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PDF file - 39K, Response by schedule and diagnosis.

PDF file - 42K, Alvocidib pharmacokinetic parameters.

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma).Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted.Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses.Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. Clin Cancer Res; 20(22); 5652–62. ©2014 AACR.

Purpose: This phase I study was conducted to identify the maximum-tolerated dose (MTD) of alvocidib when combined with vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2. Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination.Experimental Design: Patients received vorinostat (200 mg orally, three times a day, for 14 days) on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-hour intravenous infusion, daily × 5; or a 30-minute loading infusion followed by a 4-hour maintenance infusion, weekly × 2. The alvocidib dose was escalated using a standard 3+3 design.Results: Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-minute loading infusion) followed by 20 mg/m2 (4-hour maintenance infusion) on days one and eight, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose-limiting toxicities (DLT) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved although 13 of 26 evaluable patients exhibited stable disease. Alvocidib seemed to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and downregulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent.Conclusions: Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules. Clin Cancer Res; 19(7); 1873–83. ©2013 AACR.

Purpose and Design: Mechanism(s) by which the multikinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal, and pancreatic adenocarcinoma cells has been defined.Results: Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal, and pancreatic adenocarcinoma cells in multiple short-term viability (24-96 h) and in long-term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase-8 and, to a lesser extent, by inhibition of caspase-9. Twenty-four hours after exposure, the activities of extracellular signal-regulated kinase 1/2, AKT, and nuclear factor-κB were only modestly modulated by sorafenib and vorinostat treatment. However, 24 h after exposure, sorafenib- and vorinostat-treated cells exhibited markedly diminished expression of c-FLIP-s, full-length BID, BCL-2, BCL-XL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK, and BAD. Expression of eIF2α S51A blocked sorafenib- and vorinostat-induced suppression of c-FLIP-s levels and overexpression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase-8. Knockdown of CD95 or FADD expression significantly reduced sorafenib/vorinostat-mediated lethality.Conclusions: These data show that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple antiapoptotic proteins and promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the proapoptotic signals from CD95 to promote mitochondrial dysfunction and death.

Supplementary Materials. Supplemental Table 1. C1D1 alvocidib pharmacokinetics by dose Supplemental Figure 1. Sample alvocidib concentration-time profile. Samples were obtained pre-infusion, immediately following infusion, and at 1, 2, 4, 8, 12, and 24 hours post-infusion.

Purpose: AZD6244 is a MEK1/2 inhibitor with significant preclinical activity in multiple myeloma cells. This phase II study used a two-stage Simon design to determine the AZD6244 response rate in patients with relapsed or refractory multiple myeloma.Experimental Design: AZD6244 (75 mg) was administered orally, twice a day, continuously for 28-day cycles. Response was evaluated after three cycles.Results: Thirty-six patients received therapy. The median age was 65 years (range: 43–81) and the median number of prior therapies was 5 (range: 2–11). The most common grade 3 and 4 toxicities included anemia, neutropenia, thrombocytopenia, diarrhea, and fatigue. Three deaths occurred possibly related to AZD6244 (2 due to sepsis, 1 due to acute kidney injury). After AZD6244 discontinuation, three additional deaths occurred due to disease progression. The response rate (CR + PR) was 5.6% with a mean duration of response of 4.95 months and median progression-free survival time of 3.52 months. One patient had a very good partial response (VGPR), 1 patient had a partial response, 17 patients had stable disease, 13 patients had progressive disease, and 4 patients could not be assessed for response. Pharmacodynamic studies revealed variable effects on bone marrow CD138+ cell MEK1/2 and ERK1/2 phosphorylation. The best clinical response, a prolonged VGPR, occurred in a patient with an MMSET translocation.Conclusions: Single-agent AZD6244 was tolerable and had minimal activity in this heavily pretreated population. Clin Cancer Res; 22(5); 1067–75. ©2015 AACR.

PDF file - 41K, Pharmacokinetic parameters of vorinostat and its major metabolites.

PDF file - 45K

Supplementary Table S1. RAS/BRAF mutation status

Supplementary Figures S1-S2; Supplementary Tables S1-S2.

Supplementary Figures S1-S18 from Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation

Introduction: Previous studies have shown that cannabis use is common in adults with sickle cell disease (SCD), and that many patients report using cannabis to treat pain. Methods: We performed a cross-sectional study of adults with SCD and compared daily users of cannabis with others using validated patient-reported measures of pain and quality of life as well as opioid and health care utilization. Results: Daily cannabis users with SCD had worse pain episode severity scores than others (56.7 vs. 48.8, p=0.02) yet had 1.8 fewer annual admissions (p=0.01) and 1.2 fewer annual emergency room (ER) visits (p=0.01), and similar amounts of opioids dispensed to others after matching for age, gender, SCD genotype, hydroxyurea use, and pain impact scores. Conclusions: We show that people with SCD with more severe pain crisis are more likely to use daily cannabis, yet have lower rates of hospital admission and ER use as compared with others with similar disease severity and pain impact. Randomized controlled trials should be performed.

More than one-third of adults with sickle cell disease (SCD) report using cannabis-based products. Many states list SCD or pain as qualifying conditions for medical marijuana, but there are few data to guide practitioners whether or whom should be certified. We postulated that certifying SCD patients may lead to a reduction in opioid use and/or health care utilization. Furthermore, we sought to identify clinical characteristics of patients who would request this intervention. Retrospective data obtained over the study period included rates of health care and opioid utilization for 6 months before certification and after certification. Patients who were certified but failed to obtain medical marijuana were compared with those who obtained it. Patients who were certified were invited to participate in a survey regarding their reasons for and thoughts on certification. Patients who were certified for medical marijuana were compared with 25 random patients who did not request certification. Fifty adults with SCD were certified for medical marijuana and 29 obtained it. Patients who obtained medical marijuana experienced a decrease in admission rates compared with those who did not and increased use of edible cannabis products. Neither group had changes in opioid use. Patients who were certified for medical marijuana had higher rates of baseline opioid use and illicit cannabis use compared with those who did not request certification. Most patients with SCD who requested medical marijuana were already using cannabis illicitly. Obtaining medical marijuana decreased inpatient hospitalizations.

BACKGROUND Chronic red blood cell transfusions reduce acute care utilization for sickle cell disease (SCD) pain. However, little is known about whether chronic transfusions treat or prevent the development of non-crisis pain. We investigated patient-report of pain in adults with SCD receiving chronic exchange transfusions (CET) compared to adults not on CET with similar disease characteristics. STUDY METHOD AND DESIGN Eleven participants receiving chronic exchange transfusion (CET) for at least one year were compared to 33 participants not receiving CET. Participants completed validated patient-reported outcomes regarding pain impact and quality of life at regularly scheduled visits or before CET. One year of health care utilization and opioid prescriptions were examined. RESULTS After 1:1 propensity matching was performed for age, genotype, WBC and neutrophil counts, patients on CET had lower Pain Impact scores (-5.1, p = 0.03) and higher Neuropathic (7.4, p < 0.001) and Nociceptive Pain Quality (3.7, p < 0.001) scores, all indicating worse pain. However, CET was associated with a reduction in annual all cause admissions (-3.1, p < 0.001), length of stay (-2.1 days, p < 0.001) and ED visits (-2.7, p < 0.001). CET was not associated with differences in opioids dispensed. CONCLUSIONS After adjusting for disease characteristics, CET was associated with worse pain impact and neuropathic and nociceptive pain quality, lower health care utilization and with similar levels of opioids dispensed. This data suggest that CET may reduce hospitalizations for acute pain but may not adequately treat nociceptive or neuropathic pain in SCD.

Purpose A novel strategy for management of acute pain associated with sickle cell disease (SCD), referred to as the oral tier approach, is described. Summary SCD is an inherited blood disorder characterized by episodic acute pain known as vaso-occlusive crisis (VOC), which is the most common reason for emergency department visits and hospital admissions in patients with SCD; these patients are often treated with parenteral opioids on admission and then transitioned to oral opioids prior to discharge. In this report, experience with use of the oral tier approach in 3 patients with SCD hospitalized for management of VOC is reported. As per usual practice, acute pain was initially managed with parenteral opioids via patient-controlled analgesia (PCA). Once pain control was established, an oral tier was added. The oral tier consisted of 3 orders. The first order was for an oral opioid, to be administered every 3 hours on a scheduled basis; however, the patient could refuse 1 or more of these scheduled doses. Two additional orders specified that the patients could receive additional oral opioids in incremental doses for moderate (grade 4–7) or severe (grade 8–10) pain if appropriate. To facilitate transition to an oral regimen with which the patients might be discharged, they were encouraged to use oral opioids in preference to parenteral opioids. Opioid usage and average daily pain scores for the 3 patients are reported. Conclusion Healthcare providers can use the oral tier approach to facilitate rapid inpatient conversion from i.v. PCA to oral opioids while providing adequate pain control in patients with SCD who develop VOC.

We report the results of a phase 1 dose-escalation study of belinostat and bortezomib in adult patients with acute leukemia or MDS or CML with blast crisis. Thirty-eight patients received IV belinostat days 1-5 and 8-12 with IV bortezomib days 1, 4, 8, and 11 every 21 days. QTc prolongation was the only identified DLT. The RP2Ds were 1.3 mg/m(2) bortezomib and 1000 mg/m(2) belinostat. One patient with highly refractory MLL-ENL rearranged biphenotypic AML with multiple karyotypic aberrations had a complete pathologic and karyotypic response. One patient with post-MPN AML remained on study with stable disease (SD) for 32 cycles. Whole-exome sequencing revealed no aberrations in the first patient and a hyper-mutator genotype in the second. Eighteen patients had a best response of SD. We conclude that this treatment strategy is feasible but has limited activity in this population. Nevertheless, the factors that predict exceptional responses to this strategy warrant further investigation.

Introduction: Legal access to marijuana, most frequently as “medical marijuana,” is becoming more common in the United States, but most states do not specify sickle cell disease as a qualifying condition. We were aware that some of our patients living with sickle cell disease used illicit marijuana, and we sought more information about this. Materials and Methods: We practice at an urban, academic medical center and provide primary, secondary, and tertiary care for ∼130 adults living with sickle cell disease. We surveyed our patients with a brief, anonymous, paper-and-pen instrument. We reviewed institutional records for clinically driven urine drug testing. We tracked patient requests for certification for medical marijuana. Results: Among 58 patients surveyed, 42% reported marijuana use within the past 2 years. Among users, most endorsed five medicinal indications; a minority reported recreational use. Among 57 patients who had at least one urine drug test, 18% tested positive for cannabinoids only, 12% tested positive for cocaine and/or phencyclidine only, and 5% tested positive for both cannabinoids and cocaine/phencyclidine. Subsequent to these studies, sickle cell disease became a qualifying condition for medical marijuana in our state. In the interval ∼1.5 years, 44 patients have requested certification. Conclusion: Our findings and those of others create a rationale for research into the possible therapeutic effects of marijuana or cannabinoids, the presumed active constituents of marijuana, in sickle cell disease. Explicit inclusion of sickle cell disease as a qualifying condition for medical marijuana might reduce illicit marijuana use and related risks and costs to both persons living with sickle cell disease and society.

Background. Patients with SCD now usually live well into adulthood. Whereas transitions into adulthood are now often studied, little is published about aging beyond the transition period. We therefore studied age-associated SCD differences in utilization, pain, and psychosocial variables.Methods. Subjects were 232 adults in the Pain in Sickle Cell Epidemiology Study (PiSCES). Data included demographics, comorbidity, and psychosocial measures. SCD-related pain and health care utilization were recorded in diaries. We compared 3 age groups: 16–25 (transition), 26–36 (younger adults), and 37–64 (older adults) years.Results. Compared to the 2 adult groups, the transition group reported fewer physical challenges via comorbidities, somatic complaints, and pain frequency, though pain intensity did not differ on crisis or noncrisis pain days. The transition group utilized opioids less often, made fewer ambulatory visits, and had better quality of life, but these differences disappeared after adjusting for pain and comorbidities. However, the transition group reported more use of behavioral coping strategies.Conclusion. We found fewer biological challenges, visits, and better quality of life, in transition-aged versus older adults with SCD, but more behavioral coping. Further study is required to determine whether age-appropriate health care, behavioral, or other interventions could improve age-specific life challenges of patients with SCD.

Background Despite the clinical significance of red blood cell (RBC) alloantibodies, there are currently no laboratory tests available to predict which patients may be at risk of antibody formation after transfusion exposure. Given their phagocytic and inflammatory functions, we hypothesized that differences in circulating monocytes may play a role in alloimmunization. Study design and methods Forty-two adults with sickle cell disease (SCD) were recruited, with data extracted from the electronic medical record and peripheral blood analyzed by flow cytometry for total monocytes, monocyte subsets (CD14 high/CD16 low+ classical monocytes, CD14 high/CD16 high+ intermediate monocytes, and CD14 intermediate/CD16 high+ non-classical/inflammatory monocytes), and FcγR1 (CD64) expression. Thirteen "non-responder" patients (non-alloimmunized patients with documented RBC transfusion at the study institution) were compared to 20 alloimmunized "responder" patients, who had a total of 44 RBC alloantibodies identified. Results There were no significant differences in the percentages of total monocytes, monocyte subsets, or measured cytokines between non-responders and responders. However, non-responders had higher CD64 expression on classical monocytes (MFI mean 3424 ± standard deviation 1141) compared to responders (MFI mean 2285 ± 1501), p = 0.029, and on intermediate monocytes (MFI mean 3720 ± 1191) compared to responders (MFI mean 2497 ± 1640), p = 0.033. Conclusions Monocytes and the inflammatory milieu increasingly are being appreciated to play a role in some complications of SCD. The differences in FcγR1 expression on monocyte subsets noted between responders and non-responders, which cannot be directly explained by the serum cytokines evaluated, warrant further investigation.

// Andrew Poklepovic 1, 2 , Sarah Gordon 2 , Danielle A. Shafer 1, 2 , John D. Roberts 1, 2, 7 , Prithviraj Bose 1, 2, 8 , Charles E. Geyer Jr. 1, 2 , William P. McGuire 1, 2 , Mary Beth Tombes 1 , Ellen Shrader 1 , Katie Strickler 1 , Maria Quigley 1 , Wen Wan 1, 3 , Maciej Kmieciak 1 , H. Davis Massey 4 , Laurence Booth 5 , Richard G. Moran 1, 6 , Paul Dent 1, 5 1 Department of Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA 2 Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia, USA 3 Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA 4 Department of Pathology, Virginia Commonwealth University, Richmond, Virginia, USA 5 Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia, USA 6 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, USA 7 Current address: Department of Medical Oncology, Yale School of Medicine, New Haven, Connecticut, USA 8 Current address: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to: Andrew Poklepovic, email: andrew.poklepovic@vcuhealth.org Keywords: clinical trial, pemetrexed, solid tumors, sorafenib Received: February 26, 2016 Accepted: April 16, 2016 Published: May 18, 2016 ABSTRACT Purpose: To determine if combination treatment with pemetrexed and sorafenib is safe and tolerable in patients with advanced solid tumors. Results: Thirty-seven patients were enrolled and 36 patients were treated (24 in cohort A; 12 in cohort B). The cohort A dose schedule resulted in problematic cumulative toxicity, while the cohort B dose schedule was found to be more tolerable. The maximum tolerated dose (MTD) was pemetrexed 750 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Because dosing delays and modifications were associated with the MTD, the recommended phase II dose was declared to be pemetrexed 500 mg/m 2 every 14 days with oral sorafenib 400 mg given twice daily on days 1–5. Thirty-three patients were evaluated for antitumor activity. One complete response and 4 partial responses were observed (15% overall response rate). Stable disease was seen in 15 patients (45%). Four patients had a continued response at 6 months, including 2 of 5 patients with triple-negative breast cancer. Experimental Design: A phase I trial employing a standard 3 + 3 design was conducted in patients with advanced solid tumors. Cohort A involved a novel dose escalation schema exploring doses of pemetrexed every 14 days with continuous sorafenib. Cohort B involved a modified schedule of sorafenib dosing on days 1–5 of each 14-day pemetrexed cycle. Radiographic assessments were conducted every 8 weeks. Conclusions: Pemetrexed and intermittent sorafenib therapy is a safe and tolerable combination for patients, with promising activity seen in patients with breast cancer.

// hatem h. soliman 1 , susan e. minton 1 , hyo sook han 1 , roohi ismail-khan 1 , anthony neuger 1 , fatema khambati 1 , david noyes 1 , richard lush 1 , alberto a. chiappori 1 , john d. roberts 2 , charles link 3 , nicholas n. vahanian 3 , mario mautino 3 , howard streicher 4 , daniel m. sullivan 1 and scott j. antonia 1 1 h. lee moffitt cancer center and research institute, tampa, florida, usa 2 massey cancer center, virginia commonwealth university, richmond, virginia, usa 3 newlink genetics inc., ames, iowa, usa 4 cancer therapeutics evaluation program, national cancer institute, bethesda, maryland, usa correspondence to: hatem h. soliman, email: // keywords : indoleamine 2,3 dioxygenase, 1-methyl-d-tryptophan, indoximod, immunomodulator received : february 11, 2016 accepted : march 10, 2016 published : march 20, 2016 abstract purpose: indoximod is an oral inhibitor of the indoleamine 2,3-dioxygenase pathway, which causes tumor-mediated immunosuppression. primary endpoints were maximum tolerated dose (mtd) and toxicity for indoximod in patients with advanced solid tumors. secondary endpoints included response rates, pharmacokinetics, and immune correlates. experimental design: our 3+3 phase i trial comprised 10 dose levels (200, 300, 400, 600, and 800 mg once/day; 600, 800, 1200, 1600, and 2000 mg twice/day). inclusion criteria were measurable metastatic solid malignancy, age ≥18 years, and adequate organ/marrow function. exclusion criteria were chemotherapy ≤ 3 weeks prior, untreated brain metastases, autoimmune disease, or malabsorption. results: in 48 patients, mtd was not reached at 2000 mg twice/day. at 200 mg once/day, 3 patients previously treated with checkpoint inhibitors developed hypophysitis. five patients showed stable disease >6 months. indoximod plasma auc and cmax plateaued above 1200mg. cmax (~12 μm at 2000 mg twice/day) occurred at 2.9 hours, and half-life was 10.5 hours. c reactive protein (crp) levels increased across multiple dose levels. conclusions: indoximod was safe at doses up to 2000 mg orally twice/day. best response was stable disease >6 months in 5 patients. induction of hypophysitis, increased tumor antigen autoantibodies and crp levels were observed.

Background Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. Patients and methods In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. Results Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28:26, median age 56 years (range 20–82 years), ECOG performance status 0:1:2 = 24:28:2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3–14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1–7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. Conclusion Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.

In 2011 Yale New Haven Hospital, in response to high utilization of acute care services and widespread patient and health care personnel dissatisfaction, set out to improve its care of adults living with sickle cell disease. Re-organization components included recruitment of additional personnel; re-locating inpatients to a single nursing unit; reducing the number of involved providers; personalized care plans for pain management; setting limits upon access to parenteral opioids; and an emphasis upon clinic visits focused upon home management of pain as well as specialty and primary care. Outcomes included dramatic reductions in inpatient days (79%), emergency department visits (63%), and hospitalizations (53%); an increase in outpatient visits (31%); and a decrease in costs (49%). Providers and nurses viewed the re-organization and outcomes positively. Most patients reported improvements in pain control and life style; many patients thought the re-organization process was unfair. Their primary complaint was a lack of shared decision-making. We attribute the contrast in these perspectives to the inherent difficulties of managing recurrent acute and chronic pain with opioids, especially within the context of the imbalance in wellness, power, and privilege between persons living with sickle cell disease, predominantly persons of color and poor socio-economic status, and health care organizations and their personnel.

DNA methylation plays a key role in X-chromosome inactivation (XCI), a process that achieves dosage compensation for X-encoded gene products between mammalian female and male cells. However, differential sex chromosome dosage complicates genome-wide epigenomic assessments, and the X chromosome is frequently excluded from female-to-male comparative analyses. Using the X chromosome in the sexually dimorphic mouse liver as a model, we provide a general framework for comparing base-resolution DNA methylation patterns across samples that have different chromosome numbers and ask at a systematic level if predictions by historical analyses of X-linked DNA methylation hold true at a base-resolution chromosome-wide level. We demonstrate that sex-specific methylation patterns on the X chromosome largely reflect the effects of XCI. While our observations concur with longstanding observations of XCI at promoter-proximal CpG islands, we provide evidence that sex-specific DNA methylation differences are not limited to CpG island boundaries. Moreover, these data support a model in which maintenance of CpG islands in the inactive state does not require complete regional methylation. Further, we validate an intragenic non-CpG methylation signature in genes escaping XCI in mouse liver. Our analyses provide insight into underlying methylation patterns that should be considered when assessing sex differences in genome-wide methylation analyses.

Background Pain diary assessment in sickle cell disease (SCD) may be expensive and impose a high respondent burden. Objective To report whether intermittent assessment could substitute for continuous daily pain assessment in SCD. Design Prospective cohort study. Setting Academic and community practices in Virginia. Patients. A total of 125 SCD patients age 16 years or older in the Pain in Sickle Cell Epidemiology Study. Measurements. Using pain measures that summarized all diaries as the gold standard, we tested the statistical equivalence of four alternative strategies that summarized diaries only from the week prior or the month prior to study completion; one week per month; or one day per week (random day). Summary measures included percent pain days, percent crisis days (self-defined), mean pain (0-9 Likert scale) on all days, and mean pain on pain days. Equivalence tests included comparisons of means, regression intercepts, and slopes, as well as measurement of R2. Results Compared with the gold standard, the one-day-per-week and one-week-per-month strategies yielded statistically equivalent means of six summary pain measures, and the week prior and month prior yielded equivalent means as some of the measures. Regression showed statistically equivalent slopes and intercepts to the gold standard using one-day-per-week and one-week-per-month strategies for percent pain days and percent crisis days, but almost no other equivalence. R2 values ranged from 0.64 to 0.989. Conclusions It is possible to simulate five- to six-month daily assessment of pain in SCD. Either one-day-per-week or one-week-per-month assessment yields an equivalent mean and fair regression equivalence.

A phase 1 study was conducted to determine the dose-limiting toxicities and maximum tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory CLL/SLL or B- or T-cell lymphoma. Eighteen treated patients were evaluable for response. The MTD was 1.3 mg/m2 bortezomib and 10 mg/m2 romidepsin; median treatment duration was 3 cycles at this dose. The dose-limiting toxicities were grade 3 fatigue, vomiting, and chills. Two patients had partial responses, one lasting >2 years, 8 had stable disease, and 8 had progressive disease. The median duration of stable disease was 3.5 cycles. Correlative studies examining expression of NF-κB, XIAP, Bcl-xL, and Bim yielded variable results. The safety profile was consistent with that reported for single-agent bortezomib and romidepsin. This regimen has modest activity in heavily pre-treated patients with relapsed/refractory CLL or B- or T-cell lymphoma. NCT00963274.

Purpose: This phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, Waldenstrom macroglobulinemia, and mantle cell lymphoma). Experimental Design: Patients received bortezomib (intravenous push), followed by alvocidib (1-hour infusion), on days 1, 4, 8, and 11 of a 21-day treatment cycle. Patients experiencing responses or stable disease continued on treatment at the investigator's discretion. A standard 3+3 dose-escalation design was used to identify the MTD based on DLTs, and pharmacokinetic and pharmacodynamic studies were conducted. Results: A total of 44 patients were enrolled, with 39 patients assessed for response. The MTD was established as 1.3 mg/m2 for bortezomib and 40 mg/m2 for alvocidib. The most common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. The most common nonhematologic toxicities included diarrhea, fatigue, and sensory neuropathy. Three complete remissions (8%) and 10 partial remissions (26%) were observed for a total response rate of 33%. Pharmacokinetic findings with the current dosing regimen were consistent with the comparable literature and the hybrid dosing regimen. Pharmacodynamic study results did not correlate with clinical responses. Conclusions: The combination of bortezomib and alvocidib is tolerable, and an MTD has been established for this schedule. The regimen appears to be efficacious in patients with relapsed/refractory multiple myeloma or indolent non-Hodgkin lymphoma. As the nonhybrid regimen is less cumbersome than the previous hybrid dosing schedule regimen, the current schedule is recommended for successor studies. Clin Cancer Res; 20(22); 5652–62. ©2014 AACR.

The fraction of gauche conformers of N,N-dimethylsuccinamic acid (1) and its Li(+), Na(+), K(+), Mg(2+), Ca(2+), and N(Bu)4(+) salts were estimated in DMSO and D2O solution by comparing the experimental vicinal proton-proton couplings determined by (1)H NMR spectroscopy with those calculated using the Haasnoot, de Leeuw, and Altona (HLA) equation. In DMSO, the gauche preferences were found to increase with decreasing Ahrens ionic radius of the metal counterion. The same trend was not seen in D2O, where the gauche fraction for all of the metallic salts were estimated to be approximately statistical or less. This highlights the importance of metal chelation on the conformation of organic molecules in polar aprotic media, which has implications for protein folding.

Background: Hospital readmission rates and acute care utilization among adults with sickle cell disease (SCD) are almost twice the rates of children. Adult patients may have complex medical and psychosocial needs that are not adequately addressed in fragmented healthcare systems. Few systems have implemented evidence-based, comprehensive care for SCD adults, shown to improve both medical and psychosocial outcomes in chronic diseases. Case management (CM) and community health workers (CHWs) are two evidence-based health management strategies that can help reduce health risks, reduce readmission rates, and improve patient-provider relationships. Methods: After years of attempting adult SCD CM with two MDs and one advanced practice provider (APP), Virginia Commonwealth University Medical Center (VCU) built upon a pilot study of CM and CHWs and implemented a multi-disciplinary Adult Sickle Cell Medical Home that assigned one of two CHWs for CM of the 50 highest SCD adult utilizers ranked by calendar year (CY) 2017 VCU charges, then by CY 2017 inpatient days. CHWs followed patients in and out of the hospital, and met with them at home. They were joined by a social worker who provided CM and behavioral therapy, an additional APP, and a project manager. This team met weekly. Medical Home leaders and quality improvement (QI) specialists enlisted other periodic caregivers to form QI teams with Medical Home workers focusing on behavioral health, ambulatory management, inpatient management, and emergency department (ED) management. A prior authorization specialist handled administrative access to opioids. Evaluation compared utilization during CY 2017 (pre-intervention) versus CY 2018 (intervention). For all patients we compared the average 30-day readmission rate, the average length of stay (ALOS), the average 3-Day ED return rate, the number of ED discharges, the numbers of inpatient days, inpatient discharges, and outpatient visits, the number of patients who used the ED, and total VCU charges. For the 50 highest utilizers, we compared the 30-day readmission rate, ALOS, total inpatient days and total VCU charges. VCU had no ambulatory SCD infusion unit, and the VCU ED did not have a special SCD rapid triage protocol. There was no control group. Analysis consisted of chi square and paired and unpaired t-tests. Results: Among 567 SCD adults (Table), including 231 males and 336 females, ages 18 - 80, comparing pre-intervention to intervention, average utilization and VCU charges were either numerically or statistically significantly reduced, with the exception of outpatient visits, which remained flat. For the 50 highest utilizers, mean 30-day readmission rates were flat (45.98% vs 44.35%, p=0.7257), ALOS was significantly reduced (6.1 days vs 4.8 days, p Conclusions: At VCU, a multi-disciplinary Adult Sickle Cell Medical Home that featured intensive CM and CHWs, but no infusion center or rapid ED triage, reduced annual utilization for adult SCD patients. CM program elements that were most effective should be studied in the future. A randomized controlled trial of CM and CHWs would strengthen evidence of their efficacy in improving utilization. Table. Disclosures Smith: Novartis: Consultancy, Honoraria. Lipato:Novartis: Honoraria. Roberts:Truven Health Analytics: Consultancy; Community Health Network of Connecticut: Consultancy.

Introduction: More than half of adults with sickle cell disease (SCD) develop chronic pain which is present at baseline and associated with higher levels of opioid use, worse clinical outcomes, and worse quality of life. This pain was previously thought to be nociceptive pain, or pain due to the stimulation of neurons by tissue damage or inflammation. Recent studies have shown that people with SCD can also have neuropathic pain, which is pain due to dysfunctional peripheral or central nerves which either have a reduced threshold for firing (sensitization) or fire spontaneously. We hypothesized that validated patient reported outcome measures could be used to distinguish types of chronic pain in adults with SCD. Methods: Patients enrolled were adults with any genotype of SCD who receive care in the Adult Sickle Cell Program at Yale New Haven Hospital, were in their usual state of health and denied the presence of any acute pain. These patients also reported that any pain they experienced in the past 7 days was their regular baseline pain. Blood was drawn and patients were asked to complete the Adult Sickle Cell Quality of Life Information System (ASCQ-Me) domains for pain episode frequency and severity, pain impact, social impact, emotional impact, sleep, and stiffness and the Patient Reported Outcomes Measurement Information System (PROMIS) domains for neuropathic pain, nociceptive pain and anxiety. The ASCQ-Me pain episode frequency and severity domains reference the past 12 months, social impact past 30 days, other domains the past 7 days. Significant pain impact was defined as having a score that is worse than the median score of the ASCQ-me reference population of adults with SCD. Neuropathic pain was defined as a score of 55 or higher which has high sensitivity for the presence of neuropathic pain. Health care and opioid utilization data was obtained from the electronic medical record from 1/1/2016 to 12/31/2016. Means and standard deviations for the groups were compared using an analysis of variance test followed by pairwise comparisons for parametric data and medians and quartiles were compared using the Kruskal Wallis test for non-parametric data. Results: Of the 48 patients were enrolled, 21 (44%) were categorized as not having significant pain impact and not having neuropathic pain quality (Less Than Average Impact), 12 (25%) were categorized as having significant pain impact but no neuropathic pain quality (Nociceptive), and 15 (31%) were categorized as having both pain with significant pain impact and neuropathic pain quality (Neuropathic) (Figure 1). Patients with neuropathic pain also had more severe mean pain impact and nociceptive pain than the reference populations (43.3 95% CI 40.6 - 46.0 p Conclusion: Of patients with SCD who reported worse than average pain impact, 56% had neuropathic pain and 44% did not. This suggests that baseline pain in SCD is heterogenous and may be attributed to different pathologies, some to tissue damage or inflammation, and some to neurodysfunction. Patients with nociceptive pain only had high rates of admissions and ED use and showed a trend of having more inflammation and being more anemic which may suggest higher levels of ongoing hemolysis, though this needs to be studied further. Those with neuropathic pain did not show high ED use and but higher levels of anxiety and worse sleep, possibly suggesting central sensitization. Recognizing different types of pain in SCD may improve pain treatment by allowing for targeted therapy toward distinct pain pathophysiology. Disclosures Roberts: Community Health Network of Connecticut: Consultancy; Truven Health Analytics: Consultancy.

Introduction: Adults living with sickle cell disease (SCD) have high utilization of emergency departments (ED) and hospitals, and utilization typically is skewed with a subgroup with very high utilization. We sought to promote a shift from ED/hospital utilization to ambulatory care (Amb) services in our state through ED/hospital visit-prompted communication with ED/hospital and Amb practitioners. Methods: The Community Health Network of Connecticut, Inc. (CHNCT) is the medical administrative services organization (contractor) for the physical health benefit of the state's Medicaid Program, HUSKY Health. Among HUSKY members ages 16 years and older (16+) with Medicaid-only insurance and with at least one Medicaid payment claim with a primary or secondary ICD-9/ICD-10 diagnosis of sickle cell disease from Feb 28, 2016 thru Feb 25, 2017, we identified high ED/hospital utilizing members. CHNCT monitored high utilizing 16+ member ED/hospital visits in real time using admission, discharge, and transfer data, and provided practitioner team members with individual member utilization data (mUD) to be shared via telephone contact with ED/hospital and Amb practitioners when 16+ members visited an ED or were hospitalized. Shared mUD included numbers of ED/hospital visits, names of ED/hospital facilities visited, and information about Amb services visits. ED/hospital practitioners were encouraged to advise members to seek regular care from one of the state's hospital-based SCD programs or other practitioners. No formal hypotheses were declared for testing for statistical significance. Differences in utilization were compared with the Mann-Whitney U test. Results: We identified 705 16+ members living with SCD. In phase 1, high utilizing members (HUM1) were defined as individuals with 12+ ED visits or 8+ hospital visits in the reference year. We identified 45 (6%) HUM1 who accounted for approximately half of all 16+ member ED visits [1364 (56%) of 2436] and hospital visits [368 (47%) of 788]. Among HUM1, the distribution of visits was highly skewed with individual HUM1 accounting for up to 184 ED and up to 27 hospital visits. HUM1 used up to 27 facilities, some out-of-state. In phase 2, we identified an additional 47 members (HUM2) with 6+ ED visits or 4+ hospital visits in the reference year. From Aug 2017 to Jun 2019, CHNCT notified clinical team members of 504 ED/hospital visits involving 51 HUM, and clinical team members shared mUD with practitioners on 342 (68%) occasions. For data analysis, the HUM1 pre-information sharing period was defined as 1/1/16 thru 11/9/16; the post-information sharing period was defined as 7/11/16 thru 7/10/17. For HUM2, pre- 6/6/17 thru 6/5/18, and post- 6/6/18 thru 12/13/18. As the duration of time periods differed, data were expressed as visits (or dollars) per year. ED visit rates fell by one third for HUM1 (33%), but were little changed for HUM2 (see Table 1). Hospitalization rates fell by about one third for both HUM1 (39%) and HUM2 (32%). P values for changes in ED visit rates for HUM1 and HUM2 and in hospitalization rates for HUM2 ranged from 0.005 to 0.01. Medicaid ED and hospital expenditures per year fell more than one third (35%), or about $2.2M. Conclusions: Six percent of CT Medicaid members 16 years and older living with SCD accounted for approximately half of all those members ED and hospital utilization. Visit-prompted sharing of utilization data of these high utilizing members with ED, hospital, and Amb practitioners coupled with a recommendation to advise these members to seek regular Amb services led to decreases in ED visits, hospitalizations, and total expenditures by about one third. The same intervention applied to a cohort of the next highest utilizing members resulted in a similar change in hospitalizations but minimal change in ED visits. Medicaid expenditures for ED visits and hospitalizations for the groups combined fell by about one third, or $2.2 million per year. It will be important to ascertain whether information sharing changed utilization of Amb services. This quality improvement project is HIPAA compliant; no institutional review board approval was required. Table Disclosures Roberts: Community Health Network of Connecticut: Consultancy; Truven Health Analytics: Consultancy. Andemariam:Emmaus: Membership on an entity's Board of Directors or advisory committees; New Health Sciences: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Other: DSMB Member; Imara: Research Funding; Cyclerion: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Community Health Network of Connecticut: Consultancy. Latham:Community Health Network of Connecticut: Employment. Cyr:Community Health Network of Connecticut: Employment. Magras:Community Health Network of Connecticut: Employment.

The conformational preferences of N,N-dimethylsuccinamic acid and its Li(+) salt were estimated by comparing the respective experimental NMR vicinal proton-proton coupling constants to semiempirical coupling constants for each staggered conformer as derived by the Haasnoot-De Leeuw-Altona method. The strong gauche preferences for the Li(+) salts clearly depended more on the solvents' hydrogen-bond donating strength (α) than on their hydrogen-bond accepting (β) counterpart, where α and β are the corresponding Kamlet-Taft parameters.

The conformational populations of cis-1,3- cyclopentanedicarboxylic acid (1) and its mono- and dianion were established in DMSO solution by comparing the vicinal proton−proton coupling constants (^3JHH) obtained in solution to their theoretical counterparts. Geometries used for ^3JHH theoretical estimation (using Karplus-type equations) were obtained from optimized structures at the B3LYP/6-31G-(2d,2p) level. The diacid (1) adopted many conformations, whereas the ionized species (1A mono- and 1B dianion) assumed single conformations. A downfield chemical shift of 19.45 ppm (Δδ_H = 7.43 ppm) observed at −60 °C was indicative of intramolecular hydrogen bonding in 1A, which was later corroborated by determining the ratio of the first (K_1) to the second (K_2) ionization constants. K_1/K_2 in DMSO (1.3 × 10^7) was significantly larger than the value in water (2 × 10). In addition, K_1/K_E = 200 (where K_E is the acidity constant of the monomethylester of 1) was greater than the intramolecular hydrogen bonding threshold value of 2. The calculated intramolecular hydrogen bond strength of 1A was ∼3.1 kcal mol^(−1), which is ∼2.7 kcal mol^(−1) more stable than the values for cis- 1,3-cyclohexanedicarboxylic acid (2A). Thus, the relative energies of intramolecular hydrogen bonding in the monoanions 1A and 2A suggests that 1,3-diaxial conformers are more favored for cyclopentane than for cyclohexane rings.

Purpose Preclinical studies in human melanoma cell lines and murine xenograft tumor models suggest that the proteasome inhibitor bortezomib enhances the activity of the cytotoxic agent dacarbazine. We performed a phase I trial of bortezomib and dacarbazine in melanoma, soft tissue sarcoma, and amine precursor uptake and decarboxylation tumors. The primary objective was to identify recommended phase II doses for the combination. Experimental design Bortezomib and dacarbazine were both administered intravenously once weekly. All patients received prophylactic antiemetics. Dose escalation proceeded using a standard 3 + 3 design. Response was assessed according to NCI RECIST v1.0. Results Twenty eight patients were enrolled to six dose levels. Bortezomib 1.6 mg/m2 and dacarbazine 580 mg/m2 are the recommended phase II weekly doses. The combination was generally well tolerated. Among 15 patients with melanoma there was one durable complete response in a patient with an exon-11 cKIT mutation, and one partial response. Among 12 patients with soft tissue sarcoma there was one partial response. Conclusions Bortezomib 1.6 mg/m2 and dacarbazine 580 mg/m2 administered intravenously once weekly is well tolerated and has at least minimal activity in melanoma and soft tissue sarcoma.

Classical phase II trial designs, including “adaptive” designs, require the prospective characterization of tumors. We propose a 2-stage phase II design that allows for characterization of tumors and selection of a tumor subtype of interest at the conclusion of stage 1. The stage 2 objective is either a classical estimate of the response rate for either the tumor or a subtype, or a formal test of the hypothesis that the response rate for a subtype is greater than the overall response rate. Considering likely scenarios, stage 1 sample sizes approximately range from 20 to 100 with a usual size of 50. This compares with typical classical stage 1 sample sizes of 12 to 30. Total sample sizes range from sizes identical to classical designs (tens to scores) to large sizes typical of phase III trials in metastatic disease (hundreds). Our design is more efficient than previous adaptive designs because it allows for the selection of a tumor subtype of interest on the basis of results from stage 1. It complements classical phase II and phase III designs in which investigators compare different treatments in similar patients and tumors by positioning a treatment as fixed (control) and using tumor subtype as the variable of interest. Clin Cancer Res; 17(17); 5538–45. ©2011 AACR.

Purpose: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma, and mantle cell lymphoma). Experimental Design: Patients received bortezomib by intravenous push on days 1, 4, 8, and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion. Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and pharmacodynamic studies were conducted. Results: Sixteen patients were treated. The MTD was established as 1.3 mg/m2 for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%). Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. Conclusions: The combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen appears active in patients with relapsed and/or refractory multiple myeloma or non–Hodgkin's lymphoma, justifying phase II studies to determine the activity of this regimen more definitively. Clin Cancer Res; 17(10); 3388–97. ©2011 AACR.