Darla Liles

Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease

Background The up‐regulation of P‐selectin in endothelial cells and platelets contributes to the cell–cell interactions that are involved in the pathogenesis of vaso‐occlusion and sickle cell–related pain crises. The safety and efficacy of crizanlizumab, an antibody against the adhesion molecule P‐selectin, were evaluated in patients with sickle cell disease. Methods In this double‐blind, randomized, placebo‐controlled, phase 2 trial, we assigned patients to receive low‐dose crizanlizumab (2.5 mg per kilogram of body weight), high‐dose crizanlizumab (5.0 mg per kilogram), or placebo, administered intravenously 14 times over a period of 52 weeks. Patients who were receiving concomitant hydroxyurea as well as those not receiving hydroxyurea were included in the study. The primary end point was the annual rate of sickle cell–related pain crises with high‐dose crizanlizumab versus placebo. The annual rate of days hospitalized, the times to first and second crises, annual rates of uncomplicated crises (defined as crises other than the acute chest syndrome, hepatic sequestration, splenic sequestration, or priapism) and the acute chest syndrome, and patient‐reported outcomes were also assessed. Results A total of 198 patients underwent randomization at 60 sites. The median rate of crises per year was 1.63 with high‐dose crizanlizumab versus 2.98 with placebo (indicating a 45.3% lower rate with high‐dose crizanlizumab, P=0.01). The median time to the first crisis was significantly longer with high‐dose crizanlizumab than with placebo (4.07 vs. 1.38 months, P=0.001), as was the median time to the second crisis (10.32 vs. 5.09 months, P=0.02). The median rate of uncomplicated crises per year was 1.08 with high‐dose crizanlizumab, as compared with 2.91 with placebo (indicating a 62.9% lower rate with high‐dose crizanlizumab, P=0.02). Adverse events that occurred in 10% or more of the patients in either active‐treatment group and at a frequency that was at least twice as high as that in the placebo group were arthralgia, diarrhea, pruritus, vomiting, and chest pain. Conclusions In patients with sickle cell disease, crizanlizumab therapy resulted in a significantly lower rate of sickle cell–related pain crises than placebo and was associated with a low incidence of adverse events. (Funded by Selexys Pharmaceuticals and others; SUSTAIN ClinicalTrials.gov number, NCT01895361.)

Sleep disorders in adult sickle cell patients.

STUDY OBJECTIVES While sleep apnea has been studied in children with sickle cell disease (SCD), little is known about sleep disorders in adult sickle cell patients. The objective of this study was to evaluate sleep disordered breathing and its polysomnographic characteristics in adult patients with sickle cell disease. METHODS The analysis cohort included 32 consecutive adult SCD patients who underwent a comprehensive sleep evaluation and overnight polysomnography in an accredited sleep center after reporting symptoms suggesting disordered sleep or an Epworth Sleepiness Scale score ≥ 10. Epworth score, sleep parameters, comorbid conditions, and narcotic use were reviewed and compared in patients with and without sleep disordered breathing. SCD complication rates in the two groups also were compared. RESULTS In adult SCD patients who underwent overnight polysomnography, we report a high prevalence (44%) of sleep disordered breathing. Disease severity was mild to moderate (mean apnea-hypopnea index = 17/h (95% CI: 10-24/h). Concomitant sleep disorders, including insomnia complaints (57%) and delayed sleep-phase syndrome (57%), also were common in this population. In this limited cohort, we did not find increased SCD complications associated with sleep disordered breathing in adult patients with sickle cell disease. CONCLUSIONS A high burden of sleep disordered breathing and other sleep-related complaints were identified in the adult sickle cell population. Our results provide important information on this unique population.

Outbreak of Mycobacterium mucogenicum bloodstream infections among patients with sickle cell disease in an outpatient setting.

OBJECTIVE To study an outbreak of Mycobacterium mucogenicum bloodstream infections in an outpatient setting. DESIGN Outbreak investigation and retrospective chart review. SETTING University outpatient clinic. Patients. Patients whose blood cultures tested positive for M. mucogenicum in May or June 2008. METHODS An outbreak investigation and a review of infection control practices were conducted. During the process, environmental culture samples were obtained. Isolates from patients and the environment were genotyped with the DiversiLab typing system to identify the source. Chart reviews were conducted to study the management and outcomes of the patients. RESULTS Four patients with sickle cell disease and implanted ports followed in the same hematology outpatient clinic developed blood cultures positive for M. mucogenicum. A nurse in the clinic had prepared intravenous port flushes on the sink counter, using a saline bag that was hanging over the sink throughout the shift. None of the environmental cultures grew M. mucogenicum except for the tap water from 2 rooms, 1 of which had a faucet aerator. The 4 patient isolates and the tap water isolate from the room with the aerator were found to have greater than 98.5% similarity. The subcutaneous ports were removed, and patients cleared their infections after a course of antibiotic therapy. CONCLUSION The source of the M. mucogenicum bacteremia outbreak was identified by genotyping analysis as the clinic tap water supply. The preparation of intravenous medications near the sink was likely an important factor in transmission, along with the presence of a faucet aerator.

An Unusual Cause of New-onset Atrial Flutter: Primary Cardiac Lymphoma

Primary cardiac lymphoma is a rare disease with a high mortality rate due to the advanced stage of myocardial involvement at presentation. The diagnosis is extremely difficult to make because of the rarity of the disease, variability of clinical manifestations, limited noninvasive diagnostic techniques available, and difficulties and/or delays in the use of invasive measures. The incidence of the disease is increasing, especially among immunocompromised patients, with those suffering from acquired immunodeficiency syndrome accounting for the greatest increase. We report the case of an immunocompetent 76-year-old black woman who presented with near-syncopal episodes. Transthoracic echocardiogram revealed a right atrial mass. Surgical resection was performed, and a diagnosis of large B-cell non-Hodgkins lymphoma was made. Primary cardiac lymphoma should be considered in any patient with a cardiac mass. Prompt diagnosis and treatment of primary cardiac lymphoma is imperative for survival.

Randomized Phase II Trial of Irinotecan/Docetaxel or Irinotecan/Docetaxel Plus Cetuximab for Metastatic Pancreatic Cancer: An Eastern Cooperative Oncology Group Study.

Objectives:The primary objective was to determine the response rate in patients with metastatic pancreatic cancer treated in first line with irinotecan/docetaxel combination (Arm A) or with irinotecan/docetaxel/cetuximab combination (Arm B). Secondary endpoints were progression-free survival (PFS), overall survival (OS), toxicity, and the rate of thromboembolic events with prophylactic enoxaparin sodium. Patients and Methods:Patients were eligible who had measurable, metastatic adenocarcinoma of the pancreas, and normal bilirubin. All patients received anticoagulation. Docetaxel (35 mg/m2) and irinotecan (50 mg/m2) were administered once a week for 4 weeks followed by 2 weeks rest (Arm A) alone or with the addition of cetuximab (Arm B). The primary endpoint was response rate. Results:A total of 87 eligible patients were enrolled and treated. Grade 3/4 toxicity was observed in 74% of patients in Arm A and 76% in Arm B. The principal grade 3/4 toxicity was diarrhea. Response rates were 4.5% in Arm A and 7% in Arm B. Median PFS and OS were 3.9 and 6.5 months in Arm A and 4.5 and 5.4 months in Arm B. Conclusions:Docetaxel/irinotecan combination is associated with considerable toxicity. Objective responses were infrequent and addition of cetuximab in an unselected population was not beneficial, but PFS and OS were comparable with those achieved with other regimens. Docetaxel/irinotecan therapy is active in metastatic pancreatic cancer.

High-Dose Intensity Pulse Interleukin-2 with Famotidine Has Activity in Metastatic Melanoma

Daily short intravenous (i.v.) infusions (pulses) of interleukin-2 (IL-2) have been developed to decrease toxicity while maintaining anticancer activity of this agent against melanoma. Such IL-2 schedules have previously been shown to promote lymphokine-activated killer (LAK) cell activity. Famotidine may increase LAK activity by increasing IL-2 internalization by the IL-2 receptor on lymphocytes. We treated 16 patients with metastatic melanoma using pulse IL-2 18 (15 patients) or 9 million IU/M2 (1 patient) i.v. over 15-30 minutes preceded by famotidine 20 mg i.v. daily for 5 days on an oncology inpatient unit. Cycles were repeated every 3 weeks until disease progression. Patient characteristics were as follows: 11 males, median age, 66, median ECOG performance status, 1; common metastatic sites: lymph nodes, lungs, subcutaneous, liver, and bone. Median number of cycles received was 3. Overall, 93% of planned doses were delivered. Most common toxicities were hypomagnesemia, fever, rigors, hypophosphatemia, and nausea/emesis. Three (3) patients had partial responses (19% response rate; 95% confidence interval: 6%-44%). A fourth patient, after resection of residual disease, remains a surgical complete responder at > 12 months. Responses occurred in lung, liver, lymph nodes, bone, and subcutaneous sites. Median response duration was 7 months. Pulse IL-2 with famotidine has activity in melanoma.

Edmonton symptom assessment system for outpatient symptom monitoring of sickle cell disease

Objectives Although the extension of palliative care methodology to sickle cell disease (SCD) care has been proposed, there is no current standard for symptom assessment. Our goal was to assess the feasibility of integrating the Edmonton Symptom Assessment System (ESAS) into the outpatient management of SCD. Methods Seventy-five adult patients presenting for outpatient visits at a comprehensive SCD center were enrolled. Patients completed the ESAS (self-report of 10 symptoms during the last 24 hours) and a survey regarding their opinion of the ESAS at enrollment and follow-up. Results Pain (P = 0.0272) was the only symptom score that changed significantly between the initial and follow-up visits. In patients with a self-reported pain crisis, pain (P < 0.0001), fatigue (P = 0.0025), depression (P = 0.0458), nausea (P = 0.0384), and symptom distress scores (P = 0.0019) were significantly higher than for patients without a pain crisis. On the initial visit, 92% of all patients agreed or strongly agreed that the ESAS was easy to complete; 83% were satisfied or very satisfied with the ESAS as a way to report symptoms. Conclusions Our data suggest that the ESAS is well received and can be successfully included as part of the longitudinal symptom management strategy for SCD.

Pulmonary artery occlusion pressure may overdiagnose pulmonary artery hypertension in sickle cell disease.

A high prevalence of Pulmonary Hypertension (PH) in sickle cell disease (SCD) has been reported in several studies. However, few studies that describe the hemodynamics have actually measured pulmonary artery occlusive pressure (PAOP). Furthermore, even PAOP has been shown to be unreliable in discriminating pulmonary artery hypertension from pulmonary venous hypertension. We prospectively examined the accuracy of PAOP using simultaneous left ventricular end diastolic pressure (LVEDP) measurement as the gold standard.

A Comparison of White and African American Outcomes from a Three-Arm, Randomized, Phase III Multicenter Trial of Advanced or Metastatic Non-small Cell Lung Cancer

Purpose: To investigate the effect of race on the efficacy and safety of standard chemotherapy doublet regimens in African American patients, we conducted a subgroup analysis of a phase III randomized trial. Patients and Methods: Chemonaïve patients with a performance status of 0 or 1 and stage IIIB or IV non-small cell lung cancer were randomized to arm A: gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1; arm B: the same schedule of gemcitabine plus paclitaxel 200 mg/m2 on day 1; or arm C: paclitaxel 225 mg/m2 on day 1 plus carboplatin area under the curve 6.0 on day 1. Cycles were repeated every 21 days up to 6. A site selection tool identified institutions with potential to recruit a minority population. Outcome and toxicity data of white and African American patients were compared. Results: Of 1135 total patients, 972 were white (85.6%) and 138 were African American (12.2%). Median survival was 8.3 months for white patients (95% confidence interval [CI]: 7.7–9.3) and 9.1 months for African American patients (95% CI: 8.2–11.1). Response rates were 29.1 and 29.0%, respectively. Rates of grade 3 or 4 toxicities were comparable. Among African Americans, median survival was 7.2 months (95% CI: 5.1–10.1) for gemcitabine-carboplatin (n = 47), 10.5 months (95% CI: 7.1–15.4) for gemcitabine-paclitaxel (n = 42), and 10.2 months (95% CI: 8.5–13.2) for paclitaxel-carboplatin (n = 49). Conclusion: Whites and African Americans had similar outcomes, although there was some variability in survival among African Americans across the three treatment groups.

Opioid Induced Sleep Disordered Breathing in Sickle Cell Patient

Opioid Induced Sleep Disordered Breathing in Sickle Cell Patient Chronic opioid use is a risk factor for sleep disordered breathing (SDB) like obstructive sleep apnea (OSA), Biot’s or ataxic breathing, central sleep apnea and sleep related hypoventilation. Withdrawal of opioids may be the optimal management but it is not always feasible. Continuous positive airway pressure (CPAP) therapy, which is effective treatment for OSA, may not resolve central events. Opioid induced sleep disordered breathing has been described mostly in patients with chronic back pain on narcotics. We present a case of sickle cell disease who is a 37 year old male on short and long acting Morphine presenting with excessive daytime sleepiness, fatigue and memory loss. Baseline nocturnal polysomnography (NPSG) showed central sleep apnea (Biot’s breathing) with AHI of 27. After initial failure of CPAP, ASV at IPAPmax/ EPAPmin (inspiratory and expiratory positive airway pressures) of 25/7 cm of H2O with a pressure support setting of 0-15 and auto back-up rate was applied with complete resolution of Biot’s breathing and symptoms. This case highlights the increased risk of central sleep apnea induced by opioids in a population with improving life expectancy and chronic use of narcotics. It also adds to the small but growing body of evidence suggesting the beneficial role of ASV in opioid induced sleep disordered breathing where narcotics /opioids cannot be discontinued.