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Gilad J Regev,1,2 Roi Treister,3 Silviu Brill,2,4 Dror Ofir,1,2 Khalil Salame,1,2 Zvi Lidar,1,2 Morsi Khashan,1,2 Rivka Litvin,5 Uri Hochberg2,4 1Spine Surgery Unit, Neurosurgical Department, Tel Aviv Medical Center, Tel Aviv, Israel; 2Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel; 3The Cheryl Spencer Department of Nursing, Faculty of Social Welfare & Health Sciences, University of Haifa, Haifa, Israel; 4Institute of Pain Medicine, Division of Anesthesiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 5Department of surgery, Tel Aviv Medical Center, Tel Aviv, IsraelCorrespondence: Uri Hochberg, Institute of Pain Medicine, Division of Anesthesiology, Tel Aviv Medical Center, 6 Weismann St. Tel-Aviv, Israel, Tel +972-3-6974477, Email urih@tlvmc.gov.ilPurpose: While advanced medical technology and unlimited access to medical information might benefit and empower patients, these same advantages may pose some risks, especially in the cases where patients have direct access to advanced imaging studies. The aim of this work was to evaluate three domains related to patients with lower back pain: the patients’ perceptions, misconceptions and the experience of anxiety-related symptoms following direct access to their thoraco-lumbar spine radiology report. An additional aim was the assessment of possible associations with catastrophization.Patients and Methods: Patients who were referred to the spine clinic, following the completion of a CT or MRI of their thoraco-lumbar spine were surveyed. Patient perceptions of the importance of having direct access to their imaging report and of the concern they attribute to the medical terms found in their report were evaluated using a set of questionnaires. The medical terms severity scores were then correlated to a reference clinical score created for the same medical terms by spine surgeons. Lastly, patients’ anxiety-related symptoms and Pain Catastrophizing Scale (PCS) after reading their radiology report were evaluated.Results: Data from 162 participants (44.6% female), with mean age of 53.1 ± 15.6 years, were collected. Sixty-three percent of the patients stated that reading their report helped them gain better understanding of their medical condition and 84% agreed that having early access to the report helped improve communication with the physician. Patients’ degree of concern associated with the medical terms in their imaging report ranged between 2.07 and 3.75, on a scale of 1– 5. The patient’s degree of concerns were significantly higher for six common medical terms and significantly lower in one, when compared to experts’ opinions. A mean (± SD) of 2.86± 2.79 anxiety-related symptoms was reported. The mean Pain Catastrophizing Scale (PSC) score was 29.18 ± 11.86, ranging from 2 to 52. Both the degree of concerns and the number of symptoms reported were significantly associated with the PCS.Conclusion: Direct access to radiology reports might provoke anxiety symptoms, especially in patients with a tendency for catastrophic thinking. Increasing awareness amongst spine clinicians and radiologist about possible risks associated with direct access to radiology reports could contribute to preventing patients’ misconceptions and unnecessary anxiety-related symptoms.Keywords: low back pain, pain catastrophizing, anxiety, radiology reports

Mutational profiling has demonstrated utility in predicting the likelihood of disease progression in patients with myelofibrosis (MF). However, there is limited data regarding the prognostic utility of genetic profiling in MF patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). We performed high-throughput sequencing of 585 genes on pre-transplant samples from 101 patients with MF who underwent allo-HCT and evaluated the association of mutations and clinical variables with transplantation outcomes. Overall survival (OS) at 5 years post-transplantation was 52%, and relapse-free survival (RFS) was 51.1 % for this cohort. Nonrelapse mortality (NRM) accounted for most deaths. Patient's age, donor's age, donor type, and Dynamic International Prognostic Scoring System score at diagnosis did not predict for outcomes. Mutations known to be associated with increased risk of disease progression, such as ASXL1, SRSF2, IDH1/2, EZH2, and TP53, did not impact OS or RFS. The presence of U2AF1 (P = .007) or DNMT3A (P = .034) mutations was associated with worse OS. A Mutation-Enhanced International Prognostic Scoring System 70 score was available for 80 patients (79%), and there were no differences in outcomes between patients with high risk scores and those with intermediate and low risk scores. Collectively, these data identify mutational predictors of outcome in MF patients undergoing allo-HCT. These genetic biomarkers in conjunction with clinical variables may have important utility in guiding transplantation decision making.

Introduction: The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression and leukemic transformation in patients with myelofibrosis (MF) is well established. Further, emerging data suggests that the number and type of mutations may impact response to therapies such as ruxolitinib or imetelstat. Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only potentially curative treatment for MF patients. However, the impact of somatic mutations on overall survival (OS) and relapse-free survival (RFS) is poorly understood. Using next-generation sequencing of pre-transplant blood and bone marrow samples from a well clinically-annotated cohort of MF patients who underwent allo-HSCT, we sought to determine the impact of mutational burden on outcomes. Methods: A multicenter retrospective analysis of a cohort of 84 patients was carried out. This included 52 patients treated on the MPD-RC 101 prospective study (NCT00572897), 18 patients treated at Prince Margaret Hospital, and 14 patients treated at Memorial Sloan Kettering Cancer Center. Patient and transplant characteristics are displayed in Table 1. DNA was extracted from pre-transplant bone marrow aspirate samples or peripheral blood samples. High-throughput sequencing of a panel of genes was performed. Average coverage of 829x (standard deviation of ±130) was obtained. Mutect was utilized to call single point variants (comparing our samples to a pool of normal samples) and PINDEL was used to call short insertions and deletions. We excluded all mutations present in at least one database of known non-somatic variants (DBSNP and 1000 genomes) and absent from COSMIC. Univariate Cox regression and Kaplan-Meier graphics were used to investigate the association of patient, transplant, and disease characteristics with OS and RFS. Results: JAK2V617F was the most frequent mutation detected in 41(48.8%) patients (Table 2). Eighteen patients (21.4%) had triple negative disease (negative for JAK2, MPL, and CALR mutations). Univariate analysis included the following: patient characteristics (age, gender), transplant characteristics (related vs. unrelated donor, matched vs. mismatched donor and myeloablative vs. reduced intensity conditioning) and disease characteristics (DIPSS and presence of mutations). Decreased OS was associated with unrelated donor status (HR 2.09, 95% CI: 1.03-4.23, p=0.04), reduced intensity conditioning (HR 4.21, 95% CI: 1.01-17.59, p=0.049), triple negative disease (HR 2.09, 95% CI: 1.02-4.30, p=0.04), and presence of U2AF1 (HR 2.53, 95% CI: 1.10-5.81, p=0.03) or SUZ12 mutations (HR 3.92, 95% CI: 1.19-12.21, p=0.02). Decreased RFS was associated with unrelated donor status (HR 2.27, 95% CI: 1.16-4.45, p=0.02), and the presence of SUZ12 mutation (HR 6.97, 95% CI: 2.37-20.49, p Conclusions: Our analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-HSCT, suggesting transplant may be able to overcome the impact of these mutations. However, mutations in SUZ12 and U2AF1 are associated with reduced OS in univariate and multivariate analysis (together with donor type). Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. Disclosures Rampal: Incye and CTI: Consultancy. Mascarenhas:Janssen: Research Funding; CTi Biopharma: Research Funding; Promedior: Research Funding; Merk: Research Funding; Incyte: Research Funding. Mesa:Galena: Consultancy; Gilead: Research Funding; Promedior: Research Funding; Incyte: Research Funding; CTI Biopharma: Research Funding; Celgene: Research Funding; Ariad: Consultancy; Novartis: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding.

The introduction of JAK inhibitors into clinical practice has produced significant clinical benefits for patients with MPNs, including reduction of splenomegaly and improvement in symptom burden. However, JAK inhibitors have demonstrated limited clinical ability to alter the natural history and biology of disease (such as reversal of fibrosis) in MPNs, and have produced only modest reductions in JAK2 V617F allele burden. This has prompted the evaluation of other therapeutic strategies in MPN patients. Heat Shock Protein 90 (Hsp90) inhibitors have recently emerged as promising potential treatment for MPN patients. Hsp90 physically interacts with JAK2, and inhibition of Hsp90 induces degradation of JAK2. Hsp90 is also a client chaperone for a variety of other proteins involved in pathways known to be critical for cancer cell differentiation, proliferation and survival. Preclinical studies have demonstrated that Hsp90 inhibitor therapy results in dose-dependent degradation of JAK2 and inhibition of downstream signaling pathways including STAT5, STAT3 and MAPK, as well as inhibition of growth of cells expressing mutant JAK2. In vivo treatment with Hsp90 inhibitors in MPN retroviral murine models led to normalized of peripheral blood counts, reduction in organomegaly, and improvement in overall survival. Based on these promising preclinical data, we conducted an open label phase II trial to assess the efficacy and confirm the safety of a novel Hsp90 inhibitor, AUY922 (Novartis) in patients with primary myelofibrosis (PMF), post-polycythemia vera and post-essential thrombocythemia myelofibrosis (IPSS-2 or higher) and in patients with polycythemia vera or essential thrombocythemia, who were refractory to, intolerant of, or ineligible for conventional therapy. The primary objective of the study was to determine the efficacy of AUY922 in this patient population. Secondary objectives included confirmation of safety and tolerability along with exploration of how treatment modified the biology of the disease. From 2012-2014, 6 patients were treated, 4 female, median age 55 (53-72), with MPNs; 4 with primary-MF, 1 with PV and 1 with ET, 4 patients were JAK2 V617F positive. Prior treatments included hydroxyurea in 5, anagrelide in 3, interferon in 1, azacitadine and pamidronate in 1. Median length of treatment was 39.5 months (1-145). 3 patients with MF experienced stable disease (including two patients with blast-phase disease), and one experienced an anemia response as measured by the European LeukemiaNet (ELN) response criteria. The patient with ET experienced stable disease as measured by the Revised International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT). Notable (greater than grade 2) adverse events included diarrhea in 5 patients, night blindness in 4, alkaline phosphatase elevation in 2, nausea in 2, emesis in 2, blurred vision in 1 and CPK elevation in 1 patient Serious Adverse Events (SAEs) included nausea, vomiting, diarrhea and altered mental status. As well, three patients experienced gastrointestinal bleeding as an SAE (grade 2 and 3). Two of these events were associated with an ileocecal ulcer. Two events were deemed to be possibly related to exposure to the study drug. The trial was terminated for this reason. Evaluation of the impact on JAK-STAT signaling is underway with evidence of reduction in total JAK2 protein following infusion (figure 1). Further evaluation of JAK-STAT signaling, impact on cytokine production, and JAK2 allele burden is under evaluation and results will be presented. In summary, treatment with AUY922 in patients with has demonstrated response including stable disease (including in blast-phase myelofibrosis patients) as well as anemia response and clinical improvement in one myelofibrosis patient. These data indicate that Hsp90 inhibition has clinical activity in MPN patients, and that further clinical therapeutic efforts targeting Hsp90 warrant investigation in this patient population. Figure 1. Responses to treatment with AUY922 per Revised International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet criteria (ELN). Figure 1. Responses to treatment with AUY922 per Revised International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet criteria (ELN). Figure 2. Western Blot analysis of total JAK2 from peripheral blood of patient at baseline, cycle 1 day 2, and end of treatment. Figure 2. Western Blot analysis of total JAK2 from peripheral blood of patient at baseline, cycle 1 day 2, and end of treatment. Disclosures Mauro: Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Ariad: Consultancy. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.