Dosing pole recommendations for lymphatic filariasis elimination: A height-weight quantile regression modeling approach.

BACKGROUND: The World Health Organization (WHO) currently recommends height or age-based dosing as alternatives to weight-based dosing for mass drug administration lymphatic filariasis (LF) elimination programs. The goals of our study were to compare these alternative dosing strategies to weight-based dosing and to develop and evaluate new height-based dosing pole scenarios. METHODOLOGY/PRINCIPAL FINDINGS: Age, height and weight data were collected from >26,000 individuals in five countries during a cluster randomized LF clinical trial. Weight-based dosing for diethylcarbamazine (DEC; 6 mg/kg) and ivermectin (IVM; 200 ug/kg) with tablet numbers derived from a table of weight intervals was treated as the "gold standard" for this study. Following WHO recommended age-based dosing of DEC and height-based dosing of IVM would have resulted in 32% and 27% of individuals receiving treatment doses below those recommended by weight-based dosing for DEC and IVM, respectively. Underdosing would have been especially common in adult males, who tend to have the highest LF prevalence in many endemic areas. We used a 3-step modeling approach to develop and evaluate new dosing pole cutoffs. First, we analyzed the clinical trial data using quantile regression to predict weight from height. We then used weight predictions to develop new dosing pole cutoff values. Finally, we compared different dosing pole cutoffs and age and height-based WHO dosing recommendations to weight-based dosing. We considered hundreds of scenarios including country- and sex-specific dosing poles. A simple dosing pole with a 6-tablet maximum for both DEC and IVM reduced the underdosing rate by 30% and 21%, respectively, and was nearly as effective as more complex pole combinations for reducing underdosing. CONCLUSIONS/SIGNIFICANCE: Using a novel modeling approach, we developed a simple dosing pole that would markedly reduce underdosing for DEC and IVM in MDA programs compared to current WHO recommended height or age-based dosing.

The safety of double- and triple-drug community mass drug administration for lymphatic filariasis: A multicenter, open-label, cluster-randomized study.

BACKGROUND: The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. METHODS AND FINDINGS: Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 µg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. CONCLUSIONS: In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. TRIAL REGISTRATION: Clinicaltrials.gov registration number: NCT02899936.

Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study.

Background: Multiple myeloma (MM) is one of the most common hematologic malignancies in the United States and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). This study investigates the role of obesity in the progression of MGUS to MM. Methods: A retrospective identified cohort of patients in the US Veterans Health Administration database diagnosed with MGUS between October 1, 1999, and December 31, 2009, was followed through August 6, 2013. Patient-level clinical data were reviewed to verify MM diagnosis, if any. Survival analyses utilizing interval-censored data were used to investigate the risk of progression of MGUS to MM. Statistical tests were two-sided. Results: The analytic cohort consisted of 7878 MGUS patients with a median follow-up of 68 months. Within the cohort, 39.8% were overweight and 33.8% were obese; 64.1% were of white race. During follow-up, 329 MGUS patients (4.2%) progressed to MM: 72 (3.5%) normal-weight patients (median follow-up = 61.9 months), 144 (4.6%) overweight patients (median follow-up = 69.1 months), and 113 (4.3%) obese patients (median follow-up = 70.6 months). In the multivariable analysis, overweight (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.16 to 2.06) and obesity (HR = 1.98, 95% CI = 1.47 to 2.68) were associated with an increased risk of transformation of MGUS to MM. Moreover, black race was associated with a higher risk of MM (HR = 1.98, 95% CI = 1.55 to 2.54). Conclusions: Obesity and black race are risk factors for transformation of MGUS to MM. Future clinical trials should examine whether weight loss is a way to prevent the progression to MM in MGUS patients.

Weight change trends and overall survival in United States veterans with follicular lymphoma treated with chemotherapy.

Understanding weight change patterns in follicular lymphoma (FL) may be important for the assessment of prognosis as well as the long-term care of survivors. A retrospective cohort of United States veterans with a new diagnosis of FL between October 1, 1998 and September 30, 2010 was assembled. Weight changes were evaluated before, during, and after treatment in 896 FL patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab (CHOP ± R); cyclophosphamide, vincristine, and prednisone, with or without rituximab (CVP ± R); or rituximab monotherapy. Weight decreased an average of 1.4 kg during therapy, and >5% weight loss during this time period was associated with worse overall survival. Weight increased to an average of 1.4 kg above baseline by 24 months after treatment initiation, with 15% gaining greater than 10% of their baseline weight. Weight management strategies may be an important part of long-term survivorship planning.

Statins Are Associated With Reduced Mortality in Multiple Myeloma.

Purpose The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have activity in one of the pathways influenced by nitrogen-containing bisphosphonates, which are associated with improved survival in multiple myeloma (MM). To understand the benefit of statins in MM, we evaluated the association between statin use and mortality in a large cohort of patients with MM. Patients and Methods From the Veterans Administration Central Cancer Registry, we identified patients diagnosed with MM between 1999 and 2013. We defined statin use as the presence of any prescription for a statin within 3 months before or any time after MM diagnosis. Cox proportional hazards regression assessed the association of statin use with mortality, while controlling for known MM prognostic factors. Results We identified a cohort of 4,957 patients, of whom 2,294 received statin therapy. Statin use was associated with a 21% decrease in all-cause mortality (adjusted hazard ratio, 0.79; 95% CI, 0.73 to 0.86; P < .001) as well as a 24% decrease in MM-specific mortality (adjusted hazard ratio, 0.76; 95% CI, 0.67 to 0.86; P < .001). This association remained significant across all sensitivity analyses. In addition to reductions in mortality, statin use was associated with a 31% decreased risk of developing a skeletal-related event. Conclusion In this cohort study of US veterans with MM, statin therapy was associated with a reduced risk of both all-cause and MM-specific mortality. Our findings suggest a potential role for statin therapy in patients with MM. The putative benefit of statin therapy in MM should be corroborated in prospective studies.

Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B-cell lymphoma treated with CHOP-based chemotherapy.

While sarcopenia has been associated with decreased overall survival in diffuse large B-cell (DLBCL) patients, the impact of sarcopenia on treatment tolerance has not been well-studied. We evaluated the association of sarcopenia with febrile neutropenia hospitalization, treatment-related mortality, and ability to complete standard number of cycles in a retrospective cohort of United States veterans diagnosed with DLBCL between 1998 and 2008 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab. Baseline body composition parameters were evaluated using computed tomography analysis. In total, 522 patients were included in the study, of whom 245 (47%) had baseline sarcopenia. After controlling for other variables, baseline sarcopenia was independently associated with increased risk of febrile neutropenia hospitalization (adjusted Odds Ratio (aOR) 1.64, 95% confidence interval (CI) 1.01-2.65) and inability to complete standard number of treatment cycles (aOR 1.49, 95% CI 1.02-2.16) compared with no baseline sarcopenia. There was a non-statistically significant trend toward higher treatment-related mortality in sarcopenic patients than non-sarcopenic patients (aOR 1.77, 95% CI 0.92-3.41). Sarcopenia is associated with increased risk of treatment intolerance and may be useful in guiding treatment planning and supportive care measures. Am. J. Hematol. 91:1002-1007, 2016. © 2016 Wiley Periodicals, Inc.

Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans.

BACKGROUND: Body composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity. METHODS: A retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided. RESULTS: Three hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CI = 15.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CI = 14.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74). CONCLUSIONS: DLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.

Short- and Long-term weight changes among United States veterans with diffuse large B-cell lymphoma treated with CHOP chemotherapy.

Identifying weight changes associated with treatment of diffuse large B-cell lymphoma (DLBCL) has the potential to improve the long-term health of survivors. A retrospective cohort of United States veterans with a new diagnosis of DLBCL between October 1, 1998 and September 30, 2008, with follow-up until April 23, 2013, was assembled. Weight changes were evaluated before, during, and after treatment in 1935 DLBCL patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab (CHOP+/- R). One year prior to treatment, 79% of patients were obese or overweight. During the 12 months leading up to treatment, 57% of the cohort lost weight. Among patients surviving 24 months after treatment initiation, weight increased an average of 2.9 kg above weight at treatment completion. The weight change trends observed in these DLBCL patients suggest that weight management strategies may be an important part of long-term survivorship planning after conclusion of treatment.

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study.

BACKGROUND: Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS: We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. FINDINGS: We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49­96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25­0·87). INTERPRETATION: For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. FUNDING: Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.

Comparative effectiveness of anthracycline-containing chemotherapy in United States veterans age 80 and older with diffuse large B-cell lymphoma.

OBJECTIVES: While anthracycline-based treatment can cure diffuse large B-cell lymphoma, most patients over age 80 do not receive doxorubicin due to toxicity concerns. This study evaluated this practice, as patients age 80 and older are largely excluded from clinical trials. The primary outcome of interest was overall survival. Secondary outcomes included treatment-related mortality and anthracycline dose intensity. MATERIALS AND METHODS: We assembled a cohort of 530 newly diagnosed diffuse large B-cell lymphoma patients age 80 or older diagnosed within United States Veterans Health Administration. Treatment and survival information were obtained to determine associations between anthracycline use, dose intensity, treatment-related mortality and overall survival. RESULTS: Of the 530 patients, 285 received systemic treatment and 193 received an anthracycline. After controlling for potential confounders, rituximab decreased mortality (hazard ratio, 0.62; 95% confidence interval [CI]: 0.44-0.88), while doxorubicin was not significantly associated with mortality (hazard ratio, 0.87; 95% CI: 0.64-1.17). Completion of treatment with anthracycline dose intensity ≥85% of expected was only 14%. Patients treated with anthracycline dose intensity <85% had better one year survival compared to those treated at ≥85% (70% vs. 59%, p=0.029). CONCLUSION: These results suggest that full dose anthracycline therapy may be less important in the treatment of diffuse large B-cell lymphoma patients over age 80. The low frequency of completion of full dose intensity treatment suggests that standard doses are an unrealistic standard of care for patients this age. Alternate treatment strategies and risk stratification should be considered for these patients.

Coexisting chronic conditions associated with mortality and morbidity in adult patients with asthma.

OBJECTIVE: Many asthma patients suffer from chronic conditions other than asthma. We investigated the specific contribution of common comorbidities on mortality and morbidity in adult asthma. METHODS: In an observational study of adults with incident asthma identified between 1999 and 2003 using National Veterans Affairs and Centers for Medicare and Medicaid Services encounter databases (n = 25 975, follow-up 3.0 ± 1.7 years), association between 13 most prevalent comorbidities (hypertension, ischemic heart disease (IHD), osteoarthritis, rheumatoid arthritis, diabetes, mental disorders, substance/drug abuse, enlarged prostate, depression, cancer, alcoholism, HIV and heart failure) and four conditions previously associated with asthma (sleep apnea, gastroesophageal reflux disease (GERD), rhinitis and sinusitis) and mortality, hospitalizations and asthma exacerbations were assessed using multivariate regression analyses adjusted for other clinically important covariates. RESULTS: HIV followed by alcoholism and mental disorders among 18-45-years old, and heart failure, diabetes, IHD and cancer among those ≥ 65 years old were associated with an increased risk of all-cause mortality. Many conditions were associated with increased risk for all-cause hospitalizations, but the increased risk was consistent across all ages for mental disorders. For asthma exacerbations, mental disorder followed by substance abuse and IHD were associated with increased risk among those 18-45 years old, and chronic sinusitis, mental disorder and IHD among those ≥ 65-years old. GERD was associated with decreased risk for asthma exacerbation in all ages. CONCLUSIONS: Many comorbidities are associated with poor outcome in adult asthmatics and their effect differs by age. Mental disorders are associated with increased risk of mortality and morbidity across ages.