Naveen Sanath Kumar

Probable Invasive Aspergillosis without Prespecified Radiologic Findings: Proposal for Inclusion of a New Category of Aspergillosis and Implications for Studying Novel Therapies

BACKGROUND The European Organization for Research and Treatment of Cancer (EORTC) and the Mycosis Study Group (MSG) definition of invasive aspergillosis used in clinical trials lacks sensitivity. We hypothesize that giving lower weight to the prespecified radiologic findings in patients with a positive serum galactomannan index test result will improve the definitions diagnostic sensitivity. METHODS The medical records of 121 patients with 125 cases of invasive aspergillosis treated at a referral cancer institute from January 2003 through December 2009 were reviewed. Aspergillosis was diagnosed as EORTC-MSG proven or probable (controls, 83) or probable invasive aspergillosis without prespecified radiologic criteria (cases, 42). The latter differed from the former by the inclusion of patients whose pulmonary infiltrates, although well described in invasive aspergillosis, do not fulfill EORTC-MSG invasive aspergillosis requirements. The host, clinical, and mycologic characteristics and survival of cases and controls served as end points. RESULTS A total of 114 (91%) of 125 patients had multiple myeloma. Patients had a median age was 65 years (range, 26-81 years), and 74 were male. All had received antineoplastic therapy, including stem cell transplantation (58 [46%]). Aspergillosis involved lungs (88 patients), sinuses (9 patients), or both (28 patients). Except for higher median baseline platelet count and shorter duration of neutropenia among cases, there were no statistically significant differences between groups on all predefined end points, including 4-, 6-, and 12-week survival. Eleven of 26 cases were reclassified as controls on the basis of subsequent imaging. CONCLUSIONS Except for less well-circumscribed consolidations, the host, clinical, radiologic, and mycologic characteristics and outcome of patients with probable invasive aspergillosis but without prespecified radiologic criteria are similar to those with EORTC-MSG invasive aspergillosis. Enrolling such patients in clinical trials of novel therapies will increase the pool of eligible study participants and improve trial speed and efficiency.

Seven-year median time to progression with thalidomide for smoldering myeloma: partial response identifies subset requiring earlier salvage therapy for symptomatic disease

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. We conducted a phase 2 trial in 76 eligible patients with SMM, combining thalidomide (THAL, 200 mg/d) with monthly pamidronate. In the first 2 years, THAL dose reduction was required in 86% and drug was discontinued in 50%. Within 4 years, 63% improved, including 25% qualifying for partial response (PR); by then, 34 patients had progressed and 17 required salvage therapy. Unexpectedly, attaining PR status was associated with a shorter time to salvage therapy for disease progression (P < .001), perhaps reflecting greater drug sensitivity of more aggressive disease. Low beta-2-microglobulin levels less than 2 mg/L were independently associated with superior overall and event-free survival. Four-year survival and event-free survival estimates of 91% and 60%, respectively, together with a median postsalvage therapy survival of more than 5 years justify the conduct of a prospective randomized clinical trial to determine the clinical value of preemptive therapy in SMM. Trial registered at http://www.clinicaltrials.gov under identifier NCT00083382.

Earlier Response Assessment in Invasive Aspergillosis Based on the Kinetics of Serum Aspergillus Galactomannan: Proposal for a New Definition

BACKGROUND Current criteria for assessing treatment response of invasive aspergillosis (IA) rely on nonspecific subjective parameters. We hypothesized that an Aspergillus-specific response definition based on the kinetics of serum Aspergillus galactomannan index (GMI) would provide earlier and more objective response assessment. METHODS We compared the 6-week European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) response criteria with GMI-based response among 115 cancer patients with IA. Success according to GMI required survival with repeatedly negative GMI for ≥2 weeks. Time to response and agreement between the 2 definitions were the study endpoints. RESULTS Success according to EORTC/MSG and GMI criteria was observed in 73 patients (63%) and 83 patients (72%), respectively. The GMI-based response was determined at a median of 21 days after treatment initiation (range, 15-41 days), 3 weeks before the EORTC/MSG time point, in 72 (87%) of 83 responders. Agreement between definitions was shown in all 32 nonresponders and in 73 of the 83 responders (91% overall), with an excellent κ correlation coefficient of 0.819. Among 10 patients with discordant response (EORTC/MSG failure, GMI success), 1 is alive without IA 3 years after diagnosis; for the other, aspergillosis could not be detected at autopsy. The presence of other life-threatening complications in the remaining 8 patients indicates that IA had resolved. CONCLUSIONS The Aspergillus-specific GMI-based criteria compare favorably to current response definitions for IA and significantly shorten time to response assessment. These criteria rely on a simple, reproducible, objective, and Aspergillus-specific test and should serve as the primary endpoint in trials of IA.

A prospective evaluation of the biochemical, metabolic, hormonal and structural bone changes associated with bortezomib response in multiple myeloma patients

We prospectively evaluated the bone changes associated with proteasome inhibition using single agent bortezomib in relapsed or refractory myeloma patients. Ten patients received bortezomib 1.3 mg/m2 per days 1, 4, 8 and 11 for three 21-day cycles, and 6 patients received 1 mg/m2 per day with the same schedule. Bone architecture and metabolism changes were assessed by bone markers, micro-CT, bone histomorphometry, tetracycline labeling and serum parathormone levels. Bone parameter variations were compared by response to treatment. Microarchitectural changes were observed in all evaluable responsive patients. Bone alkaline phosphatase changes were associated with disease response (≥PR vs. others P=0.03 cycle 1, day 11) serum parathormone levels were also significantly increased (P=0.04 on days 11, 21, 33) in responding individuals. This study demonstrates that the myeloma control produced by proteasome inhibition is associated with bone changes and to a discrete pattern of hormonal variation. (Clinicaltrials.gov identifier: NCT00569868)

Baseline Platelet Count and Creatinine Clearance Rate Predict the Outcome of Neutropenia-Related Invasive Aspergillosis

BACKGROUND Invasive aspergillosis (IA) is a life-threatening infection for immunocompromised patients. Improvement in IA outcome has been hampered by lack of early prognostic factors, namely, those available before starting chemotherapy (baseline) or early in the course of IA (nonbaseline). We hypothesized that prognostic factors can be identified before chemotherapy, ≤7 days from the first positive serum Aspergillus galactomannan index (s-GMI). METHODS We analyzed 98 patients with multiple myeloma who developed neutropenia-related IA and had a positive s-GMI. Three response criteria were used: kinetics of s-GMI, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) definitions, and 6-week survival. Baseline and nonbaseline variables were analyzed separately. RESULTS Independent response predictors at baseline were a platelet count ≥65,000 platelets/mm(3) (odds ratio [OR], 1.009; 95% confidence interval [CI], 1.001-1.017; P = .03) by s-GMI kinetics, and a platelet count ≥65,000 platelets/mm(3) (OR, 1.009; 95% CI, 1.002-1.017; P = .01) and a creatinine clearance rate ≥53 mL/min (OR, 1.024; 95% CI, 1.006-1.042; P = .009) by EORTC/MSG criteria, with response rates of 83% and 28% when both variables were above or below these cutoffs, respectively (P < .001). Only baseline creatinine clearance rate ≥53 mL/min predicted 6-week survival (P = .003). Normalization of the s-GMI ≤7 days after the first positive s-GMI and neutrophil recovery were the nonbaseline factors associated with positive outcomes. CONCLUSIONS Two simple, inexpensive to measure, widely available, and routinely collected prechemotherapy values, platelet count and creatinine clearance rate, predict IA outcome and stratify patients into low-, intermediate-, and high-risk categories, while early evaluation of s-GMI allows timely treatment modification. These findings may improve patient outcomes by optimizing management strategies for this serious infection and may prove valuable in designing clinical trials of interventions to improve IA outcomes.

Influenza A Outbreak in an Ambulatory Stem Cell Transplant Center

Background  In the era of cost-consciousness regarding healthcare , provision of medical services in an outpatient setting has become increasingly attractive. We report an influenza outbreak in an ambulatory stem cell transplant center in 2013 that highlights unique identification and infection control challenges in this setting. Methods  Nasopharyngeal swabs were performed on patients with suspected influenza-like illnesses (ILI), defined by subjective fever or measured temperature of ≥37.7°C (≥100°F) with cough or sore throat during July 25, 2013 through August 7, 2013. In addition, testing was triggered by an elevated C-reactive protein (CRP). Specimens were analyzed by using eSensor Respiratory Viral Panel. Clinical and epidemiologic information was collected in real time, and frequencies were calculated on demographics, baseline clinical parameters, treatment methods, comorbidities, and symptoms of affected persons. Results  Thirty-one patients had influenza A (H3N2) infection during July 25, 2013 through August 7, 2013. Only 7 patients (23%) met the Centers for Disease Control and Prevention and Council of State and Territorial Epidemiologists ILI case definition. Twenty-five patients (81%) had received ≥1 transplant, with 13 (42%) having occurred within 1 year before the outbreak. Twenty-five patients (81%) had received B-cell active chemotherapy <60 days before influenza diagnosis, 6 (19%) were neutropenic, and 25 (81%) lymphopenic. Among clinical and laboratory markers analyzed, abnormal CRP was the most sensitive screening tool for influenza. Twelve (39%) patients were hospitalized (median stay, 10 days; range, 2–20). No deaths occurred. Conclusions  Immunocompromised hosts with influenza have atypical presentations. Existing surveillance case definitions might be insufficient to reliably identify influenza outbreaks in such patients.

438Genetic Variants Associated with the Development of Clostridium Difficile Infection during Autologous Stemcell Transplantation

Difficile Infection during Autologous Stemcell Transplantation Senu Apewokin, MD; Elizabeth Coleman, PhD; Carol Enderlin, PhD; Julia Goodwin, PhD; Jeannette Lee, PhD; Stephen Erickson, PhD; Kent Mckelvey, MD, PhD; Vinay Raj, PhD; Naveen Sanath Kumar, MD; Zhou Daohong, PhD; The Myeloma Institute for Research and Therapy/University of Arkansas for Medical Sciences, Little Rock, AR; University of Arkansas for Medical Sciences, Little Rock, AR

459Clinical Characteristics and Outcomes of West Nile Neuroinvasive Disease in Immunocompromised Hosts: A case-Control Study

Disease in Immunocompromised Hosts: A case-Control Study Senu Apewokin, MD; Aasiya Matin, MD; Naveen Sanath Kumar, MD; Shebli Atrash, MD; Bakhous Aziz; Jameel Muzaffar; Vyjayanthi Ganga, MD; Monica Grazziutti, MD; Medicine, University Of Arkansas For Medical Sciences, Little Rock, AR; Myeloma Institute or Research and Therapy, UNIVERSTIY OF ARKANSAS FOR MEDICAL SCIENCES, LITTLE ROCK, AR; The Myeloma Institute for Research and Therapy/University of Arkansas for Medical Sciences, Little Rock, AR; Myeloma, UAMS myeloma institute., little rock, AR; Mirt, 4301 West Markham, little ROCK, AR

Severe mucositis and Clostridium difficile infection in adult autologous stem cell recipients: another question of the chicken or the egg?

We read with much interest the article by Alonso et al. where they studied Clostridium difficile infection (CDI) in 873 autologous stem cell transplant recipients and reported various risk factors associated with development of CDI [1]. In their discussion, theymentioned grade 2mucositis was a risk factor for development of CDI, and 2 possible explanations were offered. Their first explanation was a potential sampling bias because CDI testing was only by indication. In the second explanation, they postulated that mucosal damage resulting from chemotherapy-induced colitis as well as alteration in gut microbiome led to CDI, thereby implying severe mucositis preceded CDI. In our opinion, although this may be the possible pathogenesis, it is important to also consider an alternate hypothesis; which is that acquisition of CDI in such patients leads to the development of higher grades of mucositis and not necessarily the converse. In other words, severe mucositis could be a manifestation of CDI. In data published by Silva et al. [2] where lethal doses of methotrexate were administered to hamster models, they demonstrated that in the absence of CDI-active antibiotic treatment, enterocolitis developed in 85% of the hamsters.