Myeloablative high-dose therapy and single autologous stem cell transplantation (HDT) is frequently performed early in the course of multiple myeloma, supported by some randomized controlled trials (RCTs) indicating overall survival (OS) and progression-free survival (PFS) benefit compared with nonmyeloablative standard-dose therapy (SDT). Other RCTs, however, suggest variable benefit. We therefore undertook a systematic review and meta-analysis of all RCTs evaluating upfront HDT versus SDT in myeloma. The primary objective was to quantify OS benefit with HDT, with PFS benefit a secondary objective. Anticipating heterogeneity, sensitivity and subgroup analyses were undertaken to assess robustness of results. Assessment of harms (treatment-related mortality) was also undertaken. We searched the PubMed, Embase, and Cochrane Collection of Controlled Trials databases using the terms myeloma combined with autologous or transplant or myeloablative or stem cell. In total, 3407 articles were accessed, and 10 RCTs prospectively comparing upfront HDT with SDT, with > or =2-year follow-up, and reporting OS benefit on an intent-to-treat basis were identified. Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (with 95% confidence interval) were determined. Nine studies comprising 2411 patients were fully analyzed. Significant heterogeneity was present. The combined hazard of death with HDT was 0.92 (95% confidence interval, 0.74-1.13). The combined hazard of progression with HDT was 0.75 (95% confidence interval, 0.59-0.96). The totality of the randomized data indicates PFS benefit but not OS benefit for HDT with single autologous transplantation performed early in multiple myeloma. Sensitivity and subgroup analyses supported the findings and indicated that, contrary to current reimbursement criteria, PFS benefit with upfront HDT is not restricted to chemoresponsive myeloma. However, the overall risk of developing treatment-related mortality with HDT was increased significantly (odds ratio, 3.01; 95% confidence interval, 1.64-5.50). Hence, evaluating alternative therapeutic options upfront may also be reasonable.

SummaryHuman granulocytic ehrlichiosis (HGE) is a recently recognized rickettsial tick-borne febrile illness that may occasionally be complicated by coagulopathy. The agent of HGE (aHGE) is an obligate intracellular pathogen, which replicates in endosomes within neutrophils and their precursors. We hypothesized that aHGE might cause DIC via induction of monocyte tissue factor procoagulant activity (TF PCA). Peripheral blood mononuclear cells (PBMNC) and HL-60 cells were used to model the effect of aHGE infection on monocytes/macrophages. Mononuclear cells inoculated with aHGE in vitro demonstrated approximately a 12-15-fold increase in TF PCA, with peak activity occurring at 8-12 h. HL-60 cells inoculated with aHGE also manifested a 4-6 fold induction of TF PCA, with maximal activity occurring at about 8 h. By comparison, E. Coli lipopolysaccharide (LPS) also induced an increase in TF PCA of an equivalent magnitude, and with a similar time course. Induction of TF did not require inoculation of HL-60 cells with live organism, since heat-inactivated aHGE still stimulated TF PCA expression in the target cells. Furthermore, filtered supernatants from heat-inactivated organisms induced TF PCA suggesting that the effect is due to a soluble mediator produced by the organism. Although aHGE is a gram negative organism, the soluble mediator did not appear to be classic endotoxin in that the supernatants tested negative for endotoxin by the Limulus Amoebocyte assay, and polymixin had no inhibitory effect on aHGE supernatants. We conclude that aHGE induces cells of the myelo-monocytic lineage to synthesize TF, which may contribute to the clinical coagulopathy that can be observed in this condition. An atypical soluble mediator or cellular component of the organism appears to be critically important in TF induction by aHGE.

Background Genome sequencing has emerged recently as a technology that can be used to address questions regarding the clonal evolution of cancers. This has the potential to be translated into practical applications in a clinical setting. We have undertaken a case study by carrying out whole exome sequencing of a patient with CML since its clinical outcome varies amongst patients during the progression of disease. Our study is an attempt for a better understanding of why patients differ in their response to different dose of drug regimen and to determine its role in clinical outcome. Our case involves a patient with BCR–ABL positive CML. She has been responding to Imatinib, at 200 mg once a day, a dosage lower than the recommended 400mg /day. She has been taking 200 mg / day irregularly for two years and there were frequent interruptions of regular dosage schedule because of severe symptomatic cytopenias requiring blood transfusions. At the end of 2 years, there has been no progression of disease. Her bone marrow aspirate and biopsy have been normal and the BCR-ABL transcript has been below detectable levels. It was by serendipity that we happened to study the whole exome of this patient before we started her on Imatinib. As her dose response was erratic, we decided to do a longitudinal study. We examined the whole exome of the patient with CML at different points during the progression of disease. The aim of this study is to identify novel polymorphisms or variants which might be associated with the case, there by resisting the disease to progress. We were interested in the process of understanding the variability of the clinical outcome to standard treatment from a genomics perspective. Results The exome sequencing of the bone marrow aspirate was performed at the time of diagnosis and two years post treatment with Imatinib. Matched skin biopsy was used as a control. This study has been approved by the Institutional Ethical Review Board of St. John's Medical college and Hospital. The SNVs of the skin data were used as the control in this experiment to account for germ line mutations. We observe severe genome instability in terms of single nucleotide variants (SNVs) at the time of diagnosis. The counts of SNVs are observed to be drastically reduced in the treated bone marrow sample than at the time of diagnosis. No insertions or deletions were observed in this longitudinal case study. It was also observed that the SNV counts were not dominated in any particular chromosome. The SNVs picked up by exome sequencing were hence contrasted at the stage of diagnosis and post treatment. These SNVs were compared to dbSNP to retain only those which are novel and not previously reported. This finally gave rise to three discreet sets to consider: 1). The SNVs present in the genome of the patient at diagnosis 2). Post treatment, and 3). a subset common to both of them. The non-synonymous coding mutations with single base substitutions were 1,08,436 at the time of diagnosis and reduced to 163 in a stage of remission. The overlaps between these two categories were 169 in number. These hits in respective categories were further filtered based on the score of SNV call, relevance to the disease, presence within domain boundaries and final predicted impact on the function of the coded protein. We have identified novel mutations within the ABL, BCR, Kit and NOTCH genes with high probability of impact on function in the bone marrow sample at diagnosis. These will further be validated experimentally to be confirmed as a probable marker for screening patients. This study will be extended to screen a cohort of patients with similar prognosis as the patient in our case study. The novel mutations will be mapped on the protein structure to show which functional domains could be affected and to provide a structural basis for the deleterious effects of such mutations. We hence attempt to understand this clinical case with an integrated view involving basic experimental biology, bio-informatics and structural biology. These polymorphisms would provide insights on the evolution of CML and eventually allow us to use such readouts as a screen across CML patients to identify cases with better disease prognosis. With the distinct population groups and diverse spectrum of diseases, we believe that our work lays the foundation for larger studies in both CML and other diseases requiring such approaches. Disclosures: No relevant conflicts of interest to declare.

88 Background: Smart phone web based applications (apps) can be effective communication tools for monitoring compliance and increasing adherence to oral anti-cancer therapy in the outpatient setting. Methods: Cancer patients age 18-90 treated with various oral anti-cancer therapies were recruited to this prospective, 3 month observational trial at our large community cancer center to determine feasibility of using an app for oral anti-cancer therapy compliance. Enrolled patients are randomized to either Arm 1 App arm and nurse counseling or Arm 2 nurse counseling only. The free apps MyMeds and Medisafe incorporate medication reminders and record doses. Patients complete the validated RAND 36- item quality of life (QOL) questionnaire and a free text feedback. Results: 91 patients were screened between 11/2015 to 9/2016 (45 declined enrollment due to various factors). 46 patients were randomized with 25 to Arm 1 and 21 to Arm 2. Demographics included 10 men (various tumor types but mostly multiple myeloma) and 36 women; 22 with breast cancer. MyMeds app lacked the necessary real-time communication so patients were switched to the MediSafe app which features email alerts. 15 patients have completed the study through Month 3. Four patients on Arm 1 missing their monthly visit or were non-compliant with the app. 23 patients remain active in the study. Differences are a higher QOL score in Arm 1 vs Arm 2 in measured domains of Energy/Fatigue (56% in Arm 1 compared to 44% for Arm 2) and Pain (72% in Arm 1 compared to 58% in Arm 2). Patients randomized to the app found the electronic alerts very helpful. Conclusions: Our limited pilot study demonstrated the potential of smart device apps as effective communication tools for improving patients’ adherence to oral anti-cancer therapy and QOL. Ultimately, convenient ways to monitor patients’ compliance with anti-cancer therapy will impact survival and facilitate provider-patient communication.

334 Background: Myeloproliferative neoplasms (MPN) represent a heterogenous group of disorders associated with complicated symptom profiles and a propensity for disease transformation that may portend poor prognosis. Clinicians treating patients with MPN may improve treatment planning, disease monitoring, and care coordination by ensuring they check for driver mutations, assess and document symptoms, and evaluate prognostic factors. MPN is relatively uncommon, so clinicians may forget to apply these practices. Blending continuing education with implementation science approaches may help clinicians provide consistent, high-quality care for patients with MPN. This project was supported by an educational grant from Bristol Myers Squibb. Methods: Three hospital-based cancer centers participated in this 18-month longitudinal, multiphase CME/CE and QI initiative. Each hospital performed a baseline assessment by reviewing how their clinicians diagnosed and treated MPN. This process involved chart reviews (N = 38), focus group discussions, and online surveys. Clinicians also participated in two CE interventions and identified ways to implement practice changes that would lead to better care. Each hospital developed improvement projects that addressed one or more of the following: molecular diagnostics, symptom assessment and documentation, prognostic scoring, and treatment selection/planning. Clinicians assessed the feasibility of ideas such as reflex testing protocols, scheduled audit/feedback, patient registries, and clinical documentation shortcuts (eg, SmartText/Phrases).Results: As a result of the CE activities combined with the QI projects, the following competency-based educational outcomes were observed among clinicians: 40% increase (29.6% to 70%) regarding prognostic risk stratification; 41% increase (25.9% to 66.7%) in personalizing treatment plans based on disease-/patient-specific factors; and 24% increase (47.4% to 71.4%) in prioritizing goals of treatment. Based on patient chart data, the QI projects resulted in 15.8% increase (84.2% to 100%) in patients with MPN receiving molecular testing (eg, JAK2, CALR, and MPL genes); 66.7% increase (0% to 66.7%) in patients with MPN who have a documented symptom burden score based on a validated tool (eg, MPN-10); 24.1% increase (34.2% to 58.3%) in patients with MPN who have a documented prognostic score (eg, DIPSS); and 38.8% increase (22.7% to 61.5%) in eligible patients with MPN who are treated with JAK inhibitors. Conclusions: This project demonstrates how multiphase education and QI methods can help clinicians improve care for patients with MPN. Implementation strategies that triggered appropriate reminders and facilitated clinical documentation were considered most useful and sustainable for routine clinical practice.