Heidi E. Kosiorek

IAP antagonists induce anti-tumor immunity in multiple myeloma

The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.

Symptomatic Profiles of Patients With Polycythemia Vera: Implications of Inadequately Controlled Disease

PURPOSE Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with disabling symptoms and a heightened risk of life-threatening complications. Recent studies have demonstrated the effectiveness of JAK inhibitor therapy in patients with PV patients who have a history of prior hydroxyurea (HU) use (including resistance or intolerance), phlebotomy requirements, and palpable splenomegaly. We aimed to determine how these features contribute alone and in aggregate to the PV symptom burden. PATIENTS AND METHODS Through prospective evaluation of 1,334 patients with PV who had characterized symptom burden, we assessed patient demographics, laboratory data, and the presence of splenomegaly by disease feature (ie, known HU use, known phlebotomy requirements, splenomegaly). RESULTS The presence of each feature in itself is associated with a moderately high symptom burden (MPN symptom assessment form [SAF] total symptom score [TSS] range, 27.7 to 29.2) that persists independent of PV risk category. In addition, symptoms incrementally increase in severity with the addition of other features. Patients with PV who had all three features (PV-HUPS) faced the highest total score (MPN-SAF TSS, 32.5) but had similar individual symptom scores to patients with known HU use (PV-HU), known phlebotomy (PV-P), and splenomegaly (PV-S). CONCLUSION The results of this study suggest that patients with PV who have any one of the features in question (known HU use, known phlebotomy, or splenomegaly) have significant PV-associated symptoms. Furthermore, it demonstrates that many PV symptoms remain severe independent of the number of features present.

MUC1 Vaccines, Comprised of Glycosylated or Non-Glycosylated Peptides or Tumor-Derived MUC1, Can Circumvent Immunoediting to Control Tumor Growth in MUC1 Transgenic Mice

It remains challenging to produce decisive vaccines against MUC1, a tumor-associated antigen widely expressed by pancreas, breast and other tumors. Employing clinically relevant mouse models, we ruled out such causes as irreversible T-cell tolerance, inadequate avidity, and failure of T-cells to recognize aberrantly glycosylated tumor MUC1. Instead, every tested MUC1 preparation, even non-glycosylated synthetic 9mer peptides, induced interferon gamma-producing CD4+ and CD8+ T-cells that recognized glycosylated variants including tumor-associated MUC1. Vaccination with synthetic peptides conferred protection as long as vaccination was repeated post tumor challenge. Failure to revaccinate post challenge was associated with down-regulated tumor MUC1 and MHC molecules. Surprisingly, direct admixture of MUC1-expressing tumor with MUC1-hyperimmune T-cells could not prevent tumor outgrowth or MUC1 immunoediting, whereas ex vivo activation of the hyperimmune T-cells prior to tumor admixture rendered them curative. Therefore, surrogate T-cell preactivation outside the tumor bed, either in culture or by repetitive vaccination, can overcome tumor escape.

Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia

Importance Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon. Objective To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm. Design, Setting, and Participants This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio. Main Outcomes and Measures Odds ratio (OR) assessment for AID-directed therapies. Results Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug’s category was observed. Conclusions and Relevance In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti–tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

Comprehensively understanding fatigue in patients with myeloproliferative neoplasms.

Patients with myeloproliferative neoplasms (MPNs) experience a high persistence, prevalence, and severity of fatigue. There is currently only limited information regarding factors that contribute to fatigue in patients with MPNs.

Predictive testing for Alzheimer's disease: suicidal ideation in healthy participants.

The Risk Evaluation and Education for Alzheimer’s Disease (REVEAL) study1 showed that disclosure of apolipoprotein E (APOE) genotype, the most prevalent genetic risk factor for Alzheimer’s disease (AD),2 can be done safely, but with the caveats that participants in this study were carefully screened for psychiatric problems and those with suicidal ideation were excluded. Further, participants had extensive education, counseling, and followup, all steps that characterize a best practice but which are unlikely to occur outside of the protective walls of a research trial. In an effort to explore the perspectives of unscreened and unsheltered individuals who are likely to seek presymptomatic testing for AD we administered a questionnaire through an online website and found that nearly 12% of more than 4000 respondents (who had not undergone genetic testing), when asked how they might react if found to be a “high risk” for AD endorsed “seriously consider suicide.”3 With the advent of presymptomatic clinical trials, recruitment strategies include mass screening of individuals harboring genetic or biomarker evidence of high risk for AD.4–6 The present study explores possible demographic, cognitive, psychological, and personality characteristics that might identify a potential research participant as one at high risk of suicidal ideation by administering the same questionnaire to our longstanding research cohort, the Arizona APOE Cohort.7 METHODS As previously described3 this survey was developed from a 2-part interview with members of the Arizona APOE Cohort to get a sense of what features of presymptomatic AD testing seemed most relevant to them (eg, whether they felt any form of predictive testing for AD was appropriate, and how they might handle such information if it was disclosed to them). The final questionnaire comprised of yes/no and multiple choice questions addressing demographics, genetic testing, biomarker testing, and possible reactions to such information was then mailed to the remaining cognitively normal members of the cohort. Members of the Arizona APOE Cohort are cognitively normal residents of Maricopa County age 21 years and above recruited through local media ads, genotyped for APOE, and who undergo longitudinal neuropsychological assessment every 2 years.7 The participants agreed to have the results of the APOE test withheld from them as a precondition to their participation in this study. Neuropsychological tests encompassed general intellect, memory, executive, language, and visuospatial skills. Behavioral measures included the Personality Assessment Inventory (PAI), Hamilton Depression Scale, Beck Depression Rating Scale, Geriatric Depression Scale, and the Neuropsychiatric Inventory Questionnaire. Also included were paired subjective cognition questionnaires, the Multidimensional Assessment of Neurodegenerative Symptoms, self and informant versions.8 Personality was assessed with the Five Factor Neuroticism, Extraversion, and Openness (NEO) Inventory. Socioeconomic status was approximated in 3 ways. Income was estimated by zip code median income, major occupational background was quantified with the Dictionary of Occupational Titles General Educational Development (Reasoning, Mathematical, Language),9 and subjective community and socioeconomic standing was selfassessed by patients using the subjective scale of social status indicated on a 10 rung ladder (1 lowest, 10 highest). Members were asked 2 questions pertaining to consideration of suicide based on the following 2 scenarios. The first question addressed risk of AD based on genetic test results and a second question asked about presymptomatic AD based on biomarker test results. Members were eligible for analysis related to consideration of suicide if they answered both the genetic test and biomarker risk questions. Members not answering both questions were excluded from this analysis. Univariate analysis of responses to questions regarding reactions to presymptomatic testing including consideration of suicide was performed for each demographic and behavioral variable. Variables that were statistically significant on univariate Received for publication February 4, 2015; accepted April 10, 2015. From the *Department of Neurology; zCenter for Individualized Medicine; yClinical Studies Unit; 8Section of Biostatistics, Mayo Clinic Arizona, Scottsdale; wSandra Day O’Connor College of Law; #Center for Biology and Society, and School of Life Sciences, Arizona State University, Tempe, AZ; and zBanner Alzheimer Institute, Phoenix, AZ. Supported by NIA P30AG19610, R01AG031581, and the Arizona Alzheimer’s Research Consortium. In addition to these funding sources, R.J.C. also receives research funding support from Merck, and J.L. receives research support from Genentech and Novartis. The authors declare no conflicts of interest. Reprints: Richard J. Caselli, MD, Department of Neurology, Mayo Clinic Arizona, 13400 East Shea Blvd, Scottsdale, AZ 85259 (e-mail: Caselli.richard@mayo.edu). Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Website, www.alzheimerjournal.com. Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved. BRIEF REPORT

Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group.

The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients’ characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients’ characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

CO-EXISTING PROSTATE CANCER AND DIABETES MELLITUS: IMPLICATIONS FOR PATIENT OUTCOMES AND CARE

OBJECTIVE To investigate how diabetes mellitus (DM) impacts short-term overall survival (OS) for patients with prostate cancer and to examine how prostate cancer impacts glycemic control in DM. METHODS Patients with DM and prostate cancer newly diagnosed from 2007 to 2014 were identified from the institutional cancer registry and matched to patients with prostate cancer but no DM according to age and year of prostate cancer diagnosis. RESULTS The study included 276 cases and 276 controls; the mean age was 72 years, most (93%) were white, the most common Gleason score (52%) was 7, and the majority (56%) were tumor stage II. Patients with DM had a higher mean body mass index (P = .03). Alcohol use and performance status differed by group (P<.001), but the 2 groups otherwise were not significantly different. Among those with DM, the mean hemoglobin A1c (HbA1c) was 6.7%. In Kaplan-Meier survival analysis (median follow-up time, 43.7 months), the 5-year OS rates were estimated at 88% and 93% for patients with and without DM, respectively (hazard ratio, 1.64; 95% confidence interval, 0.77-3.46; P = .20). Mean glucose among patients with DM was significantly higher (P<.001) compared with non-DM patients, but mean HbA1c and glucose values did not change significantly over 1 year (P≥.13). CONCLUSION DM did not adversely impact survival in patients with prostate cancer. In addition, prostate cancer and its treatment did not affect glycemic control. Patients and their providers can be reassured that the concurrent diagnoses do not adversely interact to worsen short-term outcomes. ABBREVIATIONS DM = diabetes mellitus; HbA1c = hemoglobin A1c; OS = overall survival.

The role of sexuality symptoms in myeloproliferative neoplasm symptom burden and quality of life: An analysis by the MPN QOL International Study Group.

Patients with myeloproliferative neoplasms (MPNs) including polycythemia vera, essential thrombocythemia, and myelofibrosis, are faced with oppressive symptom profiles that compromise daily functioning and quality of life. Among these symptoms, sexuality‐related symptoms have emerged as particularly prominent and largely unaddressed. In the current study, the authors evaluated how sexuality symptoms from MPN relate to other patient characteristics, disease features, treatments, and symptoms.

Pegylated interferon alpha – 2a is clinically effective and tolerable in myeloproliferative neoplasm patients treated off clinical trial

Polycythemia vera, essential thrombocytosis, and myelofibrosis are chronic Philadelphia-negative myeloproliferative neoplasms that are characterized by clonal hematopoiesis, splenomegaly, risk of hemorrhagic and thrombotic sequelae, and profound symptom burden. We review the outcomes of 75 myeloproliferative neoplasm patients treated with pegylated interferon alpha 2a off study at an academic medical center. In the 56 treated polycythemia vera and essential thrombocytosis patients, a complete or partial response was obtained in 78.6% of patients per ELN/IWG-MRT revised criteria, with >80% of polycythemia vera patients becoming phlebotomy independent and 60% of essential thrombocytosis patients having platelet normalization with therapy. In the 19 treated myelofibrosis patients, stable disease was seen in 63.2% of patients. Vascular events occurred in 2/75 (2.6%) of treated patients while on therapy. Grade 3 toxicity was uncommon with leukopenia noted in 1 patient (1.3%). The most common adverse event overall was grade 1 fatigue in 18.7%. This retrospective single center analysis demonstrates pegylated interferon alpha 2a is active and well-tolerated therapy outside the support of a clinical trial. These results substantiate the previously reported efficacy of pegylated interferon alpha 2a in myeloproliferative neoplasms. Further prospective and randomized clinical trial data is required to better delineate pegylated interferon alpha 2as use in myeloproliferative disease, with emphasis placed on comprehensive molecular characterization, allelic burden quantification, and measurement of histologic response.