Introduction Inflammation, marked by a "cytokine storm" of circulating proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor- α (TNF-α), and C-reactive protein (CRP), and increases in intracellular NLRP3 inflammasomes is an important component of sickle cell disease (SCD). Although current treatments have limited anti-inflammatory effects, targeting inflammation is a promising but unrealized treatment approach. Colchicine, a tubulin inhibitor, is a promising anti-inflammatory agent for SCD. It is useful in gout, familial Mediterranean fever, pericarditis and other inflammatory diseases. In these contexts, it often reduces the same inflammatory proteins and cellular components that are elevated in SCD. We sought preliminary evidence for colchicine as an anti-inflammatory treatment for SCD. Methods Humanized sickle mice (HbSS-BERK) are knockout for murine α and β globins and express human α and βS globins (>99% βS) on a mixed genetic background. HbSS-BERK have severe disease including hyperalgesia. Experiments were performed following protocols approved by the Institutional Animal Care and Use Committee. Female mice of ~ 3.5 months of age received either colchicine 100 µg/kg body weight or vehicle (phosphate-buffered saline) intraperitoneally daily for 14 d. Pain-related behavior testing was performed before treatment and 1 h, 24 h, 7 d, and 14 d after the 1st dose of study agent. Mechanical hyperalgesia was tested by paw withdrawal frequency (PWF) in response to the application of a von Frey monofilament to the mid-plantar surface of the hind paw. Musculoskeletal/deep tissue hyperalgesia was tested by measurement of the peak tensile force exerted by a forelimb upon traction. Cold hyperalgesia was tested by PWF/2 min upon placement of mice on a cold plate maintained at ~4°C. After the 14 d of dosing, mice were euthanized; blood was collected; mice were necropsied; and 4 mm diameter punch biopsies of dorsal skin were harvested and incubated in culture medium for 24 hours to allow for release of proteins into the skin secretagogue Plasma serum amyloid-P (SAP) and IL-6 were analyzed with enzyme-linked immunosorbent assays. Limited blood volumes prevented assay of other circulating proteins. Automated and manual cytometry were used to characterize circulating blood cells. Skin secretagogue was assayed for cytokines IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, monocyte chemoattractant protein 1 (MCP-1), interferon gamma (IFN-γ), TNF-α, macrophage inflammatory protein-1 alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and regulated on activation, normal T-cell expressed and secreted protein (RANTES) using Q-PlexTM microarray. Data was analyzed using conventional descriptive statistics. Results As per usual laboratory practice, we considered mouse circulating SAP levels as surrogate for human CRP levels. Following 14 d of dosing, plasma IL-6 levels were ~67% lower (~130 v ~48 µg/g protein; p<0.01), and plasma SAP levels were ~45% lower (~33 v ~18 µg/g protein; p<0.01) in colchicine-treated mice. There were no significant differences in blood cell parameters. Concentrations of IL-3, IL-1, IFN-γ, and GM-CSF were 40% (p<0.05), 20% (p<0.05), 40% (p<0.01), and 40% (p<0.01) lower, respectively, in the skin secretagogue of colchicine-treated mice. Given the chronic nature of inflammation in SCD, we did not anticipate phenotypic changes after only a 14-day exposure to colchicine. Indeed, no significant differences in hyperalgesia or mouse/organ weight were observed. We think that next steps should be dose-finding studies of colchicine in adults living with SCD followed by randomized, placebo-controlled trials with clinically relevant endpoints such as repeated measures of pain interference using a validated instrument. The anticipated lack of colchicine effect upon blood cell parameters suggests that patients would benefit more from a combination of a disease-modifying agent such as hydroxyurea in combination with colchicine.

Supplementary Table S1. RAS/BRAF mutation status

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.

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

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

PDF file - 42K, Alvocidib pharmacokinetic parameters.

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

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

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.

We developed a mathematical model for autologous stem cell therapy to cure sickle cell disease (SCD). Experimental therapies using this approach seek to engraft stem cells containing a curative gene. These stem cells are expected to produce a lifelong supply of red blood cells (RBCs) containing an anti-sickling hemoglobin. This complex, multistep treatment is expensive, and there is limited patient data available from early clinical trials. Our objective was to quantify the impact of treatment parameters, such as initial stem cell dose, efficiency of lentiviral transduction, and degree of bone marrow preconditioning on engraftment efficiency, peripheral RBC numbers, and anti-sickling hemoglobin levels over time. We used ordinary differential equations to model RBC production from progenitor cells in the bone marrow, and hemoglobin assembly from its constituent globin monomers. The model recapitulates observed RBC and hemoglobin levels in healthy and SCD phenotypes. Treatment simulations predict dynamics of stem cell engraftment and RBC containing the therapeutic gene product. Post-treatment dynamics show an early phase of reconstitution due to short lived stem cells, followed by a sustained RBC production from stable engraftment of long-term stem cells. This biphasic behavior was previously reported in the literature. Sensitivity analysis of the model quantified relationships between treatment parameters and efficacy. The initial dose of transduced stem cells, and the intensity of myeloablative bone marrow preconditioning are predicted to most positively impact long-term outcomes. The quantitative systems pharmacology approach used here demonstrates the value of model-assisted therapeutic design for gene therapies in SCD.

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.

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.

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a medically and socially complex, multisystem illness that affects individuals throughout the lifespan. Given improvements in care, most children with SCD survive into adulthood. However, access to adult sickle cell care is poor in many parts of the United States, resulting in increased acute care utilization, disjointed care delivery, and early mortality for patients. A dearth of nonmalignant hematology providers, the lack of a national SCD registry, and the absence of a centralized infrastructure to facilitate comparative quality assessment compounds these issues. As part of a workshop designed to train health care professionals in the skills necessary to establish clinical centers focused on the management of adults living with SCD, we defined an SCD center, elucidated required elements of a comprehensive adult SCD center, and discussed different models of care. There are also important economic impacts of these centers at an institutional and health system level. As more clinicians are trained in providing adult-focused SCD care, center designation will enhance the ability to undertake quality improvement and compare outcomes between SCD centers. Activities will include an assessment of the clinical effectiveness of expanded access to care, the implementation of SCD guidelines, and the efficacy of newly approved targeted medications. Details of this effort are provided.

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: Dronabinol is used to treat a variety of conditions, including loss of appetite in people with AIDS and severe nausea and vomiting caused by cancer chemotherapy. Its therapeutic potential for pain management is now being explored in specific populations. Monitoring dronabinol compliance is challenging because its active ingredient, Delta-9-tetrahydrocannabinol (THC), is also present in cannabis. We developed a rapid LC-MS/MS assay with minimal specimen preparation to quantitate 11 cannabinoids in urine. Using this assay coupled with urine samples from normal controls, cannabis, and dronabinol users, we show the ability to differentiate cannabis from dronabinol use. Methods: Residual clinical urine samples from 55 cannabinoid positive subjects and 31 negative controls, as well as prospective samples from 5 patients receiving dronabinol therapy were obtained for analysis. Results: In the dronabinol group, only the THC metabolites 11-nor-9-carboxy-tetrahydrocannabinol (THC-COOH) and 11-hydroxy-Delta-9 tetrahydrocannabinol (THC-OH) were detected. Minor cannabinoids were detected in 91% of cannabis group samples and their detection was more frequent in samples with increased THC metabolite concentrations. Of minor cannabinoids evaluated, cannabigerol (CBG) and cannabidiol (CBD) had the greatest sensitivity in detecting cannabis use. Conclusions: This method has a high sensitivity for the detection of cannabis use with implications for evaluating dronabinol compliance.

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.

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<0.0001), inpatient days were reduced (206 days vs 106 days), and total charges were significantly reduced (25.43%, $5,297,323.73 vs $3,950,267.26, p=0.0037). 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.

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.

BACKGROUNDDespite 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 METHODSForty‐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.RESULTSThere 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.CONCLUSIONSMonocytes 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.