade inhibitors is emerging and future randomized prospective trials are needed. Disclosures No relevant conflicts of interest to declare.

Introduction: Targeted immunotherapy includes monoclonal antibodies, antibody-drug conjugates and chimeric antigen receptor T-cells (CAR-T cells). With recent advancements, the study of novel agents that target various cellular receptors involved on myeloma cells, have been actively pursued. The main aim of our study is to review and summarize published literature on the efficacy and safety of these targeted immunotherapies in patients (pts) with multiple myeloma (MM). Methods: We performed a comprehensive literature search on articles published after 2012 using the following databases (Pubmed, Embase, Cochrane, Web of Science and Clinicaltrials.gov). We included 6 completed and 16 ongoing phase II, III trials involving both newly diagnosed MM (NDMM) as well as relapsed/refractory MM (RRMM) pts. Results: Siltuximab: We included 3 phase II trials of Siltuximab (S) involving 243 pts. One hundred ninety-one pts had RRMM while 52 pts had NDMM. The overall response rate (ORR) was 45.50 % and 88% in RRMM and NDMM pts respectively. In a phase II trial involving 52 transplant ineligible NDMM pts, S (11mg/kg) in combination with bortezomib (V), melphalan (M) and prednisolone was given. In 49 evaluable pts, the ORR was 88% with complete response (CR) in 27% pts, very good partial response (VGPR) in 71% pts, and partial response (PR) in 61% pts. The median progression-free survival (mPFS) was 17 months (mo) while the overall survival (OS) at 1 year (y) was 88%. The most common grade 3 and 4 adverse effects (AEs) were neutropenia (62%), thrombocytopenia (44%), pneumonia (17%), and anemia (13%). In a phase II trial involving 142 pts with RRMM, S (6mg/kg) in combination with V was given. The number (no.) of prior therapies were 1-3. In 131 evaluable pts, ORR was 55% with CR in 11% pts and PR in 44% pts. The mPFS was 8 mo (p=0.345) while the OS at 1 y was 81%. The most common grade 3 and 4 AEs were neutropenia (49%), and thrombocytopenia (48%). In another phase II trial involving 49 pts with RRMM, S (6mg/kg) in combination with dexamethasone (D) was given. The median no. of prior therapies was 4. In 47 evaluable pts, the ORR was 19% while the mPFS and OS were 3.7 mo (95% CI= 2.8-4.9) and 20.4 mo (95% CI= 11.4-32.3) respectively. The most common grade 3 and 4 AEs were neutropenia (36.7%), thrombocytopenia (53%), anemia (32.6%), leukopenia (8%), and fatigue (16.3%). Only one ongoing phase II study was found (Table 2). No phase III studies were found. Isatuximab (SAR650984): In a phase II trial involving 97 pts with RRMM, escalating doses of isatuximab (3-20 mg/kg) were given. The median age of pts was 62.5 y. The median no. of prior therapies was 5. At dose ≥10 mg/kg, maximum ORR of 24% was observed. The most common AEs were nausea (33%), fatigue (30%), dyspnea (26%), and cough (24%). Two ongoing phase II studies and 3 ongoing phase III studies were found (Table 2). Pembrolizumab and nivolumab: In a phase II study involving 48 pts with RRMM, pembrolizumab (200mg) in combination with pomalidomide and D was given. The median no. of prior therapies was 3. The ORR was 60% with CR in 8.33% pts, VGPR in 19% pts, and PR in 33% pts. The mPFS was 17.4 mo. The most common grade 3 and 4 AEs were neutropenia (42%), thrombocytopenia (13%), anemia (21%), and lymphopenia (15%). Two ongoing phase II/III studies each was found for Pembrolizumab. One ongoing phase II and III study each was found for nivolumab (Table 2). Tabalumab: In a phase II trial involving 148 pts with RRMM, tabalumab (100-300mg) in combination with D and V was given. The ORR was 58.1-59.5%. The mPFS was 6.6-7.5 mo. The most common grade 3 and 4 AEs were thrombocytopenia (15.6%), anemia (10.9%), and fatigue (7.5%). No phase III studies were found. Conclusion: Our study demonstrated that siltuximab combination regimens have shown excellent efficacy in NDMM pts compared to RRMM pts with an ORR of 88% vs. 46%. Similarly, better OS (88% vs. 81%) and mPFS (17 months vs. 8 months) were found in NDMM pts compared to RRMM pts. Neutropenia and thrombocytopenia were the major side effects reported with siltuximab. Pembrolizumab and tabalumab have shown moderate efficacy in RRMM pts with an ORR of 60%. However, isatuximab has shown mild efficacy in RRMM pts with an ORR of 24%. These drugs are well tolerated compared to siltuximab. Significant data in the literature are lacking and data from larger study population are needed. Disclosures No relevant conflicts of interest to declare.

Introduction: Intracellular molecular inhibitors act by inducing apoptosis due to inhibition of intracellular proteins like 20S proteasome subunit, histone deacetylases (HDAC's), exportin 1 (XPO1), cyclin-dependent kinases (CDKs) and kinesin spindle protein (KSP). These proteins are involved in the regulation of cell cycle. The aim of our analysis is to report published literature on the clinical efficacy of intracellular molecular inhibitors in relapsed and refractory multiple myeloma (RRMM) patients. Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after 2011. Four hundred eighty-nine articles were identified using the following five databases (Pubmed, Embase Cochrane, Web of Science and Clinical Trials.gov). After a detailed screening, we finalized 13 studies involving 902 RRMM patients. We included phase I/II, II and III studies. The studies involving drugs approved by the US Food and Drug Administration were excluded. Results:Selective inhibitor of nuclear export (SINE) compounds: Selinexor A total of 112 RRMM patients were included. Thirty-three patients were in phase I/II while 79 patients were in phase II. All patients received selinexor (60-100 mg) in different combination regimens. Forty-eight patients were quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) while 31 patients were penta-refractory (including isatuximab/daratumumab). In 110 evaluable patients, the pooled overall response rate (ORR) was 35.45%. The ORR in the subset of quad-refractory and penta-refractory patients was 21% and 20% respectively. The best response was seen when selinexor was used in combination with bortezomib (V) and dexamethasone (d) i.e. 77%.HDAC inhibitors: Vorinostat and Ricolinostat A total of 562 RRMM patients were included. Seventy-seven patients were in phase I/II, 168 patients in phase II, and 317 patients were in phase III. Five hundred and eighteen patients received vorinostat (100-400 mg) in different combination regimens while 44 patients received ricolinostat (160-240mg) in combination with Vd. The median follow-up period was 13.2-30.8 months. In 560 evaluable patients, the pooled ORR was 42.83% and 31.81% in patients who received vorinostat and ricolinostat, respectively. The best response was seen when vorinostat was used in combination with V, doxorubicin (DX) and d i.e. 67%.Proteasome inhibitors: Oprozomib and Marizomib A total of 117 RRMM patients were included. Hundred and two patients were in phase I/II while 15 patients were in phase II. Twenty-seven, 34 and 41 patients received single-agent oprozomib in the dose of 240 mg, 150-180 mg, and 240-300 mg respectively while 15 patients received single-agent marizomib (0.5 mg/m2). Out of 107 evaluable patients, the pooled ORR was 27.65% in patients who received oprozomib while no response was seen in patients who received marizomib however stable disease was seen in 31% of patients.KSP inhibitor: Filanesib A total of 50 RRMM patients were included. All patients were in phase II. Thirty-two patients received single-agent filanesib (1.5mg/m2) while 18 patients received filanesib (1.5mg/m2) in combination with d. The pooled ORR was 22%. The ORR was 19% when filanesib was used as a single agent while it was 28% when filanesib was used in combination with d.CDK inhibitors: Dinaciclib and Palbociclib A total of 61 RRMM patients were included. All patients were in phase I/II. Twenty-nine patients received single-agent dinaciclib (30-50 mg/m2) while 32 patients received palbociclib (100mg) in combination with Vd. In 52 evaluable patients, the ORR in patients who received dinaciclib was 11% while the ORR in patients who received palbociclib was 20%. Conclusion: In RRMM patients, vorinostat and selinexor when used in combination regimens demonstrated a weak efficacy with a pooled ORR of 43% and 36% respectively. The best response was seen in combination with Vd i.e. 67% and 77% respectively. The data on other intracellular molecular inhibitors (ricolinostat, oprozomib, marizomib, filanesib, dinaciclib, and palbociclib) when used either as single agents or in combination regimens, suggested a poor efficacy with an ORR of < 35%. However, future randomized well designed prospective clinical trials involving a larger population are required to further explore the efficacy of these agents in RRMM patients. Disclosures No relevant conflicts of interest to declare.

Introduction Light chain multiple myeloma (LCMM) constitutes approximately 15% of patients with multiple myeloma (MM). It has an earlier average age of onset (54 years) and appears to have a poorer prognosis when compared to IgG or IgA variant. The main aim of our analysis is to study the published literature on the efficacy of bortezomib (V) based regimens and disease monitoring in patients with LCMM. Methods We performed a literature search of articles published after 2012 using following four databases (PubMed, Embase, Cochrane Library and Web of Science). We included only English language studies and summarized our data using medians, absolute values, and percentages. Results The literature search identified a total of 390 articles on LCMM. After detailed scrutiny, 6 studies involving a total of 1054 LCMM patients (pts) were included. In a study by Zhang et al. (2014) including 96 pts, 66 pts received 4 cycles of V (1 mg/m2) with dexamethasone (D) (20 mg) while 30 pts received non-V regimens. In bortezomib group, the overall response rate (ORR) was 95.5%. Complete response (CR) was seen in 56.1% pts while 39.4% pts showed partial response (PR). In non-bortezomib group, the ORR was 60%. CR was seen in 10% pts while 50% pts showed PR. The overall survival (OS) at 3 and 5 years in bortezomib group was 33% and 24% respectively while the OS in non-bortezomib group was 28% and 9% respectively (p=0.335). The progression free survival (PFS) at 1, 2 and 3 years in bortezomib group was 37%, 25% and 8% respectively while the PFS at 1 and 2 years in non-bortezomib group was 27% and 9% respectively (p=0.036) (Table 1). In two different studies by Mrachacz et al. (2015) and Tessenow et al. (2017), a total of 45 pts were treated with V (1.3 mg/m2) in combination with bendamustine (B) (60 mg/m2) and prednisone (P) (100 mg). ORR was 95.5% including 37.7% pts with CR, 22.2% pts with very good partial response (VGPR) and 35.5% pts with PR. Median OS at 24 and 30 months was 95% and 96 % respectively while PFS at 24 and 30 months was 90% and 68% respectively. In another study by Heaney et al. (2017) including 576 pts, 567 (98.4%) pts were identified by serum free light chain (sFLC) level compared to 460 (79.8%) pts which were identified by urine free light chain (uFLC) level. Hundred thirty-two pts were evaluated at maximum response to therapy with V. ORR was 98.4% including 43.1% pts with CR, 44.6% pts with VGPR, 10.6% pts with PR and 1.5 % pts had stable disease (SD). In a study by Dejoie et al. PFS (2016) including 113 pts, Urine Protein Electrophoresis (UPEP) was positive in 87 (78.3%) out of 111 evaluable pts while serum involved free light chain (iFLC) was positive in all (113) pts. Seventy eight %, 37% and 18% pts showed abnormal UPEP at baseline (diagnosis), treatment cycle 1 and treatment cycle 3 respectively while 100%, 71% and 46% of pts showed abnormal iFLC at baseline, treatment cycle 1 and treatment cycle 3 respectively, indicating sFLC as more sensitive indicator of the disease than UPEP. Abnormal iFLC level at the end of consolidation therapy showed a statistically significant shorter PFS than pts with normal iFLC level [p= 0.004; Hazard ratio (HR) = 2.7; 95% CI = 1.4-5.4]. UPEP did not reach any statistical significance in determining PFS [p = 0.178; HR= 1.6; 95% CI= 0.8-3.3]. No statistically significant data was found for abnormal iFLC and abnormal UPEP in determining OS [(p= 0.164; HR= 2.2; 95% CI= 0.7-6.6) and (p= 0.891; HR= 0.9; 95% CI= 0.2-4.0) respectively]. However, abnormal sFLC ratio at the end of consolidation therapy showed a statistically significant shorter PFS (p= 0.006; HR= 3.1; 95% CI= 1.4-6.8) as well as OS (p=0.047; HR=7.8; 95% CI= 1.0-58.5). In a similiar study by Bradwell et al. including 224 pts, 82 pts were evaluated at follow up after chemotherapy with vincristine, doxorubicin and melphalan. CR was seen in 26 (31.7%) pts as indicated by normal uFLC levels compared with only 9 (10.9%) pts by their normal sFLC levels, indicating false negative results with uFLC compared to sFLC. Conclusion There is a paucity of data on LCMM in the literature. V has shown superior efficacy in LCMM patients over non-V regimens with ORR > 95%. Moreover, V showed better PFS at 2 years when used with bendamustin compared to VD (95% vs. 25%). Similarly, V with B showed better OS i.e. 90% at 2 years. Moreover, sFLC levels were more sensitive in indicating the disease and predicting PFS and OS compared to uFLC levels, hence monitoring of LCMM patients should include serum assays. Disclosures No relevant conflicts of interest to declare.

Introduction: Despite the recent advancements in the treatment of multiple myeloma (MM), there is a constant need of newer therapies in order to treat the complex issue of the disease relapse and refractory disease. Isatuximab (ISA) is a non-Food and Drug Administration (FDA) anti-CD38 monoclonal antibody that acts through immune cell engagement and direct tumor targeting. We report efficacy & toxicity of ISA in newly diagnosed MM ((NDMM) as well as relapsed, refractory MM (RRMM) patients (pts). Methods: Following Prisma guidelines, we performed a comprehensive literature search on articles published after January 2012 using PubMed, Embase, Cochrane Library, Web of Science and Clinicaltrials.gov. On initial search, 246 articles were found and after a detailed screening, 6 completed and 11 ongoing phase I/II/III studies were included. Results: A total of 249 pts were included. Two hundred thirty-four pts had RRMM while 15 pts had NDMM, overall response rate (ORR) was 37.60% and 87% respectively. In a phase I trial involving 34 pts with RRMM, single-agent ISA (1-20 mg/kg) was given. The median age of pts was 64 years (y) [range (r) = 38-85]. The overall response rate (ORR) was 24% with a partial response (PR) in 18% pts. The most common adverse events (AEs) were nausea (34%), fatigue (49%), fever (29%) and headache (26%) and upper respiratory infection (23%). In a phase II trial, 97 pts with RRMM were stratified into 4 groups. Single-agent ISA [3mg/kg, every 2 week,(Q2W); 10 mg/kg, Q2W - every 4 weeks (Q4W); 10 mg/kg (Q2W), 20 mg/kg (QW-Q2W)] was given. The median age of pts was 62.5 y (r = 38-85). The ORR was 9%, 20%, 29% and 24% respectively. The cumulative ORR was 20.6%. The median time to first response was 1.4 months (M) while the median duration of response was 6.6 M. The most common AEs were nausea (33%), fatigue (30%), diarrhea (26%) and cough (24%). In a phase Ib trial, 57 pts with RRMM were stratified into 5 groups. ISA [3 mg/kg (Q2W); 5 mg/kg (Q2W); 10 mg/kg (Q2W); 10 mg/kg (QW-Q2W); 20 mg/kg (QW-Q2W)] in combination with lenalidomide (R) (25mg), and dexamethasone (D) (40 mg) was given. The median age of pts was 61 y (r = 42-76). The median time since the initial diagnosis was 4 y. The ORR was 33%, 67%, 63%, 50%, and 50% respectively. The cumulative ORR was 56% with complete response (CR) in 3.8 % pts, very good partial response (VGPR) in 32.7 % pts and PR in 19.2 % pts. The progression-free survival (PFS) was 8.5 M (r=4.73-16.59). The most common grade 3 and 4 AEs were neutropenia (60%), lymphopenia (58%), leukopenia (53%), anemia (25%), thrombocytopenia (38%), pneumonia (9%), fatigue (7%), and dyspnea (4%). In another phase Ib trial, 36 pts with RRMM were stratified into 3 groups. ISA (5 mg/kg; 10 mg/kg, 20 mg/kg) in combination with pomalidomide (P) (4 mg), and D (40 mg) was given. The ORR was 63%, 55%, and 50% respectively. The cumulative ORR was 55.5%. The median time to first response was 4.1 weeks (W) while the median duration of response was 33.1 W. The most common grade 3 AEs were neutropenia (81%), lymphopenia (75%), and leukopenia (75%). In another phase Ib trial involving 10 pts with RRMM, ISA (10-20 mg/kg) in combination with carfilzomib (CFZ) (27 mg) was given. The median number of prior lines of therapy was 4.5 (2-8). The ORR was 80% with VGPR in 20% pts and PR in 60% pts. The most common grade 3 and 4 AEs were lymphopenia (64%), anemia (9%), and neutropenia (9%). In a phase Ib trial involving 15 pts with NDMM, ISA (10 mg) in combination with bortezomib (V) (1.3 mg/m2) and cyclophosphamide (CY) (300 mg/m2) was given. The median age of pts was 71 y (r= 68-80). The ORR was 87% with CR in 33% pts, VGPR in 27% pts, and PR in 27% pts. The median time to first response was 1.5 M while the median duration of response was 11 M. The most common grade 3 and 4 AEs were lymphopenia (50%), leucopenia (18%), neutropenia (8%), anemia (6%) and thrombocytopenia (6%). Conclusion: In RRMM pts, ISA as a single agent has shown weaker efficacy when compared to combination regimens i.e. ORR 21% vs. 58%. The best result was seen when ISA was used in combination with CFZ demonstrating an ORR of 80%. In NDMM pts, combination regimens have shown excellent efficacy with an ORR of 87%. Nausea and fatigue were the major AEs reported with the monotherapy while neutropenia, leucopenia, and lymphopenia were the major AEs reported with the combination regimens. Further studies involving a larger population are required to gather evidence in favor of the improved efficacy and to evaluate AEs. Disclosures No relevant conflicts of interest to declare.

Introduction: Allogenic stem cell transplantation (allo-SCT) is a potentially curative option for hematological malignancies. Checkpoint inhibitors (CPI) have been successful in achieving remission for patients that relapse after allo-SCT. CPI can help relapsed/refractory (RR) patients to respond and bridge towards allo-SCT after achieving remission. Check point inhibition after allo-SCT carries an increased benefit of graft vs malignancy effect (GvL) but it may exaggerate the risk of immune system related toxicity such as graft versus host disease (GvHD). Methods: To assess the safety and efficacy of CPI use in conjunction with allo-SCT, after a comprehensive literature search, we included data (n=283) from a total of twenty-four studies (11 original manuscripts, 13 case reports or case series) and analysed the results. Results: Most common indication for CPI use was Hodgkin lymphoma (n=182). CPIs used in various studies included CTLA-4 inhibitors (ipilimumab, n=93) and PD-1 inhibitors (nivolumab, n=167 and pembrolizumab, n= 27). In patients who were exposed to CPI before allo-SCT (n=107), 56% patients developed acute (a) GvHD and 29% patients developed chronic (c) GvHD. The overall mortality risk (11/107) associated with GvHD was 11%. Interval between last dose of CPI and allo-SCT ranged from 28-62 days. Median cycles of CPI therapy ranged from 4-9 cycles. The overall response rate (ORR) was observed (42/62) to be 68% patients with complete remission (CR) in 47% patients and partial remission (PR) in 21% patients. Most common adverse events reported were non-infectious febrile syndrome (12%), infections (5%), hepatic sinusoidal obstruction syndrome (4%) and encephalitis (3%). In patients (n=150) who received CPI after allo-SCT for treatment of disease relapse, 13% patients developed aGvHD and 11% patients developed cGvHD. The overall mortality risk with GvHD was around 7% in this population. The interval between allo-SCT and first dose of CPI ranged from 12.5 months to 29 months. Nivolumab was given at doses 1 mg/kg to 3 mg/kg, weekly or two-weekly. Ipilimumab dose ranged from 0.1 mg/kg to 5 mg/kg. A combination with lenalidomide was also tried. Pembrolizumab was administered at 200 mg/kg every three weeks. An ORR of 48% (59/123) was observed with CR in 34 (28%), PR in 25 (20%) and disease stabilization in 7 (6%) patients. Complications, other than GvHD, include hematological side effects (22%), most notably neutropenia followed by respiratory and hepatic complications (16% and 14% respectively). Thirteen case reports evaluated safety and efficacy of CPIs after allo-SCT. Among 26 cases, the reported ORR was 85% with fifteen and seven patients achieving CR and PR, respectively. Of the four patient deaths that occurred during the study period, one died of GvHD. Most common adverse reactions noted were in the GI tract, notably hepatitis (32%), followed by skin (25%) and pulmonary disease (25%). Conclusion: CPI use before and after allo-SCT can be highly effective for relapse disease control. For patients who received Allo-SCT, CPI exposure can lead to significantly increased risk of GvHD, GvHD related morbidity and mortality. There is need for caution while making decision for CPI use in this population. Prospective well-designed clinical trials are required to further explore the safety of CPIs in allo-SCT setting. Disclosures No relevant conflicts of interest to declare.

Background Myelodysplastic Syndrome (MDS) represents a heterogeneous group of diseases with clonal proliferation, bone marrow failure and increase risk of progression to acute leukemia. Histone deacetylase inhibitors (HDACi) modulate the epigenetics of cancer cells to promote differentiation and programmed cell death. Our aim is to study the efficacy and safety of HDACi in patients with MDS/ acute myeloid leukemia (AML). HDACi can be a safer alternative in patients with high risk MDS who are not eligible for stem cell transplantation or high intensity chemotherapy. Methods A comprehensive literature search was done using following 5 databases: (Pubmed,Embase,Web of Science,Cochrane library,Clinical Trials.Gov) in accordance with the PRISMA guidelines. We included 21 trials (Phase II/III ) with a total 1654 patients,of which 1030 patients recieved HDACi and were evaluable for respone. Our primary objective was to determine efficacy of HDACi based regimen in terms of overall response rate (ORR) and composite complete response rate (CCR). A meta-analysis was done for regimen that were evaluated in more than one trials to report ORR and CRR.CMA software V.3 was used to run metaanalysis to calculate the response and the heterogenity among studies were assesed by using I2 test.A random -effect model was applied. Results: The pooled analysis (95% CI) with 1030 evaluable patients in MDS/ AML showed an overall response rate of 37.1% (32.3-42.3 : I2= 86.105 )with composite response (comp CR=CR+Cri+mCR) of 30.8%(26.8-35.1) .The median overall survival of those who received HDACi ranges from 8 -25 months.The Base line Characterstics,Outcome and Toxicity of HDACi in MDS/AML are summarized in Table 1. In the meta-analysis (n=57) of two trials (Garcia et al, 2007 & Luger et al. 2013), combination regimen of Mocetinostat- Azacytidine had an ORR of 54%(95% CI: 10.2-92.3) and composite complete response (CCR) of 18.9% (95% CI :9.3-34.7) in patients with MDS/AML. Combination of Vorinostat-Cytarabine-Idarubicin had an ORR of 50.7% (95% CI :40.7-96.5) and CCR of 30.1% (95% CI: in 111 patients with MDS/AML in a meta-analysis of trials by Prebet et al. 2013 and Manero et al. 2012. The meta-analysis of 3 trials evaluating Vorinostat-Azacitadine regimen (Craddock et al. 2017; Sekers et al. 2017 & Montalbano et al. 2016) had an ORR 38.3%( 95 % CI :18-63) CCR of 29%(95% CI: 11-58) in a total patient population of 274 patients. The regimen of Valproate- Deictibine/Cytarabine was evaluated in 3 separate trials with a total patient population of 156 which showed an ORR of 41.6% (95 % CI :20.9-65.6)and a CCR of 28.3%(95% CI 18.9-42.7) in the metanalysis. The meta-analysis of 3 trials evaluating a three-drug regimen of Valproate-Azacytadine-All trans retinoic acid(ATRA) showed an ORR of 32.2%(95% CI :24.2-41.3) and CCR of 23.7%(95 %CI 13.1-39.0) in 144 MDS/AML patients. In a trial by Manero et al (2017), the combination of Pracinostat and Azacitadine had an ORR of 67.5% (95% CI :51.7-80.01) CCR of 60%(95% CI 44.3-73.8) in 51 AML/MDS patients. A single trial evaluating regimen of Panobinostat and Azacitadine (n=40) had an ORR of 37.5% and CCR of 27.5%. Combination of Panobinostat and Decitabine in a trial by Geoffry et al in 2017 (n=52), the ORR was 21.2% and CCR of 19.2%.The Overall response rate and Composite response rate of HDACi in MDS/AML are mentioned in Table 2 and Table 3. Conclusion: Most of the HDACi like Mocetinostat,Valproic acid ,Pracinostat when used in combination with either Hypomethylating agents(Azacytidine ,decitabine) or purine analogs (cytarabine/idarubicin) produced a good response.Pracinostat in combination with azacytidine showed the best ORR among the studies but there was only single study mentioning this combination.Single agent studies with resposne were also not evaluable.Most of MDS patients get resistant to hypomethlating agent thus there is need to explore newer agents and HDACi agents is a promising group. Disclosures No relevant conflicts of interest to declare.

Introduction: Multiple myeloma (MM) is associated with end organ damage that negatively impacts the quality of life (QOL)and supportive care has a potential to improve symptoms. Methods: After detailed search on Pubmed, Cochrane, Embase and Clinical Trials.gov, we finalized total 36 articles on supportive care published after 2004. Results: Management of skeletal events: Mhaskar et al. (2017, n=3257) compared bisphosphonates (BPs) with placebo (PBO) in preventing pathological vertebral fractures, skeletal-related events (SRE), reported risk ratio (RR) of 0.74 in each; 95% CI 0.62-0.89 and 0.63-0.88 respectively. Both zoledronic acid (ZA) and clodronic acid prevent SRE, but mortality rate was better reduced with ZA (hazard ratio [HR]=0.84; p=0.0118), (Gareth et al. 2010, n=1960). In a study by Zuradelli et al. (2009, n= 240); hypocalcemia developed in 93 (38.8%) patients on ZA for a median of 2.3 months (range, 0-34.9). Vitamin D and calcium replacement is essential in patients developing hypocalcemia with BPs, (Kennel et al. 2009). Vertebral augmentation procedures improved pain after compression fracture (n=923) by 4.8, 4.6 and 4.4 points at 1 week, 1 year and beyond 1 year respectively, (Khan et al. 2014). Valerie et al. (2011, n=84) analyzed improvement in bone pain with radiotherapy (median 45 grays) in 92 % patients. Prophylaxis of infections: Leng et al. (2018, n=70,687) observed reduced risk of herpes zoster (HZ) reactivation in patients on bortezomib or carfilzomib + HZ prophylaxis (2.4%) vs 5.8% in non-prophylactic group, (attributable risk reduction: 0.42; 95% CI 0.31-0.56). Teh et al. (2016, n=199) reported reduced risk of varicella zoster virus reactivation with valacyclovir (500 mg) in patients on bortezomib based therapy and following autologous stem cell transplant (ASCT) vs no prophylaxis (HR=0.06 vs 16.9; p Role of plasmapheresis in renal impairment (RI): Alkhatib et al. (2017) showed that plasmapheresis reduced dialysis dependency by removing serum free light chains (sFLC) in patients with RI (n=147), (RR 0.45; P = 0.02). Yu-X et al. (2015, n=147), showed lower 6-month dialysis dependency ratio with plasmapheresis and chemotherapy (PP + CTH) vs CTH alone, (15.6% vs 37.2%; RR=2.02; p = 0.04). High cut-off hemodialysis lowered sFLC level in 61% (n=42) and 63% patients at day 12 and 21 respectively. Out of these, 71% and 69% patients became dialysis independent, (Hutchison et al. 2012, n=67). Peripheral neuropathy (PN): Bortezomib caused PN in 124/331 (37%) patients (Richardson et al. 2009) whereas with thalidomide, the incidence of PN was 38% and 73% at 6 and 12 months, respectively, (Mileshkin et al. 2006, n=75). PN improved in 68% patients on bortezomib with dose modifications (n=72) vs 47% patients, without dose modification (n=19). (Table 1 and 2). Significant improvement in PN was seen with duloxetine vs placebo (1.06 vs. 0.34; p= 0.003), (Smith et al. 2013, n=231). Arbaiza et al. (2007, n=36) showed improvement in neuropathic pain with tramadol (p= < 0.001). Epoetin and derivates for anemia: Castelli et al. (2017, n= 31; median creatinine 1.2 mg/dL (0.8-3.0)) reported hemoglobin (Hb) increase of ≥1g/dL and ≥2g/dL in 71% and 31.7% patients respectively with epoetin α, transfusions requirement reduced from 2.39 ± 1.05 to 1.23 ± 1.36 (p < 0.001). Begiun et al. (2013, n= 72) compared the effect of darbepoetin (D) ± iron (Fe) vs placebo on erythroid recovery after ASCT. All patients receiving D + Fe achieved Hb ≥13 g/dL (p Conclusion: Along with anti-myeloma chemotherapy therapy, management of complications (anemia, infections, renal insufficiency) and other associated symptoms is necessary to improve the quality of life. Disclosures No relevant conflicts of interest to declare.

Introduction Selinexor, a SINE (selective inhibitor of nuclear export) compound, inhibits exportin 1 (XPO1) involved in transport of tumor suppressor proteins leading to apoptosis of tumor cells. XPO1 is overexpressed in variety of cancer including ovarian cancer, pancreatic cancer, glioma, osteosarcoma, leukemia, lymphoma, and multiple myeloma. The aim of this study is to summarize clinical response and adverse events of selinexor in hematological neoplasms. Methods A comprehensive literature search on PubMed, Embase, AdisInsight and Clinicaltrials.gov was completed on July 12, 2018. Studies focusing on efficacy and/or adverse events of selinexor in patients with hematological neoplasms were included for the review. Results Out of 321 studies found on initial search, we finalized 15 studies (8 phase I and 7 phase I/II) after screening by two reviewers. AML: Selinexor in combination with high-dose cytarabine and mitoxantrone has shown overall response rate (ORR) of 70% among 20 patients with acute myeloid leukemia (AML), Wang et al., 2018. Out of 12 newly diagnosed AML (ND AML) patients, 11 (92%) patients showed response with complete response (CR) in 7, CR with incomplete recovery (CRi) in 3 and partial response (PR) in 1 patient. Among 8 relapsed/refractory AML (R/R AML) patients, only 3 patients showed CR while 5 had treatment failure (TF), ORR in this subset was 38%. In 81 evaluable R/R AML patients receiving selinexor as monotherapy only 14% of the patients showed response while 31% patients had disease progression (PD) along with grade ≥3 hematological adverse events (AEs) of thrombocytopenia, anemia and neutropenia in 19%, 15% and 13% patients, respectively (Garzon et al., 2017). MM: Relapsed refractory multiple myeloma patients receiving selinexor combined with pomalidomide and dexamethasone have achieved ORR of 60% with CR in 1 and PR in 5 patients (Chen et al., 2016 n=10) with grade ≥3 neutropenia in 8 patients. In another regimen with doxorubicin and dexamethasone the clinical benefit rate (CBR) was 26% with 15% overall response (Rachid et al., 2017 n=27). Grade ≥3 neutropenia, thrombocytopenia and hyponatremia occurred in 33%, 33% and 30% of patients, respectively. NHL: Kuruvilla et al. observed ORR in 31% patients with relapsed refractory non-Hodgkin lymphoma with single-agent selinexor. Grade ≥3 thrombocytopenia, neutropenia and anemia occurred in 47%, 32% and 27% patients, respectively. The efficacy of selinexor in phase I and I/II clinical trials is given in table 1 while toxicity is mentioned in table 2. With selinexor, the most common hematological and nonhematological AEs noted were thrombocytopenia and hyponatremia, respectively. Conclusion: Selinexor based combination regimens have shown better clinical response against AML as compared to monotherapy. The efficacy results in multiple myeloma and other hematological malignancies are also encouraging. The adverse events like cytopenias were common as in other chemotherapy regimens. Disclosures No relevant conflicts of interest to declare.

Introduction Bendamustine (B) and Melflufen (Mel) are Non-Food and Drug Administration (FDA) approved novel alkylators that exert their cytotoxic effects by cross-linking of DNA strands via alkylation, resulting in the inhibition of mitotic checkpoints leading to cell death. We report published literature on efficacy and safety of combination regimens of novel alkylators in patients (pts) with multiple myeloma. Methods We performed a comprehensive literature search on articles published after 2012 using following search engines (Pubmed, Embase, Cochrane, Web of Science and Clinical Trials.gov). We included both phase II, III studies and summarized our data using absolute values and percentages. Results Bendamustine: We included four phase II studies of B involving 217 pts. One hundred seventy-six pts had relapsed and refractory multiple myeloma (RRMM) while 41 pts had newly diagnosed multiple myeloma (NDMM). The overall response rate (ORR) was 71.75 % and 92% in RRMM and NDMM pts respectively. In a phase II trial (n=41), NDMM pts who were not eligible for autologous stem cell transplant (ASCT) were included. B (80 mg/m2 on days 1 and 2), bortezomib (V) (1.3 mg/m2 on days 1, 8 and 15) and dexamethasone (D) (20 mg on days 1, 2, 8, 9, 15 and 16) were given for every 28 days for 8 cycles. In 39 evaluable pts, the ORR was 92% with complete response (CR) in 17% pts, very good partial response (VGPR) in 59% pts, and partial response (PR) in 21% pts. The most common grade 3 and 4 adverse effects (AEs) were leukopenia (12%), thrombocytopenia (7%), neutropenia (15%), and fatigue (12%). In a phase II trial (n=50), pts with RRMM were included. B (75mg/m2 on days 1 and 2), Lenalidomide (R) (25mg on 1-21 days) and D (40mg/20mg on days 1, 8, 15, 22) were given in a 4-weekly cycle for 6 cycles. In 45 evaluable pts, the ORR was 88.9% with CR in 15.5% pts, VGPR in 40% pts, and PR in 33.3% pts. The 2-year progression-free survival (PFS) and the overall survival (OS) were 42% and 76% respectively. The most common grade 3 and 4 AEs were neutropenia (74%), leukopenia (70%), thrombocytopenia (38%), anemia (20%), and infections (14%). In another phase II trial (n=94) pts with RRMM were included. B (60 mg/m2 versus 100 mg/m2 on days 1-8 of 28 day cycle), thalidomide (T) (100 mg on days 1-21) and D (20 mg on days 1,8,15 and 22 of 28 day cycle) were given. The dose of 100 mg/m2 was later discontinued due to cytopenias. In 54 evaluable pts, the ORR was 46.3% with CR in 1.9% pts, VGPR in 3.7% pts, and PR in 40.7% pts. The PFS and OS at 12 months were 18.7% (95% CI= 9.1- 31.0) and 56% (95% CI= 39.7-69.5) respectively. The common grade 3 and 4 dose-dependent (60mg/m2 vs. 100mg/m2) AEs were neutropenia (33% vs. 64%), thrombocytopenia (31% vs. 43%), and anemia (22% vs. 36%). In another Phase II trial (n=32), pts with RRMM undergoing tandem ASCT were included. Before the first ASCT, melphalan (M) (200 mg/m2) alone was given as a conditioning regimen while before the second ASCT, M (140 mg/m2) in combination with B (200mg/m2) was given. High dose cyclophosphamide (CY) (3-4 g/m2) and granulocyte colony stimulating factor (G-CSF) were used to mobilize peripheral blood stem cells (PBSC). The ORR and CR after the first ASCT were 81.2% and 46.8% respectively while the ORR and CR after second ASCT were 90.6% and 62.5% respectively. No phase III studies were found. Melflufen: In a phase II trial (n=55), pts with RRMM were included. Melflufen (Mel) (40 mg every 3 weeks) in combination with D was given to 31 pts. The median number of prior lines of therapies was 4 (2-9). In 23 evaluable patients, the ORR was 48% with VGPR in 4.34% pts and PR in 43.47% pts. The median PFS was 7.6 months. An ORR of 43% in proteasome inhibitors (PI) refractory pts, 40% in immunomodulator (IMiD) refractory pts, 62% in alkylator refractory pts, 38% in double refractory (IMid and PI) pts and 50% in triple refractory (IMid, PI, and alkylators) pts was demonstrated. The most common grade 3 and 4 AEs were thrombocytopenia (68%), neutropenia (55%), anemia (42%), and leukopenia (32%). Conclusion Our study demonstrated that combination regimen (BVD) has shown superior efficacy with an ORR of >90% when compared to other combination regimens. Furthermore, BVD was well tolerated in patients with grade 3 and 4 toxicities < 20%. Moreover, the combination of B with M when used as conditioning regimen for ASCT showed superior efficacy than M alone (90.6% vs. 81.2%). However, there is a paucity of data regarding this and future randomized prospective trials are needed. Disclosures No relevant conflicts of interest to declare.

Background: Ixazomib (Ixa) is the first FDA approved oral proteasome inhibitor to be used for relapsed and refractory multiple myeloma (MM). We conducted a comprehensive systematic review and meta-analysis of all published prospective clinical trials to analyze the efficacy and safety of ixazomib in newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM). Method: After review of literature (last updated June 30, 2018) using database searches (Pubmed, Embase, Cochrane Library, Web of Science and Clinical Trials.gov), from a total of 1290 studies, only fifteen clinical trials (n=1387) met the inclusion criteria for RRMM and eight clinical trials (n=537) met criteria for NDMM. CMA software v.3 was used for meta-analysis. Heterogeneity among studies was assessed using the I2 test. A random-effect model was applied. Result: Based on pooled analysis, an overall response rate (ORR) of 40.6% (95% CI:19.4-66.0) with a very good partial response or better (≥VGPR) of 15.7% (95% CI: 6.8-32.1) in RRMM and ORR (CR+VGPR+PR) of 77.5% (95% CI: 73.1-81.4, I2=48.05) in NDMM was observed. Most common grade (G) ≥ 3 adverse events (AE) based on regimen were calculated using pooled analysis in MM patients. Ixazomib Based Regimen in RRMM: Ixazomib as monotherapy: Four studies (n=192) evaluated the efficacy of ixazomib as a single agent. On subgroup pooled analysis on Ixa as monotherapy, an ORR of 22.7% (95% CI: 13.3-35.9, I2=45%) was observed with ≥VGPR of 7.8% (95% CI: 2.7-20.3). Pooled analysis for safety profile on most common G ≥ 3 adverse events (AEs) were thrombocytopenia 32.3% (95% CI: 22.4-44.2), neutropenia 21.5% (95% CI: 12.6-34.1), diarrhea 13.1% (95% CI: 6.8-23.9), fatigue 11.6% (95% CI: 7.4-17.7) and peripheral neuropathy 2.2% (95% CI: 0.7-6.6). Ixazomib in two drug regimen: In RRMM, two clinical trials (n=92) evaluated the efficacy of Ixa weekly with dexamethasone (D). In this subgroup pooled analysis, ORR of 40.7% (95% CI: 22.8-61.5, I2=41.76%) with ≥VGPR of 19.5% (95% CI: 4.6-52) was calculated. One study reported event-free survival (EFS) of 8.4 months(4.5-12.8) with a 1-year overall survival rate of 96% (95% CI: 91-100). In our analysis for safety (n=102), common G≥ 3 AEs calculated was thrombocytopenia in 20% (95% CI: 7.5-43.7), neutropenia in 14.3% (95% CI: 3.7-41.6), fatigue in 9.1% (95% CI: 5.0-16.2), diarrhea in 5.7% (1.1-25.5), nausea in 5.7% (95% CI: 1.4-20.2) and peripheral neuropathy in 5.7% (95% CI: 1.4-20.2). Ixazomib in three drug regimen: In RRMM, the efficacy of Ixa was evaluated inten clinical trials (n=646), an ORR of 56.3% (95% CI: 41.8-65.5, I2=82%) with ≥VGPR of 22.8% (95% CI: 13.2-36.4) was noted. Best response was seen when Ixa was used in combination with lenalidomide (R) and dexamethasone, with reported ORR of 78.3%. Common AEs were neutropenia 23.5% (95% CI: 16-33.1), thrombocytopenia 18.8% (95% CI: 13.4-25.6) anemia 10.5% (95% CI: 8.2-13.2), diarrhea 6.3% (95% CI: 3.4 -11.3), fatigue 4.2% (95% CI:2.7-6.4), nausea 1.8% (95% CI: 0.9-3.5) and peripheral neuropathy 2.3% (95% CI: 1.3-3.9). Ixazomib Based Regimen In NDMM: Pooled analysis of subgroup study for combination regimen of Ixa as IRD, Ixa-Thalidomide (T)-D, Ixa-Cyclophosphamide (C)-D, and with Ixa -melphalan-prednisone (IMP), their estimated ORR was 83.7% (95% CI: 75.6-89.5), 80.8% (95% CI: 72.8-86.9), 75% (95% CI: 66.6-82) and 66% (95% CI: 52.4-77.4) respectively. We also measured the efficacy of Ixa as a maintenance therapy, estimated ORR was 81.5% (95% CI: 36.6-97.1, I2=90.5%). In one phase II maintenance study (n=64), a combination of IR receiving patients (n=34), an ORR of 90.4% with VGPR of 53% was reported. Median progression-free survival (PFS) was not reached after a median follow up of 37.8 months and estimated 2-year PFS was 81%. Common G≥3 AEs in NDMM patients were neutropenia 21.6% (95% CI: 11.2-37.6), thrombocytopenia 15.9% (95% CI: 4.7- 42), infections 15.2% (95% CI: 10.3-21.9) and peripheral neuropathy 7.9% (95% CI: 4.7-13). Conclusion: In our pooled analysis (95%CI), Ixazomib has shown promising efficacy both in NDMM as well as RRMM. Especially in three drug regimen it showed an estimated ORR of 84.8% in NDMM and 56.3% RRMM.Cytopenia was a common side effect.Peripheral neuropathy was noted to be a rare side-effect (2.6%) in RRMM. Further studies are required to evaluate efficacy and safety of ixazomib in combination therapies in NDMM. Disclosures No relevant conflicts of interest to declare.

Introduction Drugs that target activating mutations of Janus Kinase 2 (JAK2) have been the backbone of myelofibrosis (MF) management. With recent advancements in our understanding of the underlying molecular mechanisms involved in myelofibrosis (MF) pathogenesis, numerous novel agents have been developed in the last decade. We have systematically reviewed the mechanisms of actions, efficacy and safety of these drugs. Methods A comprehensive literature research was performed using PubMed, Cochrane, EMBASE, Web of Science and Clinicaltrials.gov. We included all trials that were under development in phase I/II/III trials. Our search identified 1642 full-length manuscripts or abstracts with published results in the last decade were screened for relevant studies. Of these, 212 articles were finalized for our final analyses. Results Hedgehog inhibitors (saridegib, glasdegib and sonidegib) targets signaling membrane protein, smoothened. The combination of sonidegib + ruxulotinib (RUX) elicited the best response. Spleen volume reduction (SVR) ≥35% and spleen length reduction (SLR) ≥50% was reported in 15 (55.6%) and 25 (92.6%) patients. Histone deacetylase inhibitors (panobinostat, pracinostat, vorinostat, givinostat) target JAK2-H3Y41-HP1 pathway involved in hematopoiesis and leukemogenesis. The combination of pracinostat + RUX demonstrated the best response in a phase II trial (n=22), with clinical improvement (IWG-MRT) in splenomegaly, symptoms and both were reported in four (18%), two (9%), and ten (45%) patients that were durable for a median of 7.5 months. Immunomodulators: Lenalidomide has shown anemia responses in 32% of patients in combination with prednisone, in a phase II trial (n=40). Improvement in bone marrow fibrosis (10/11 patients with G4 reduced to G2 or better) was also seen. Pomalidomide with or without prednisone has shown anemia responses varying from 17-24% across different trials. However, a recent phase III trial (n=32) comparing pomalidomide vs. placebo, found no difference in transfusion independence rates (16% vs. 16%, p=1.00). Azacytidine (AZA) and decitabine (DCB) are hypomethylating agents. An objective response rate (ORR) of 69% (n=39) with AZA+RUX was noted. DCB+RUX demonstrated an ORR of 57% with a median overall survival of 10.4 months, in a phase I trial (n=21). Imetelstat is a telomerase inhibitor that has shown an ORR of 21% among 33 MF patients. Responses were characterized by BMF improvement (n=4) and transfusion independence (3/7 responders). Anti Fibrotics: PRM 151, a recombinant pentraxin-2, has shown an ORR of 35% in a phase II trial (n=27). Anemia response was noted in 6/15 (40%) patients and BMF improvement in two patients, durable up to 72 weeks. Simtuzumab, an antibody lysysl oxidase like-2 (LOXL2) enzyme, failed to show any clinical benefit in a phase II study of 54 patients. Sotatercept and luspatercept are ligand "traps" that limit the activity of TGF-B superfamily ligands, involved in erythroid differentiation. Sotatercept monotherapy achieved transfusion independence (TI) in six (35%) of 17 evaluable patients. Luspatercept has recently been under investigation in patients with MF (NCT03194542). LCL-161 is a second mitochondrial activator of caspases (Smac)-mimetic, A phase II clinical trial (n=33) found an ORR of 30% (n=9). Five (56%) of the nine responders achieved anemia responses. Buparilisib and everolimus targets the PI3K/mTOR pathway. Buparilisib, a PI3K inhibitor, demonstrated a SLR ≥ 50% in 72% patients whereas everolimus, an mTOR inhibitor, showed an ORR of 23%. Conclusion The combination of ruxolitinib with some of these novel agents such as hedgehog inhibitors and hypomethylating agents have shown promising efficacy with response rates of more than 40%. LCL-161 and sotatercept has been reassuring with respect to anemia management, achieving response rates of more than 30%. PRM-151 has shown durable responses and will be the first antifibrotic for MF, if approved. Even though initial results with some of these novel agents have been ground breaking, there is a need to further explore pathways that can be targeted to help prolong survival and modify the disease course in MF patients. Disclosures No relevant conflicts of interest to declare.

Background: Ex-vivo T-cell-depleted graft is used to prevent acute and chronic GVHD for haploidentical hematopoietic SCT (HSCT). We conducted a systematic review and meta-analysis to evaluate the outcomes of T-cell-depleted grafts for peripheral blood haploidentical stem cell transplantation in patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Method: A comprehensive literature search on PubMed, Embase, Cochrane and Web of Science was conducted up to July 25, 2018. Two independent reviewers screened the literature and extracted data. The methodological quality was assessed using modified Newcastle-Ottawa Scale. CMA software v.3 was used for the analysis. Heterogeneity among studies was assessed using the I2 test. Random-effect model was applied. Results: The search strategy identified over 550 articles; three studies (n = 404 patients; 1 prospective; 1 multi-center) were selected for this meta-analysis. The sample size of the studies varied between 34 and 266 patients. The median follow-up ranged from 6 to 47 months. Two studies (Aversa, F. et al. 2005)(n=104 patients); (Ciceri, F. et al. 2008)(n=266 patients) used CD34+ selected cells and other study used TCR-αβ depleted PBSC graft (Kaynar, L. et al. 2016) (n=34). All studies used myeloablative (MA) conditioning. In vivo T-cell-depletion by ATG was used in two studies. Two studies using mega-dose of CD34+ did not use GVHD prophylaxis and other study with αβ T-cell depleted graft used mycophenolate mofetil (MMF). Engraftment rates ranged from 91% to 98%. Pooled rates (95%CI) of grade II-IV, III-IV aGVHD and chronic GVHD were 9% (4-20; I2=82%), 4.8% (1.7-13.1; I2=78%) and 10.7% (6.3-17.6; I2=64%), respectively. The pooled estimates (95%CI) showed a 2-year disease-free survival (DFS) rate of 30.8% (24.2-38.3; I2=54%), 2-year relapse incidence of 21.5% (17.4-26.2; I2=85%). The results are shown in figure 1. Conclusion: T-cell-depleted peripheral blood stem cell graft for haploidentical transplantation in acute leukemia may be an alternative treatment option. Larger prospective studies are needed to evaluate the outcomes of different manipulation techniques. Disclosures No relevant conflicts of interest to declare.

Background: Sickle cell disorder (SCD) and transfusion dependent beta-thalassemia (TDT) are inherited disorders of β-globin genes leading to ineffective erythropoiesis, hemolysis and multi-organ damage. Though allogenic hematopoietic cell transplantation (allo-HCT) in the only potentially curative therapy, lack of full HLA-matched donor, increased risk of myeloablative conditioning (MAC) regimen related toxicity, poor prognosis in older age groups (>14 years), and a high risk of infections and graft versus host disease (GVHD) culminating into a high transplant related mortality (TRM) preclude HCT as a treatment option for many patients. Gene therapy has been proposed as a relatively new treatment option for these monogenic disorders. It involves transfection of harvested CD34+ hematopoietic stem cells (HSC) with viral vector to transfer a normal beta globin gene, which are then transplanted back to the autologous donor. However, the available data on gene therapy is extremely variable. The purpose of this review is to evaluate the risks and outcomes of SCD and TDT patients undergoing gene therapy. Methods: A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on with no restrictions of language or time period. A total of 4312 articles were identified and after duplicates removal, 3508 articles were screened for relevance. Clinical studies reporting the most recent follow up results about the efficacy and safety of gene therapy in patients with hemoglobinopathies were considered for inclusion. Their quality assessment was done using the Cochrane tool, and bias was evaluated regarding the study selection, performance, detection, attrition and the reporting of the clinical trials. RESULTS (table-1): Only 7 articles qualified for the strict selection criteria with an N of 47: six studies were phase I trials (Cavazzana, M. et al 2010, Boulad, F. et al 2013, Marktel, S. et al 2017, Kwiatkowski, J. et al 2017, Cavazzana, M. et al 2017, Kanter, J. et al 2017) and one was a phase III trial (Walters, M. et al 2017). Thirty five patients (74.4%) had TDT while 12 patients (25.5%) had SCD. All these patients did not have a suitable HLA-matched HCT donor. The length of follow up was heterogeneous owing to the step wise enrollment of participants and ranged from 2-36 months. Except for 4 cases, the age of included population was >13 years. Lentivirus BB305 encoding the HbAT87Q globin gene was used for gene delivery in 81% patients (n=38). The normal beta globin gene was transduced in remaining 9 TDT cases and it involved transduction using TNS 9.3.55 vector in two cases and with GLOBE lentivirus in 7 cases. MAC with busulfan was used in 81% cases (n=38), while treosulfan+thiotepa was used in 7 cases. The non-myeloablative (NMA) conditioning with busulfan was used in only 2 cases (both TDT). Bone marrow harvest was the source of HSCs in all SCD cases. Except for 3 SCD cases in HGB-204 trial and 3 TDT cases in HGB-207 which measured the potential improvement in outcome by an increase in DP-VCN, the range of drug vector copy number (DP-VCN) was 0.3-1.5 copies per diploid genome. The total hemoglobin (HB) level at last follow up was reported for 62% cases (n=29) and it was >8.8 g/dl in all cases. Twenty-one (60%) thalassemia cases were in a transfusion (Tx) free state at last follow up, including the 7 cases (20%) who developed a complete independence from transfusions. No such Tx-free state was noted in SCD cases although they developed a reduction in the Tx-requirement and 75% SCD cases (n=9) had a 30-100% reduction in the frequency of VOCs. All the cases were alive at their recent follow up with manageable toxicity form conditioning. Acceptable safety until the median follow-up from the 7 trials was established in all cases, with no reported development of post-treatment leukemia or new malignancy in these trials. DISCUSSION: In this largest series of gene therapy for the treatment of hemoglobinopathies (to our knowledge), we find it to be clinically effective in terms of reduction in transfusion needs; data to suggest an improved OS and disease free survival is promising, however long term data is awaited. Gene therapy appears to bypass the limitations faced by allo-HCT especially a high early TRM. Randomized trials reporting the efficacy and safety outcomes with longer follow ups are urgently required. Disclosures No relevant conflicts of interest to declare.

Background: IgD multiple myeloma (MM) is a rare subtype contributing 2% of all multiple myeloma cases. Despite difficulty and delay in diagnosis, recent advances in the treatment of multiple myeloma in general also improved the outcomes for IgD myeloma subtype. The aim of this study is to summarize the data on presentation patterns, diagnosis, management approaches and outcomes for patients (pts) with IgD myeloma. Methods: A comprehensive literature search for articles published after December 2013 was performed using four databases: PubMed, Embase, Cochrane, and Clinicaltrials.gov. With initial search we identified 209 articles and after screening by two independent reviewers we included only 8 studies in the final analysis. Results: A total of 166 pts with IgD MM were included from 8 selected retrospective case series. Lambda (λ) was the predominant light chain sub-type in 136 patients (81.9%). Initial manifestations of IgD MM were Bence jones proteinuria (BJP>2 g/day-64.5%), renal dysfunction (63%), bone pain (55.9%), weakness, fatigue (34.2%) and extra medullary involvement (28.3%). Renal function was assessed by estimated glomerular filtration rate (eGFR2mg/dl) in 46.1% patients. Cytogenetic karyotype analysis in 56 pts using fluorescence in-situ hybridization (FISH) identified abnormal cytogenetics in 41 (73.2%) patients, cases were further classified as high risk (85.7%) and standard risk (14.3%). The patient characteristics and disease manifestations are mentioned in Table 1. Serum protein electrophoresis (SPEP) showed positive monoclonal spike (M) spike in 84% of the patients. The median M spike value for IgD MM was 9.42 g/l in a cohort of 17pts, (Djidjik et al.) which was lower as compared to IgG (median: 35 g/L) and IgA (median: 32 g/L) in this study. Abnormal serum free light chain ratio (sFLCR) was observed in 83% pts. Quantitative serum IgD levels were elevated only in 28% of the cases. Bone marrow (BM) plasmacytosis showing > 40% abnormal plasma cells was detected in 95.6% of the patients. N glycans are newly discovered biomarkers used for detecting abnormal protein glycosylation in MM patients. NG1(6)A2F and NG1(3)A2F were the two most significant N glycan markers for IgD MM patients with sensitivity of 95% & 95.2%, respectively and specificity of 95% & 78.6%, respectively. The prognostic significance of several other biomarkers studied in IgD MM is mentioned in Table 2. Treatment details were available for 149 patients and overall response rate (ORR) was seen in 125 (83.9%) patients while 24 (15.4%) patients had progressive or stable disease. The median overall survival (mOS) was between 9 - 62 months. Novel agents (NA) such as bortezomib, thalidomide and lenalidomide were given to 111 (74.4%) pts with the mOS between 15 - 38.6 months. Conventional agents (CA) such as melphalan, vinblastine, vincristine, epirubicin, and ifosfamide were given to 38 (25.5%) patients with mOS between 12.5 - 17 months. Data showed bortezomib based regimens resulted in a higher ORR (ORR=94%, CR=52%) compared to non bortezomib based regimens (ORR=77.8%, CR=27.7%) respectively. Stem cell transplant (SCT) was used in 37 (24.8%) patients with chemotherapy (NA=26, CA=11) which showed good response rate (ORR>90%,CR >60%). The comparison of response rate with different drugs is mentioned in the Table 3. Conclusion: N-glycan assay can overcome the limitations of SPEP and quantitative serum IgD assay in the diagnosis of IgD MM. This difficulty is posed by the lower concentrations of M spike ( SPEP) or lower-normal serum IgD value on quantitative serum assays, which can delay its diagnosis. Novel and conventional agents have good responses with ORR>90%, but mOS of conventional agents was lower when compared to novel agents. Bortezomib based regimens showed better responses when compared to non-bortezomib regimens. The best response (ORR=95%) was obtained with use of SCT in combination with novel agents. Serum free light chain levels, N glycan assay and serum IgD quantification were found to be the best prognostic markers for IgD MM. Disclosures No relevant conflicts of interest to declare.

Background: Allogenic hematopoietic cell transplantation (alloHCT) is a curative option for patients with high-risk myelodysplastic syndrome (MDS). The benefit of higher conditioning intensity in MDS is controversial. While myeloablative conditioning (MAC) regimens can mitigate the risk of relapse, they are associated with higher non-relapse mortality (NRM). In contrast, the reduced intensity conditioning (RIC) regimens are associated with higher risk of relapse. And owing to the lower NRM, they are feasible in patients with advanced age or comorbidities. Methods: We report here a systematic review and meta-analysis of randomized controlled trials (RCTs) that directly compared the safety and efficacy of MAC vs RIC regimens in MDS. The efficacy was evaluated in terms of overall survival (OS), relapse-free survival (RFS) and relapse incidence (RI). The safety was evaluated in terms of non-related mortality (NRM) and incidence of acute (a) and chronic (c) graft-versus-host disease (GVHD). A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on May 6th, 2018 with no restrictions of language or time period. RCTs comparing MAC with RIC regimens that include MDS patients were considered eligible for inclusion. After duplicates removal, a total of 683 articles were scrutinized for relevance by screening the abstracts and/or full length articles. Based on the eligibility criteria, only two randomized studies (BMT CTN 0901 Trial Scott, B. et al. 2017 & EBMT RICMAC Trial Kroger, N. et al. 2017) qualified for inclusion and quantitative synthesis. The quality assessment was done using the Cochrane tool regarding the bias in study selection, performance, detection, attrition and reporting of the clinical trials. Results: Out of total 392 MDS and acute myeloid leukemia (AML) patients enrolled in these two trial, 169 patients had MDS (N=115 in Kroger et al and N=54 cases in Scott et al). Eighty one patients received MAC and 88 patients received RIC followed by either a related or unrelated alloHCT. The median age range at the time of transplant was 50-54 years and these patients were followed for a period of 18-24 months. There were no statistically significant differences in the baseline patient characteristics between two regimen groups in the both trials. The use of RIC regimen was associated with a statistically non-significant trend towards improved OS (OR 1.52: 95% CI: 0.93-2.5, p-value= 0.097), along with a significantly reduced risk of NRM (OR 0.39: 95% CI: 0.16-0.94, p-value= 0.04). The RIC alloHCT was not associated with a higher risk of disease relapse (OR: 4.24, 95% CI: 0.34-52.22, p-value= 0.26) or inferior RFS (OR: 0.64, 95% CI: 0.196-2.06, p-value= 0.45). There was no difference between the two conditioning intensities in terms of risk of developing aGVHD (OR: 0.51, 95% CI: 0.11-2.27, p-value= 0.37) or cGVHD (OR: 0.50, 95% CI: 0.18-1.40, p-value= 0.19). The meta-analysis results are shown in figure-1. The Infectious complications were comparable for both groups in Scott, et al. But Kroger et al reported significantly lower overall infections rate at day 100 (4.3 vs. 6.9, p=0.002) and at total follow up (1.4 vs. 2.0, p= 0.002) for RIC. Conclusion: In adult patients with MDS undergoing alloHCT, RIC regimens were associated with a significantly lower risk of NRM, without increased risk of relapse, mortality or GVHD. It is unknown if any specific poor risk groups regarding clinical indicators (e.g. IPSS score) or genomic predictors (e.g. p53 mutations or RAS pathway mutations) may benefit from higher conditioning intensity and warrants further investigation. Disclosures Hamadani: Sanofi Genzyme: Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Ostuka: Research Funding; Janssen: Consultancy; Merck: Research Funding; MedImmune: Consultancy, Research Funding; Cellerant: Consultancy; Celgene Corporation: Consultancy; Takeda: Research Funding.