Citations

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 However, very soon after each one of these reviews has been published, it became outdated.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 The current view is that treatment failures of AML patients are due to persistence of leukemia stem cells (LSCs). The presence of FMS-like tyrosine kinase-3 (FLT3) Internal tandem duplication (ITD) is associated with poor prognosis. But, FLT3 tyrosine kinase inhibitors (TKI) demonstrate transient clinical activity in FLT3-ITD+ AML patients. Persistent FLT3-ITD+ AML LSC represent a source of relapse. There is a pressing need to target LSC and improve outcomes for FLT3-ITD+ AML patients. PRMT1, the predominant arginine methyltransferase, has been implicated in pathogenesis of AML rare subtype (i.e., acute megakaryoblastic leukemia). Herein, we show that PRMT1 protein expression is significantly increased in LSC-enriched AML CD34+CD38- cells relative to the counterparts of normal peripheral blood stem cells (PBSC) (AML n=9, normal n=8, p=0.0004,). Following PRMT1-knockdown (KD), AML CD34+ cells (n=15) demonstrated varying degrees of apoptosis while the survival of normal cells were not affected. Interestingly, we observed significant apoptosis-induction in a subset of samples bearing FLT3-ITD mutation (6 out of total 15) upon PRMT1-KD (ShCtrl 13.9±3.6%, ShPRMT1 32.5±4.6%, p<0.001). PRMT1-KD induced apoptosis was also more evident in cord blood (CB) CD34+ cells expressing FLT3-ITD (ShCtrl 19.4±1.3%, ShPRMT1 45.2±2.5%, p<0.001) relative to that of FLT3-WT (ShCtrl 27.47±1.8%, ShPRMT1 36.9±1.6%, p=0.0167). In 293T cells ectopically overexpressing FLT3-WT or FLT3-ITD, co-immunoprecipitation (co-IP) indicated greater interaction between PRMT1 and FLT3-ITD. Through RNA-Seq profiling two AML lines (MV4-11, OCI-AML3) plus one FLT3-ITD transduced CB CD34+ cells with PRMT1-KD, we obtained a differentially-regulated gene set as a "PRMT1 signature". This signature was enriched in FLT3-ITD+ AML relative to FLT3-WT AML according to ssGSEA analysis using two AML datasets (GSE14468, GSE10358), indicating PRMT1 may cooperate with FLT3-ITD regulating AML maintenance. Given that PRMT1 directly interacts with FLT3-ITD, we next asked whether PRMT1 catalyzes FLT3-ITD protein methylation. Through mass-spectrometry analysis of a FLT3-ITD+ AML specimen and in vitro methylation assay, we identified that PRMT1 catalyzes FLT3-ITD arginine (R) methylation (Me) at two conserved residues, 972 and 973. Using in-house R972/973 Me antibody, we validated the expression of FLT3 R-Me in FLT3-ITD AML speciemens (7 out of 7). To test R-Me function, we transduced MLL-AF9 (MA9) overexpressing murine c-Kit+ cells with methylation-deficient FLT3-ITD (R972/973K, arginine [R] to lysine [K]) construct, and found that MA9 cells expressing R972/973K underwent more apoptosis than that of WT FLT3-ITD (WT FLT3-ITD 9.7±1.1%, R972/973K 23.7±2.1%, p=0.003). The double transformed cells were further transplanted into recipients for leukemia development. Mice receiving MA9 cells expressing R972/973K exhibited longer survival (median survival: WT FLT3-ITD 36 days, R972/973K 50 days, p=0.002, n=6). Mechanistically, expression of R972/973K did not affect the total tyrosine phosphorylation level of FLT3-ITD. Additionally, FLT3-ITD R-Me expression persisted after a TKI (AC220) treatment. These facts indicated that FLT3-ITD R-Me function is independent of FLT3-ITD kinase activity. We then used a FLT3-ITD+ patient derived xenograft (PDX) model to assess the effects of TKI and PRMT1 inhibition. Following engraftment >1% in peripheral blood, we divided mice (n=24) into 4 groups and treated each with vehicle, MS023 (a type I PRMT inhibitor, ACS Chem Biol. 2016;11:772-781) (160 mg/kg/i.p), AC220 (10 mg/kg/i.g) or combination for 4 weeks. MS023 treatment downregulating FLT3 R-Me levels enhanced elimination of FLT3-ITD AML cells by AC220 treatment (AC220 24.6±13.4% vs combination 7.6±6.5%, p=0.02, n=6). At 16 weeks post-secondary BMT, significant AML burden in single drug treated transplants was observed, but less AML cells were detected in combination-treated transplants (AC220 52.3%, vs combination 25.4%, p<0.001, n=6). MS023 had little effect on long-term in vivo engraftment of CD34+ from a human CB specimen (vehicle 76.3±5.9%, MS023 72.2±3.4%, p=0.21, n=5). In summary, our study demonstrated PRMT1 overexpression contributes to AML stem/progenitor cell survival possibly through FLT3-ITD methylation, supporting further exploration into how PRMT1-mediated FLT3 methylation governs LSC survival. Disclosures Khaled: Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy; Juno: Other: Travel Funding.

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract Relapse of malignancy and lethal graft versus host disease (GVHD) are the principal causes of failure of allogeneic hematopoietic cell transplant (HCT). Recently we have shown that at seven days after HCT an algorithm using two serum biomarkers (ST2 and REG3α) can predict severe GVHD (Hartwell et al. JCI Insight 2017). We determined whether serial testing (in the first month following HCT) of patients with low probability biomarkers would improve the predictive accuracy of the algorithm and identify patients with different risks of relapse and lethal GVHD. Patients who received an HCT at 18 centers in the Mount Sinai Acute GVHD International Consortium (MAGIC) for hematologic malignancy and who supplied three blood samples were divided into a training set and validation set with equal numbers of lethal GVHD events, which was defined as death from GVHD or infection during treatment for GVHD. Patients in the training set (n=702) underwent HCT from January 1, 2006 until June 30, 2015, whereas patients in the validation set (n=906) underwent HCT from July 1, 2015 to May 1, 2017. Serum samples were analyzed using the previously published algorithm of two biomarkers up to three times (day 7, day 14, day 28 or GVHD onset, if onset occurred within the first 28 days). The algorithm generates a predicted probability of lethal GVHD between 0 and 1 for each patient. Patients were categorized as either low probability (LP) or high probability (HP) for lethal GVHD. HP thresholds of 0.20 and 0.16 were used to classify patients with and without GVHD symptoms, respectively (once categorized as HP, patients remained in that category and were not retested). All results were similar between training and validation sets, and we present here the validation set results. Serial testing identified 28% of patients as HP with a three-fold greater cumulative incidence of lethal GVHD at one year (13% vs 4%, p<0.001, Figure 1). Relapse rates were the same in both probability groups, and thus LP patients experienced significantly better relapse free survival (RFS) (69% vs 53%, p<0.001). As expected, significantly fewer LP patients experienced severe GVHD at onset (as measured by Minnesota risk), maximum grade III/IV GVHD, or steroid resistant GVHD by day 180 after HCT (Figure 2, p<0.001 for all three parameters). To measure the accuracy of prediction, at each timepoint we calculated the area under the curve (AUC) of receiver operating characteristic curves; the AUC increased significantly with each subsequent evaluation, from 0.59 at one timepoint (dotted line) to 0.74 at the third timepoint (solid line) (p<0.001), with a final sensitivity of 65% and specificity of 74% (Figure 3A). Early development of GVHD (by day 28) is a risk factor for lethal GVHD. Therefore, we next plotted RFS (dashed line), relapse (solid line), and lethal GVHD (dotted line) rates in patients who developed GVHD by day 28. 25% of patients with GVHD were categorized as HP and had a cumulative incidence of lethal GVHD more than four times higher (28%) than that of relapse (6%); however the risks were reversed for the 75% of patients who were LP, where relapse (15%) occurred twice as often as lethal GVHD (7%) (Figure 3B). In patients who did not develop GVHD in the first month, this reversal of risks was even more dramatic. Approximately half (53%) of the entire validation cohort did not develop GVHD by day 28 and was LP at all three evaluations. These patients had an exceptionally low risk of lethal GVHD and thus they relapsed (25%) much more often than they died from GVHD (3%). When malignancies were classified according to risk for relapse by the disease risk index (DRI) (Figure 3C), the probability of relapse was three fold higher than lethal GVHD in malignancies with a low DRI (12%), six fold higher for intermediate DRI (20%), and eleven fold higher for high/very high DRI (33%). We conclude that a serial monitoring strategy using GVHD biomarkers for one month after HCT is able to identify two groups of patients with very different risks of lethal GVHD and relapse. For these patients, the intensity of immunosuppression after day 28 could be tailored according to the probabilities of developing lethal GVHD and relapse in the context of clinical trials. Disclosures Aziz: Doris Duke Charitable Foundation: Research Funding. Ayuk:Therakos (Mallinckrodt): Honoraria; Novartis: Honoraria; Celgene: Consultancy; Gilead: Consultancy. Chen:REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Takeda Pharmaceuticals: Consultancy. Merli:Neovii Biotech: Honoraria; AMGEN: Honoraria. Roesler:Sanofi: Other: Travel, Accommodations, Expenses; Amgen: Equity Ownership; Jazz Pharmaceuticals: Other: Travel, Accommodations, Expenses; Immunomedics: Equity Ownership; Biogen: Equity Ownership; Merck: Consultancy; Pfizer: Consultancy. Kitko:Novartis: Consultancy, Honoraria; Mallinckrodt: Honoraria, Other: Travel, Accommodations, Expenses. Qayed:Novartis: Consultancy. Wölfl:Bristol-myers Squibb: Equity Ownership; Novartis: Equity Ownership; Taheda: Equity Ownership; Juno: Equity Ownership; Neovii: Other: Travel, Accommodations, Expenses. Mielke:Celgene: Speakers Bureau; DGHO: Speakers Bureau; EHA: Speakers Bureau; Kiadis Pharma: Speakers Bureau; Miltenyi: Speakers Bureau. Wudhikarn:Takeda Oncology: Other: Travel, Accommodations, Expenses. Nakamura:Celgene: Honoraria; Molmed: Honoraria; Merck: Consultancy; Pharmacyclics: Consultancy; Atara: Consultancy; Jazz Pharmaceuticals: Consultancy. Pulsipher:CSL Behring: Consultancy; Novartis: Consultancy, Honoraria, Speakers Bureau; Adaptive Biotech: Consultancy, Research Funding; Amgen: Honoraria. Reshef:Pfizer: Consultancy; Atara Biotherapeutics: Consultancy; Kite Pharma: Consultancy; Takeda Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy. Levine:Therakos: Consultancy; Novartis: Consultancy; Bluebird: Consultancy; Incyte: Consultancy; Kamada: Research Funding; Viracor: Patents & Royalties. Ferrara:Incyte: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Xenikos: Consultancy, Other: Travel, Accommodations, Expenses; Kamada: Consultancy, Research Funding; Viracor: Consultancy, Patents & Royalties.

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.

Abstract Introduction Older patients undergoing allogeneic stem cell transplantation may experience a higher degree of morbidity and limitations from transplant related complications. Chronic graft-versus –host disease (GVHD) causes a significant reduction in patients’ quality of life (QOL), physical functioning, and functional status. However, it is not known if moderate to severe chronic GVHD has a worse impact on QOL, or survival outcomes for older patients. Methods We analyzed data of patients with moderate or severe chronic GVHD (N=522, 1661 follow-up visits, a total of 2,183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. Moderate or severe chronic GVHD was defined by the National Institutes of Health global severity score at the time of enrollment. We examined the relationship between age group (adolescent and young adult “AYA” 18-40, “middle-aged” 41-59, and “older” ≥ 60 years) and clinical manifestations of chronic GVHD, patient-reported outcomes, functional status, non-relapse mortality and overall survival. Clinical manifestations of chronic GVHD were determined by the clinician-reported individual organ scores. Patient-reported outcomes included (1) QOL as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (FACT-BMT) and the Medical Outcome Short-Form Health Survey (SF-36) (2) chronic GVHD symptom burden as measured by the Lee Symptom Scale; and (3) physical fitness as measured by the Human Activity Profile (HAP). Functional status was assessed using the 2-minute walk test (2MWT). Because of multiple testing, p-values <0.01 were considered significant. Results There were 115 (22%) AYA, 279 (53%) middle-aged and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD included. At study enrollment, older patients (≥60) were similar to younger patients in sex, time from transplant (median 12 months), prior acute GVHD, percentage of severe chronic GVHD, and current co-morbidity scores but differed in disease distribution and conditioning regimen intensity. At enrollment, in unadjusted analyses using all available data, older patients had similar rates and severity of global and organ-specific manifestations of chronic GVHD compared to younger patients, except for genital involvement, which was more prevalent and severe in AYA patients. Although older patients reported worse physical functioning [SF-36 Physical Functioning (p=0.01)], shorter 2MWT (p=0.002), and lower HAP scores (p=0.001) than AYA and middle-aged patients suggesting they have more physical limitations, older patients had better QOL [FACT-BMT (p=0.01)] scores compared to middle-aged patients and similar to AYA patients. Older patients had better psychological [Lee Psychological Scale (p<0.001), SF-36 Mental Health (p=0.01)] and emotional functioning [FACT-Emotional Well-being (p=0.001)] and less pain [SF-36 Bodily Pain (p=0.006)] than AYA and middle-aged patients but similar chronic GVHD symptom burden [Lee Symptom Scale (p=0.47)]. In multivariable linear mixed models utilizing all visit data and adjusted for clinical covariates, older patients had QOL (FACT-BMT) that was comparable to AYA patients (estimate -0.04, p=0.99) and better than middle-aged patients (estimate 5.7, p=0.004), while the SF36 physical and mental component scores and symptom burden were not different between the groups. Non-relapse mortality and overall survival were similar between the age groups in unadjusted analyses (p=0.23, p=0.17) and after adjusting for clinical covariates (p=0.17, p=0.15) in Cox models. In a subgroup analysis, we found that there were no differences in overall and organ-specific chronic GVHD manifestations, QOL and survival between patients in the 60-64 (n=73), 65-70 (n=39), and >70 (n=16) age groups, except for more moderate-severe skin involvement in the 65-70 year olds. Conclusion Despite higher physical and functional limitations, older patients with moderate or severe chronic GVHD have preserved QOL, comparable disease manifestations and symptom burden, and similar overall survival and non-relapse mortality when compared to younger patients. Therefore we did not find evidence that older age itself is associated with worse QOL or survival in patients with moderate or severe chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: Depression is associated with increased mortality among healthy individuals and patients with various medical conditions including cardiovascular disease and cancer. The impact of an existing diagnosis of depression prior to autologous and allogeneic hematopoietic stem cell transplantation (HCT) on clinical outcomes including overall survival has not been studied. Methods: We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to compare overall survival and hospital-length-of-stay during the first 100 days after autologous (n= 3786) or allogeneic (n = 7433) HCT for adult (≥ 18 years) patients with hematologic malignancies with an existing diagnosis of pre-transplant depression requiring treatment vs. those without pre-transplant depression. Data regarding an existing diagnosis of pre-transplant depression requiring treatment were collected from medical chart reviews and reported to the CIBMTR. Data for autologous and allogeneic HCT were analyzed separately. Using Cox proportional hazards regression models adjusting for patient-, disease-(including the disease risk index for allogeneic HCT), donor-(for allogeneic HCT), and transplant-related variables, we compared overall survival between patients with or without pre-transplant depression. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation using Poisson models adjusting for patient-, disease-, and transplant-related variables. Among patients undergoing allogeneic HCT, we also compared the risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD among patients with or without pre-transplant depression using Cox proportional hazard regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-transplant depression and 6317 (85%) patients without pre-transplant depression who underwent allogeneic HCT between 2008 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and donor source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-transplant depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p = 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.14-1.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p = 0.26). Pre-transplant depression was associated with fewer days alive and out-of-the hospital (Means Ratio (MR) = 0.97, 95% CI 0.95-0.99, P = 0.004). Among patients undergoing autologous HCT, we included 512 (13.5%) patients with pre-transplant depression and 3274 (86.5%) patients without pre-transplant depression between 2007 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to disease distribution, disease status prior to HCT, time from diagnosis to transplant, conditioning regimen, and year of transplant, but they were slightly younger, more likely be to female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. Pre-transplant depression in autologous HCT recipients was not associated with overall survival in multivariable analyses (HR 1.15, 95% CI 0.98-1.34, p = 0.096), but was significantly associated with fewer days alive and out of the hospital (MR = 0.98, 95% CI 0.97-0.99, p = 0.002). Conclusion: Pre-transplant depression was associated with higher mortality and higher risk of acute GVHD among patients undergoing allogeneic HCT. Moreover, pre-transplant depression is associated with a longer hospital-length-of stay during the first 100 days after autologous and allogeneic HCT. Therefore patients with pre-transplant depression represent a highly vulnerable population at risk for post-transplant mortality and complications, and they may benefit from more intensive interventions to mitigate the risk of depression on their post-transplant outcomes. Disclosures Chen: Bayer: Consultancy, Research Funding. Lee:Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Hahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding.

Abstract Abstract 230 The prognosis for patients (pts) with acute myeloid leukemia (AML) who are aged 60 years or older at the time of initial diagnosis is poor. Even for pts achieving a first complete remission (CR1), prospects for long-term survival are poor due to the very high risk of relapse. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with conventional chemotherapy when performed in younger pts with AML in CR1. However, the toxicity of this approach in older pts is prohibitive. A reduced intensity conditioning (RIC) regimen may mitigate the risk of early toxicity and while early results in older AML pts have been encouraging and suggest disease free survival (DFS) rates above 30% at 3 yrs (Farag et al, Biol Blood Marrow Transplant 2011), most data are retrospective and pts have not been treated uniformly. We therefore sought to determine the effectiveness of a uniform RIC regimen given to older pts with AML in CR1 on a prospective multi-center phase II trial conducted by the Alliance (formerly Cancer and Leukemia Group B (CALGB)) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The study, activated in 2004, was initially limited to recipients of a matched related donor (MRD) graft but was amended in 2006 to include matched unrelated donor grafts (URD). The primary endpoint of the study was 2-year DFS. We hypothesized that DFS at 2-years would exceed 20% and powered the study to detect a 2-year DFS probability of 35% for URD recipients. We focused the primary analysis on URD recipients since the majority of older pts require an URD graft. Eligible pts were from 60–74 years old inclusive, had AML in CR1 following induction chemotherapy, availability of a 6/6 MRD or 8/8 URD, and absence of significant end-organ damage prior to transplantation. Adverse events (AE) were initially recorded according to NCI-CTCAE v3.0, amended to v4.0 in 10/2010. Accrual was completed in 12/2011. 132 pts were registered at 21 centers and 123 transplanted (MRD (47%); URD (53%). All donor grafts were mobilized and collected following G-CSF (PBSC). The median age of pts was 65 (range 60–74) and 76 pts (62%) were male. At diagnosis, 67% had an intermediate risk karyotype, 20% adverse risk, <1% favorable, and in 11% data were missing. More than 90% achieved CR following standard “7+3” based induction. CR1 was achieved after 1 (59%) or 2 (41%) induction cycles. Consolidation therapy was administered for one (50%) or two (24%) cycles and 17% received no consolidation with data missing in 9%. All but the initial 8 MRD recipients (who received fludarabine and busulfan alone) were conditioned with the same regimen containing fludarabine (30mg/m2/day × 5), busulfan (6.4mg/kg IV total dose), and antithymocyte globulin (ATG; thymoglobulin) (7.5mg/kg total dose). Only one case of primary graft failure was reported. With a median follow-up of 3.3 yrs, the results in the 123 transplanted pts are depicted below: Event Cumulative incidence at 100 days* or 2yrs† 95% CI Acute GVHD 2-4 9.4%* 4.1–15% Acute GVHD 3-4 3.4%* 1.2–6.7% Chronic GVHD 26%† 17–34% Relapse 47%† 37–57% Treatment related mortality (TRM) 14%† 7.2–21% Event Probability at 2 yrs 95% CI DFS 39% 30–50% DFS URD only 38% 26–55% Overall survival (all pts) 46% 36–57% The rates of both acute and chronic GVHD as well as TRM were relatively low. There were 81 grade 3–5 non-hematologic AE recorded, including 7 grade 5 (4 infections, 1 each cardiac, pulmonary, and second malignancy). Relapse was the most common cause of death. In conclusion, the results of this first prospective US cooperative group trial conducted in a homogeneously treated group of older AML patients in CR1 demonstrate the feasibility and effectiveness of RIC allografting using MRD or URD PBSC grafts. DFS appears better following a RIC allograft compared to results achieved historically after conventional therapies, warranting prospective comparison in pts with contemporary cytogenetic and molecular disease characterization. Future research should also focus on preventing disease relapse after RIC allografting in this population. Disclosures: Devine: Sanofi: Honoraria, Research Funding. Off Label Use: Antithymocyte globulin for GVHD prophylaxis is included in the abstract. Vij:Millennium: Speakers Bureau. Shea:Otsuka: Research Funding.

Abstract Background Ixazomib, the first oral proteasome inhibitor, is approved by the US FDA, in combination with Rd, for the treatment of MM patients (pts) who have received at least 1 prior therapy. Approval was based on the double-blind, placebo-controlled phase 3 TOURMALINE-MM1 study (NCT01564537) in 722 pts with RRMM (Moreau et al, N Engl J Med 2016), in which IRd showed superior PFS versus placebo-Rd (HR 0.74) at the final prespecified analysis, with limited additional toxicity. Prespecified subgroup analyses showed a consistent PFS benefit with IRd, but with a differential treatment effect according to prior therapy exposure. An exploratory study objective was to evaluate potential relationships between treatment outcomes and tumor gene expression patterns. c-MYC is a proto-oncogene that encodes a transcription factor regulating cell proliferation, growth, protein translation, metabolism, and apoptosis, and increased c-MYC expression is involved in MM pathogenesis/progression. We analyzed the impact of c-MYC expression on PFS in RRMM pts treated with IRd or placebo-Rd. Methods Pts with RRMM after 1-3 prior lines of therapy were randomized 1:1 to receive oral ixazomib or placebo, plus lenalidomide and dexamethasone, until disease progression or unacceptable toxicity. Randomization was stratified by number of prior therapies (1 vs 2-3), proteasome inhibitor exposure, and ISS disease stage. The primary endpoint was PFS by independent review committee assessment. Data reported here are from the final prespecified statistical analysis of PFS (median follow-up ~15 months). Bone marrow aspirate samples were collected at screening for tumor gene expression analysis. Whole transcriptome sequencing (RNAseq) of bone marrow-sorted CD138+ cells was performed using the Illumina Truseq protocol on the Illumina HiSeq platform; this generated a median of 50 million paired-end reads (100 bp length) per sample. c-MYC expression was evaluated by treatment arm and according to number of prior therapies (1 vs 2-3). PFS was analyzed in subgroups dichotomized according to median c-MYC expression (c-MYC-high/c-MYC-low). Results RNAseq data were available for 59% (427/722) of enrolled pts; 213 (50%) had high and 219 (50%) had low c-MYC expression (dichotomized according to the median). Impact of c-MYC expression (high vs low) on PFS, irrespective of treatment arm, was not significant (p=0.98). However, a significant treatment effect of IRd vs placebo-Rd was only seen in pts with high c-MYC expression (interaction p=0.024); in these pts (IRd: n=109; placebo-Rd: n=104) a significant PFS benefit was seen with IRd (HR 0.41; 95% CI: 0.26-0.65, p=0.00011). Impact of c-MYC expression was then analyzed by number of prior therapies. In the overall TOURMALINE-MM1 population, per stratification, 212/213 pts in the IRd/placebo-Rd arms had 1 prior therapy, and 148/149 had 2-3 prior therapies. After median follow-up of ~15 months, median PFS in pts with 1 prior therapy was 20.6 vs 16.6 months with IRd vs placebo-Rd (HR 0.88; 95% CI: 0.65-1.20), and in pts with 2-3 prior therapies was not reached vs 12.9 months (HR 0.58; 95% CI: 0.40-0.84, p=0.0033). The level of c-MYC expression was shown to be significantly higher in pts with 2-3 prior therapies vs 1 prior therapy, with median expression of 6.94 (SD=1.71, n=177) vs 6.52 (SD=1.74, n=250) (log2 scale), t-test p-value 0.0153. In pts with 1 prior therapy, no differences in PFS were observed between pts with low c-MYC expression (HR 1; 95% CI: 0.59-1.8, p=0.934), while a prolonged PFS benefit was observed in pts with high c-MYC expression (HR 0.48; 95% CI: 0.26-0.88, p=0.0146) (Figure, A and B). In pts with 2-3 prior therapies, both the c-MYC-high and c-MYC-low pts showed improved PFS with IRd vs placebo-Rd; the difference in PFS was statistically significant only in c-MYC-high pts (HR 0.36; 95% CI: 0.18-0.72, p=0.00269) (Figure, C and D). Conclusions In TOURMALINE-MM1, c-MYC expression was higher in MM tumor samples from pts with 2-3 vs 1 prior therapies. The IRd regimen was active in c-MYC-high and c-MYC-low pts, but its impact on PFS vs placebo-Rd was greater in c-MYC-high pts, thus providing a potential explanation for the enhanced PFS benefit with IRd vs placebo-Rd in pts with 2-3 prior therapies. The PFS benefit with IRd in c-MYC-low pts with 2-3 prior lines suggests that, in advanced MM, further genomic alterations may also be contributing to ixazomib sensitivity. Disclosures Di Bacco: Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Bahlis:BMS: Honoraria; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding, Speakers Bureau. Avet-Loiseau:Takeda: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Speakers Bureau. Masszi:Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ganly:Medipics: Equity Ownership; Novartis: Honoraria; Roche: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Langer:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Kumar:Array BioPharma: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; AbbVie: Research Funding; Onyx: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Kesios: Consultancy; BMS: Consultancy; Millennium: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Berg:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lin:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Li:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Badola:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shen:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Zhang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Esseltine:Takeda: Equity Ownership; Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Johnson and Johnson: Equity Ownership. Luptakova:Takeda Oncology: Employment. van de Velde:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Richardson:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Moreau:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria; Amgen: Honoraria.

Abstract Graft-versus-host disease (GVHD), the primary cause of non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation, does not always respond to treatment with high dose systemic corticosteroids. We have recently shown that a combination of three biomarkers (TNFR1, ST2, and REG3α) measured at onset of GVHD can predict day 28 response to treatment and 6-month NRM (Levine, Lancet Haem, 2015). Our goal in the current study was to determine if the same biomarker-based Ann Arbor GVHD algorithm can alsopredict treatment response andmortality whenapplied after one week of systemic corticosteroid treatment. The study population consisted of 378 patients (pts) with acute GVHD from 11 centers in the Mount Sinai Acute GVHD International Consortium. All pts were treated with systemic steroids and provided a plasma or serum sample obtained after one week of treatment (±3 days). The median starting dose of systemic steroids for Grade II-IV GVHD was 2.0 mg/kg/day and for Grade I was 1.0 mg/kg/day, after which treatment varied. Patients were divided into test (n=236) and validation (n=142) cohorts. We applied the Ann Arbor GVHD algorithm to concentrations of TNFR1, ST2, and REG3α measured after one week of treatment to generate a predicted probability of 6-month NRM, which we term the treatment score (TS). We employed unsupervised k-medoidclustering to partition TS values from the test cohort into two groups (high and low). This unbiased approach identified a high score group made up of 25% of pts (n=58) in the test cohort. We observed that the day 28 response rate (complete, CR + partial, PR) was significantly lower in pts with high scores compared to low scores in the test cohort (24% vs 65%, p<0.0001) (Fig 1A). Analysis of the validation cohort using the same TS definitions showed similar differences in response rates (22% vs 61%, p<0.0001) (Fig 1B). Further, nearly four times as many pts with high scores in both cohorts died within 6 months from non-relapse causes compared to pts with low scores (test: 57% vs 17%, p<0.0001; validation: 57% vs 14%, p<0.0001) (Fig 1C/D). As expected, the majority of non-relapse deaths in pts treated for GVHD were directly attributable to GVHD (test: 95%; validation: 89%). Relapse rates for high and low score pts were similar (data not shown), and thus pts with a high TS experienced significantly worse overall survival in both cohorts (test: 37% vs 72%, p<0.0001; validation: 38% vs 79%, p<0.0001) (Fig 1E/F). Approximately half of the pts in each cohort (test: 48%; validation: 44%) responded (CR+PR) to the first week of steroids and these ptshad significantly lower 6-month NRM than non-responders (NR) (test: 17% vs 36%, p=0.0002; validation: 13% vs 36%, p=0.0014). Yet the TS continued to stratify mortality risk independently of clinical response. In the test cohort, pts with a high score comprised 16% of all early responders and experienced more than twice the NRM of early responders with a low score (33% vs 13%, p=0.022) (Fig 2A). Conversely, test cohort pts who did not respond by day 7, but had a low score, fared much better than non-responders with a high score (NRM 21% vs 68%, p<0.0001) (Fig 2B). Two thirds of early non-responders comprised this more favorable group. These highly significant results reproduced in the independent validation cohort in similar proportions (CR+PR: 45% vs 6%, p=0.0003; NR: 61% vs 22%, p=0.0001) (Fig 2C/D). Finally, a subset analysis revealed that pts classified as NR after one week of steroids due to isolated, yet persistent, grade I skin GVHD (24/378, 6%) overwhelmingly had low treatment scores (22/24, 92%) and experienced rates of NRM (9%) comparable to responders with low scores, thus forming a distinct, albeit small, subset of pts with non-responsive GVHD that fares particularly well (Fig 3). In conclusion, a treatment score based on three GVHD biomarkers measured after one week of steroids stratifies pts into two groups with distinct risks for treatment failure and 6-month NRM. It is particularly noteworthy that the TS identifies two subsets of pts with steroid refractory (SR) GVHD who have highly different outcomes (Fig 2B/D). The much larger group, approximately two thirds of all SR pts, may not need the same degree of treatment escalation as is traditional for clinical non-response, and thus overtreatment might be avoided. Because the TSis measured at a common decision making time point, it may prove useful to guide risk-adapted therapy. Disclosures Mielke: Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; Gilead: Other: Travel grants; JAZZ Pharma: Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Ferrara:Viracor: Patents & Royalties: GVHD biomarker patent. Levine:Viracor: Patents & Royalties: GVHD biomarker patent.