Temperature Trajectory Subphenotypes in Oncology Patients with Neutropenia and Suspected Infection.

Rationale: Despite etiologic and severity heterogeneity in neutropenic sepsis, management is often uniform. Understanding host response clinical subphenotypes might inform treatment strategies for neutropenic sepsis. Objectives: In this retrospective two-hospital study, we analyzed whether temperature trajectory modeling could identify distinct, clinically relevant subphenotypes among oncology patients with neutropenia and suspected infection. Methods: Among adult oncologic admissions with neutropenia and blood cultures within 24 hours, a previously validated model classified patients' initial 72-hour temperature trajectories into one of four subphenotypes. We analyzed subphenotypes' independent relationships with hospital mortality and bloodstream infection using multivariable models. Measurements and Main Results: Patients (primary cohort n = 1,145, validation cohort n = 6,564) fit into one of four temperature subphenotypes. "Hyperthermic slow resolvers" (pooled n = 1,140 [14.8%], mortality n = 104 [9.1%]) and "hypothermic" encounters (n = 1,612 [20.9%], mortality n = 138 [8.6%]) had higher mortality than "hyperthermic fast resolvers" (n = 1,314 [17.0%], mortality n = 47 [3.6%]) and "normothermic" (n = 3,643 [47.3%], mortality n = 196 [5.4%]) encounters (P < 0.001). Bloodstream infections were more common among hyperthermic slow resolvers (n = 248 [21.8%]) and hyperthermic fast resolvers (n = 240 [18.3%]) than among hypothermic (n = 188 [11.7%]) or normothermic (n = 418 [11.5%]) encounters (P < 0.001). Adjusted for confounders, hyperthermic slow resolvers had increased adjusted odds for mortality (primary cohort odds ratio, 1.91 [P = 0.03]; validation cohort odds ratio, 2.19 [P < 0.001]) and bloodstream infection (primary odds ratio, 1.54 [P = 0.04]; validation cohort odds ratio, 2.15 [P < 0.001]). Conclusions: Temperature trajectory subphenotypes were independently associated with important outcomes among hospitalized patients with neutropenia in two independent cohorts.

Safety and efficacy of weight-based ganciclovir dosing strategies in overweight/obese patients.

BACKGROUND: The management of cytomegalovirus (CMV) is particularly challenging as both CMV and its usual first-line treatment, ganciclovir, are associated with neutropenia. Ganciclovir dosing is weight-based, most commonly utilizing total body weight (TBW). The subsequent high doses of ganciclovir in overweight/obese patients may increase the risk of toxicity. Utilizing adjusted body weight (AdjBW) dosing may help mitigate this risk. Therefore, the objective of this study was to evaluate the difference in toxicity and efficacy between TBW and AdjBW ganciclovir dosing strategies in overweight/obese patients. METHODS: This retrospective study conducted safety and efficacy analyses of ganciclovir courses (≥72 h) used as CMV treatment. The primary safety outcome was the incidence of neutropenia (absolute neutrophil count <1000 cells/µL), and the primary efficacy outcome was a 2-log decrease in CMV polymerase chain reaction within 4 weeks following ganciclovir initiation. In both analyses, courses were excluded in which ganciclovir was dosed outside of specified renal dosing parameters for >20% of the course. RESULTS: Among the 253 courses in the safety cohort, there was no difference in the incidence of neutropenia (17.4% vs. 13.5%, p = .50) in AdjBW compared to TBW dosing. In the 62 courses evaluating efficacy, there was no statistical difference between AdjBW and TBW dosing (60.0% vs. 45.2%, p = .28). No subgroups were identified in which AdjBW dosing was advantageous. CONCLUSION: Utilization of AdjBW ganciclovir dosing did not result in decreased neutropenia or treatment efficacy as compared to TBW dosing. Further studies with larger patient populations would be beneficial to confirm these findings.

Evaluation of Total Body Weight versus Adjusted Body Weight Voriconazole Dosing in Obese Patients.

This retrospective single-center study of a cohort of adult patients who received voriconazole with a steady-state trough concentration measured during therapy evaluated the rate of therapeutic trough attainment using adjusted body weight (AdjBW)-based and total body weight (TBW)-based dosing in overweight and obese patients. Of the 130 patients included, 45 patients received TBW-based dosing and 85 patients received AdjBW-based dosing. Therapeutic trough attainment was significantly improved with AdjBW-based dosing compared to TBW-based dosing (64.7% versus 46.7%; P = 0.047).

Multicenter comparison of high-dose cytarabine-based regimens versus liposomal daunorubicin and cytarabine (CPX-351) in patients with secondary acute myeloid leukemia.

Liposomal daunorubicin/cytarabine (CPX-351) gained FDA approval for secondary AML after demonstrating improved outcomes over daunorubicin and cytarabine (7 + 3). A number of study limitations prompted a comparison of safety/efficacy of CPX-351 against regimens containing a purine analogue and high-dose cytarabine (HIDAC). This retrospective study compared complete response rates with/without count recovery (CR/CRi) between HIDAC-based regimens and CPX-351 in 169 patients with newly diagnosed sAML. The CR/CRi rate was 62.7% in the HIDAC-based therapy arm vs. 47.9% in the CPX-351 arm (p = 0.002 [one-sided for non-inferiority]). Median time to absolute neutrophil and platelet count recovery was shorter after HIDAC-based therapy (18 and 23 days, respectively) compared to CPX-351 (36 and 38 days; p < 0.001). Median overall survival was 9.8 months in the HIDAC-based group and 9.14 months in the CPX-351 group. 30-day mortality was greater with CPX-351 (8.5%) compared to HIDAC-based (1.3%; p = 0.039). These results reveal comparable efficacy and favorable safety with HIDAC-based regimens.

Bloodstream Infections and Delayed Antibiotic Coverage Are Associated With Negative Hospital Outcomes in Hematopoietic Stem Cell Transplant Recipients.

BACKGROUND: Bloodstream infections (BSIs) are common after hematopoietic stem cell transplantation (HSCT) and are associated with increased long-term morbidity and mortality. However, short-term outcomes related to BSI in this population remain unknown. More specifically, it is unclear whether choices related to empiric antimicrobials for potentially infected patients are associated with patient outcomes. RESEARCH QUESTION: Are potential delays in appropriate antibiotics associated with hospital outcomes among HSCT recipients with BSI? STUDY DESIGN AND METHODS: We conducted a retrospective cohort study at a large comprehensive inpatient academic cancer center between January 2014 and June 2017. We identified all admissions for HSCT and prior recipients of HSCT. We defined potential delay in appropriate antibiotics as > 24 h between positive blood culture results and the initial dose of an antimicrobial with activity against the pathogen. RESULTS: We evaluated 2,751 hospital admissions from 1,086 patients. Of these admissions, 395 (14.4%) involved one or more BSIs. Of these 395 hospitalizations, 44 (11.1%) involved potential delays in appropriate antibiotics. The incidence of mortality was higher in BSI hospitalizations than in those without BSI (23% vs 4.5%; P < .001). In multivariable analysis, BSI was an independent predictor of mortality (OR, 8.14; 95% CI, 5.06-13.1; P < .001). Mortality was higher for admissions with potentially delayed appropriate antibiotics than for those with appropriate antibiotics (48% vs 20%; P < .001). Potential delay in antibiotics was also an independent predictor of mortality in multivariable analysis (OR, 13.8; 95% CI, 5.27-35.9; P < .001). INTERPRETATION: BSIs were common and independently associated with increased morbidity and mortality. Delays in administration of appropriate antimicrobials were identified as an important factor in hospital morbidity and mortality. These findings may have important implications for our current practice of empiric antibiotic treatment in HSCT patients.

Factors Associated With Clinical Deterioration Among Patients Hospitalized on the Wards at a Tertiary Cancer Hospital.

PURPOSE: Patients hospitalized outside the intensive care unit (ICU) frequently experience clinical deterioration. Little has been done to describe the landscape of clinical deterioration among inpatients with cancer. We aimed to describe the frequency of clinical deterioration among patients with cancer hospitalized on the wards at a major academic hospital and to identify independent risk factors for clinical deterioration among these patients. METHODS: This was a retrospective cohort study at a 1,300-bed urban academic hospital with a 138-bed inpatient cancer center. We included consecutive admissions to the oncology wards between January 1, 2014, and June 30, 2017. We defined clinical deterioration as the composite of ward death and transfer to the ICU. RESULTS: We evaluated 21,219 admissions from 9,058 patients. The composite outcome occurred during 1,945 admissions (9.2%): 1,365 (6.4%) had at least one ICU transfer, and 580 (2.7%) involved ward death. Logistic regression identified several independent risk factors for clinical deterioration, including the following: age (odds ratio [OR], 1.33 per decade; 95% CI, 1.07 to 1.67), male sex (OR, 1.15; 95% CI, 1.05 to 1.33), comorbidities, illness severity (OR, 1.11; 95% CI, 1.10 to 1.13), emergency admission (OR, 1.45; 95% CI, 1.26 to 1.67), hospitalization on particular wards (OR, 1.525; 95% CI, 1.326 to 1.67), bacteremia (OR, 1.24; 95% CI, 1.01 to 1.52), fungemia (OR, 3.76; 95% CI, 1.90 to 7.41), tumor lysis syndrome (OR, 3.01; 95% CI, 2.41 to 3.76), and receipt of antimicrobials (OR, 2.04; 95% CI, 1.72 to 2.42) and transfusions (OR, 1.65; 95% CI, 1.42 to 1.92). CONCLUSION: Clinical deterioration was common; it occurred in more than 9% of admissions. Factors independently associated with deterioration included comorbidities, admission source, infections, and blood product transfusion.

Carfilzomib: a second-generation proteasome inhibitor for the treatment of multiple myeloma.

PURPOSE: The pharmacology, clinical efficacy, safety, cost, dosage and administration, and place in therapy of carfilzomib for the treatment of multiple myeloma (MM) are reviewed. SUMMARY: Proteasome inhibition in MM has become a cornerstone in treatment regimens. Carfilzomib, a second-generation proteasome inhibitor, has demonstrated efficacy in patients with relapsed or refractory disease who have received at least two prior therapies including bortezomib and an immunomodulatory agent. Carfilzomib is an irreversible inhibitor and binds to a different site than bortezomib on the proteasome. A Phase II study evaluated 266 heavily pretreated patients with relapsed or refractory MM who had received at least two prior therapies, including bortezomib and either thalidomide or lenalidomide. The overall response rate was 23.7%, with a median duration of response of 7.8 months. The median overall survival time was 15.6 months. Carfilzomib has a similar adverse-effect profile to bortezomib, including anemia, thrombocytopenia, fatigue, dyspnea, and nausea; however, it does not result in the development or worsening of peripheral neuropathy. Carfilzomib is infused intravenously over 2-10 minutes for 2 consecutive days every week for three out of four weeks, with a 12-day rest period. Dosing is based on the patient's actual body surface area. Carfilzomib is available in 60-mg vials for single infusion. The total cost for a year of therapy is approximately $155,852. CONCLUSION: Carfilzomib, a second-generation proteasome inhibitor that irreversibly inhibits the 26S proteasome, has shown efficacy in clinical studies of patients with relapsed or refractory MM, though the drug's role in the management of MM is not yet clear.