Riaz, Irbaz Bin

Background: Carfilzomib (Car), a second-generation proteasome inhibitor (PI), has been approved by the US Food and Drug Administration (FDA) as therapy for relapsed and /or refractory multiple myeloma (RRMM), either as a single agent or in combination with other agents. It has proven to be superior in many ways compared to the the first generation PI, bortezomib, both in terms of superior efficacy and neuropathy related adverse effect profile. Carfilzomib has lower rate of peripheral neuropathy. In this review, we gathered data from trials which studied Carfilzomib for newly diagnosed MM (NDMM). Carfilzomib based two and three drug combination as induction regimens for the management of NDMM is an emerging approach. Through this systematic review, we explore efficacy, adverse effect profile of Car based regimens for NDMM. Methods: Per PRISMA guidelines, a thorough database search was conducted on 06/24/2019 using the following search engines; PubMed, EMBASE, Cochrane library, Scopus, Web of Science, CINAHL, and Clinicaltrials.gov. We included all published trials that used carfilzomib as an induction agent in NDMM patients and had at least response rates after induction. Results: The total number of articles identified with initial search were 1131, out of which 19 articles met our selection / eligibility criteria (n=2286). The overall response rates (ORR) after induction therapy with carfilzomib based regimens was very impressive (range: 84.3% - 100%). Two drug combination using carfilzomib and dexamethasone (n=72) had an ORR of 90% and a greater than very good partial response rate (>VGPR) of 84%. Three drug combinations used for induction therapy included carfilzomib/dexamethasone with immunomodulators (n=391) and alkylating agents (n=308). The combination of carfilzomib/dexamethasone with lenalidomide (n=189, ORR: 97% - 98%, >VGPR: 69% - 98%) and thalidomide (n=202, ORR: 90% - 94%, >VGPR: 66% - 68%) showed the best response. Alkylating agents used in combination with carfilzomib were melphalan (n=98, ORR: 90% - 93%, >VGPR: 58% - 70%), cyclophosphamide (n=192, ORR: 87% - 95%, >VGPR: 39% - 71%) and bendamustine (n=18, ORR; 100%, >VGPR: 89%). Four drug combinations with carfilzomib used were daratumumab/lenalidomide/dexamethasone (n=22, ORR: 100%, >VGPR: 90%, 12m PFS: 95%) and cyclophosphamide / thalidomide / dexamethasone (n=64, ORR; 91%, >VGPR: 69%, 24m PFS: 76%). One trial directly compared carfilzomib/melphalan/dexamethasone (n=478, ORR: 84%, >VGPR: 61%, PFS: 22.3m) with bortezomib/melphalan/dexamethasone (n=477, ORR: 79%, >VGPR: 49%, PFS: 22.1m). Another trial compared the combination of carfilzomib / dexamethasone with lenalidomide (n=315) or cyclophosphamide (n=159) that showed similar ORR (97% vs 91%) though >VGPR rate was better with lenalidomide (75% vs 60%). Efficacy data including progression free survival (PFS) for carfilzomib based regimens is reported in table 1. Most common >grade 3 hematological adverse effects reported were anemia (2% - 35%), lymphopenia (5% - 76%), thrombocytopenia (4% - 28%) and neutropenia (1% - 38%). Most Common >grade 3 non-hematological adverse events included cardiac events (5% - 10%), respiratory disorders (8% - 16%), infections (2% - 9%), hypertension (6% - 17%), renal events (9% - 10%) and hyperglycemia (6% - 23%). (Table 1) Conclusion: The overall efficacy and favorable adverse effect profile of Carfilzomib-based induction regimens seem very promising for the treatment of NDMM. Car is now approved for weekly dosing which is convenient. Due to cardiovascular toxicity seen in upto 10% cases, Car should be used very judiciously in patients with cardiovascular risk factors and heart failure. Several ongoing phase 3 clinical trials are studying Carfilzomib in various combinations will help to establish foundation for future standard therapy as well as next phase of drug development through clinical trials. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction Amyloidosis is a rare disease and there are currently no FDA approved therapies for AL amyloidosis. Most of the therapeutic and disease data come from expert guidelines, consensus and retrospective review papers. There is a paucity of data specifically for relapsed/refractory AL amyloidosis (RRAL). We conducted this systematic review of clinical trials, retrospective and prospective cohort studies to evaluate patterns of relapse and therapeutic options for RRAL. Methods PubMed and Clinicaltrials.gov were searched for clinical trials, retrospective and prospective cohort studies on RRAL. Studies were selected according to PRISMA guidelines. Cross-trial comparison of included studies and meta-analysis could not be performed for a number of reasons but mainly due to a limited number of studies on one particular treatment regimen. Results From a total of 511 studies, 11 studies (n= 698 patients) met our inclusion criteria. Five were phase I/II clinical trials, five retrospective cohort studies, and one prospective cohort study. Most studies had less than 50 patients. The largest study, a retrospective cohort by Tandon et al. included 366 patients. Mean age was 61.2. Three studies reported 2 median prior lines of therapy (n= 22, 28, and 84 patients); two reported 3 median prior lines of therapy (n= 25 and 24) and 6 studies didn't specify this data. Prior treatment options included proteasome inhibitors (PI), most commonly bortezomib (n= 259), followed by melphalan (n=211), high dose melphalan and stem cell transplant (HDM/SCT [n= 207]) and IMiDs most commonly lenalidomide (n=154). Time to progression (TTP) from first-line treatment was reported in only 4 studies as 1 month, 5 months, 5 months and 34 months respectively. The study reporting a TTP of 34-months had 11 patients who received HDM/SCT as first line treatment. Three studies reported information about their criteria for initiation of subsequent treatment. Subsequent treatment was mostly a combination regimen with dexamethasone or an alkylating agent. The only agent evaluated as single agent was bortezomib in a phase I/II clinical trial by Reece et al. Therapeutic options for RRAL are PI (non-specific) based therapy (n= 145), lenalidomide (n= 105), bortezomib (n= 99), IMiD (non-specific) based therapy (n=83), melphalan based therapy (n= 33), carfilzomib (n=28), pomalidomide (n=27), ASCT (n= 25), daratumumab (n=25) and bendamustine (n=22). Efficacy: Hematologic responses were reported to be following: bortezomib + dexamethasone/melphalan (85%, n=17/20), daratumumab + dexamethasone (76%, n= 19/25), HDM/ASCT (73%, n= 8/11), single agent bortezomib (67%, n=23/34), carfilzomib ± dexamethasone (63%, n= 15/24), lenalidomide + dexamethasone (61%, n=51/84), bendamustine + dexamethasone (55%, 11/22) and pomalidomide + dexamethasone (50%, 12/24). Five of eleven studies reported organ responses which ranged from 18% to 23%. The studies which reported organ responses had evaluated the following agents: single agent bortezomib, carfilzomib ± dexamethasone, lenalidomide + dexamethasone, and bendamustine + dexamethasone. Best survival outcomes were seen with bortezomib with median overall survival (OS) 62 months. With bendamustine and dexamethasone (retrospective cohort study n=22) median OS was 31 months. With lenalidomide + dexamethasone (prospective cohort study n=24 ) median OS was 14 months. For the remaining studies, the median OS was either not reported or not reached at the time of presentation of data. Conclusion AL amyloidosis patients progressing after front line therapy show good responses with bortezomib (median overall survival of 62 months). Novel combinations using lenalidomide, pomalidomide, carfilzomib, daratumumab, and bendamustine show promising efficacy. Ongoing trials of daratumumab (AMYDARA trial) and ixazomib (TOURAMALINE-AL1) will bring further insight into therapeutic armamentarium for RRAL patients. After relapse, a salvage HDM/ASCT can be considered. Comparisons of regimen efficacy between studies are not practical because of multiple factors which include but are not limited to heterogenous nature of AL patients, small sample sizes, variable prior treatments, exposure to novel agents, observational study versus clinical trial and variable endpoints. Table Disclosures Anwer: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; In-Cyte: Speakers Bureau.

241 Background: In a rapidly moving field, such as cancer immunotherapy, where immune checkpoint inhibitors (ICIs) are used across 14 different tumor types, patients may receive suboptimal treatment or even be harmed if information on toxicity is not readily translated for use in clinical practice. Every single systematic review and meta-analysis which attempted to summarize toxicity of immune checkpoint inhibitors (ICIs) quickly became outdated. A living systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situation. Methods: The process of creating a living systematic review started with the creation of a comprehensive search designed by a librarian experienced in systematic reviews in collaboration with the study’s principle investigator. Search was constantly updated every 3 months and evidence is synthesized in a series of steps (microtasks) using a combination of human and augmented intelligence. A complete infrastructure is being developed and it includes automated cumulative meta-analysis and an online reporting platform which will constantly update information for clinicians and patients in a live manner. Results: We screened 6746 studies during Sep 2018-March 2019 and identified 6746 studies and we were able to successfully maintain up-to-date toxicity estimates for immune mediated adverse events over this period while maintaining the rigor of a conventional systematic review. Eventually, we will integrate the steps of LSR into one, user-friendly, semi-automated format which can independently provide accurate estimates and feed into and support a living guidelines platform through shared Application Programing Interface (APIs). Conclusions: LSRs are feasible, efficient, and when fully developed can reduce redundancy and waste in medical research, improve the quality of evidence, reduce human effort and support living and dynamic guidelines to facilitate truly informed shared decision making.

80 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune Checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Methods: In order to dynamically display content -- including textual data, tables, charts, and graphs – standard data formats and protocols were designed for various components of the systematic reviews carried out by researchers. Given these standardized formats, software was written to interpret this data and output the information in the appropriate format, such as a forest plot or data table. Finally, a dynamic interface that enables user inputs (such as which aspect of the meta-analysis to view) and displays the associated output was designed. The overall living Systematic Review infrastructure includes monthly literature searches, cumulative meta-analysis, and an online reporting platform. Results: We have developed a Living Systematic Review engine that can take in standardized data and reflect this data in an interactive, intuitive manner in the form of text, tables, and plots. This interface can also be manipulated via user input to organize and sort data tables or omit/highlight specific pieces of data. Conclusions: We have initiated the first living systematic review in immune-oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. The Living Systematic Review interface allows users to easily and intuitively access the most recent available clinical evidence on toxicity of ICIs.

Abstract Background: The incidence and types of hematologic complications from immune check point inhibitors are not well known. We conducted this review to describe immune-mediated hematologic complications reported in clinical trials, case series, and case reports. Methods: A pre-defined comprehensive search strategy was used to identify case reports, case series, and clinical trials using PubMed. Any study that reported hematologic complications was included. Data were extracted for demographic characteristics and occurrence of immune-mediated hematologic complications. We pooled the data to calculate the frequency of immune-mediated hematologic adverse effects. Results: A total of 689 of studies were retrieved using the search criteria and 75 were included in the analysis (31 case reports and case series and 44 clinical trials). There were 44 patients reported having immune-mediated hematologic complications, 4 of them in clinical trials. The complications included aplastic anemia, autoimmune hemolytic anemia, cryoglobulinemia, graft versus host disease, hemophilia A (acquired), immune neutropenia, immune thrombocytopenia, macrophage activation syndrome, myelodysplastic syndrome, pure red cell aplasia, and thrombotic thrombocytopenic purpura. However, the overall rates were very low, ranging from 1-2.2% in clinical trials. Immune thrombocytopenia was the most common (29.5%), followed by autoimmune hemolytic anemia (15.9%), and immune neutropenia (13.6%). Immune-mediated hematologic complications were reported in all classes of checkpoint inhibitors including anti-programmed cell death protein 1 (nivolumab and pembrolizumab), anti-programmed death ligand 1 (avelumab and durvalumab), and anti-cytotoxic T-lymphocyte-associated protein 4 inhibitors (ipilimumab and tremelimumab). Among patients reported in case reports and case series, the median age was 57 years (range, 29-85) and most were males (52.9%). The majority of the complications occurred in patients treated with ipilimumab (38.8%), nivolumab (27.7%) and pembrolizumab (16.0%). The onset was usually within the first week of receiving the first dose but could occur up to 17 months after drug initiation. Indefinite discontinuation of the immunotherapy was the mainstay of treatment resulting in resolution of complications in the majority (74.5%) of the patients. Two patients were re-challenged with the same checkpoint inhibitor and one experienced a relapse of immune cytopenia (autoimmune hemolytic anemia). Conclusion: Immune-mediated hematologic complications associated with checkpoint inhibitors are rare. They are usually reversible after discontinuation of such treatment. Relapses may occur with re-challenge. Disclosures No relevant conflicts of interest to declare.

Background Male breast cancer (MBC) is a rare disease for which there is limited understanding of treatment patterns and prognostic factors. Methods Men with TNM stage I to stage III breast cancer diagnosed between 2004 and 2014 in the National Cancer Data Base were included. Trends in treatment modalities were described using the average annual percentage change (AAPC) and estimated using Joinpoint software for the analysis of trends. Kaplan‐Meier curves and the multivariate Cox proportional hazards regression model were used to compare survival between subgroups and to identify prognostic factors. Results A total of 10,873 MBC cases were included, with a median age at diagnosis of 64 years. Breast‐conserving surgery was performed in 24% of patients, and 70% of patients undergoing breast conservation received radiotherapy. Approximately 44% of patients received chemotherapy, and 62% of patients with estrogen receptor–positive disease received endocrine therapy. Oncotype DX was ordered in 35% of patients with lymph node–negative, estrogen receptor–positive/human epidermal growth factor receptor 2 (HER2)‐negative tumors. During the study period, there was a significant increase in the rates of total mastectomy, contralateral prophylactic mastectomy, radiotherapy after breast conservation, ordering of Oncotype DX, and the use of endocrine therapy ( P < .05). On multivariate analysis, factors found to be associated with worse overall survival were older age, black race, higher Charlson Comorbidity Index, high tumor grade and stage of disease, and undergoing total mastectomy. Residing in a higher income area; having progesterone receptor–positive tumors; and receipt of chemotherapy, radiotherapy, and endocrine therapy were associated with better overall survival. Conclusions Despite the lack of prospective randomized trials in patients with MBC, the results of the current study demonstrated that the treatment of this disease has evolved over the years. These findings further the understanding of the modern treatment and prognosis of MBC, and identify several areas for further research.

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.

6596 Background: Several previous systematic reviews and meta-analyses have attempted to summarize toxicity of Immune checkpoint inhibitors (ICIs). However, very soon after each one of these reviews has been published, it became outdated. ICIs are currently used in 14 different cancers and data is rapidly evolving from new clinical trials. A living Systematic review, which is defined as a systematic review that is continually updated to incorporate relevant new evidence as it becomes available, is necessary in this situations. Therefore, we performed an updated systematic review and a meta-analysis which will serve as a foundation of a living Systematic review. Methods: MEDLINE, EMBASE and Cochrane were searched to identify phase 2 and 3 RCTs of PD-1/PD-L1 ICIs. Included studies compared either immunotherapy alone or combination with existing standard of care treatment and reported data for AE’s of interest. DerSimonian-Laird random effects Meta-Analysis was performed to derive pooled odds Ratio (OR) estimates for AE’s of interest. An infrastructure of a living systematic review is being developed and it includes monthly literature searches, cumulative meta-analysis and an online reporting platform. Results: We screened 6746 studies and 31 phase 3 and 2 phase 2 RCTs (n = 21,421) were included in the analysis. 22 RCTs used PD-1/PD-L1 ICIs as a single agent and 11 as a combination therapy. Selected toxicity estimates are summarized in a table. Conclusions: The meta-analysis updates previously published toxicity estimates and provides additional information about the risk of toxicities in single versus combination regimens. We have initiated the first living systematic review in oncology that will be continuously updated, incorporating relevant new evidence as it becomes available, and will provide accurate and up to date toxicity estimates to support clinical decision making. [Table: see text]