The personal impact of living with a myeloproliferative neoplasm.

OBJECTIVE: The aim of this study is to gain insight into the physical, psychological and social impact of having a myeloproliferative neoplasm (MPN), a rare type of cancer with an often chronic course. METHODS: An online survey was conducted among 455 Dutch MPN patients (62.7% female, age M 63) to explore the impact of the disease by measuring the MPN symptom burden (MPN-SAF TSS) and quality of life (QoL) (EORTC QLQ-C30) and its subscales within a hierarchical QoL model. We examined differences in MPN symptom burden and QoL in relation to sociodemographic and disease-related factors. Hierarchical regression analysis was used to explain variances in QoL. RESULTS: Most patients (97%) experienced MPN-related health complaints, with a significantly higher MPN symptom burden in women (M 31.50) compared to men (M 24.10). Regarding to fatigue and cognitive functioning MPN patients suffered more compared to a reference group of other cancers. MPN subtype or type of treatment did not show significant differences in MPN symptom burden or QoL. However, experiencing side effects, complications or comorbidities significantly negatively affected MPN symptom burden and QoL. 48.8% of patients reported that MPN affected their ability to work. The explained variance in overall QoL was 58%, most importantly by disease progression, comorbidities, MPN symptom burden and role, emotional and social functioning. CONCLUSION: This study revealed that having an MPN has a negative impact on several domains of QoL. Symptom assessment and support should be included in the healthcare management of MPN patients.

Busulfan Exposure Target Attainment in Adults Undergoing Allogeneic Hematopoietic Cell Transplantation: A Single Day Versus a Multiple Day Therapeutic Drug Monitoring Regimen.

Busulfan exposure has previously been linked to clinical outcomes, hence the need for therapeutic drug monitoring (TDM). Study objective was to evaluate the effect of day 1 TDM-guided dosing (regimen d1) versus days 1 + 2 TDM-guided dosing (regimen d1 + 2) on attaining adequate busulfan exposure. In this observational study, we included all adults who received an allogeneic HCT with intravenous once daily busulfan over 4 days as part of the conditioning regimen at the University Medical Centre Utrecht or between July 31, 2014 and November 12, 2021. The primary outcome was attainment of the therapeutic busulfan target (cumulative area under the curve [AUCcum] 80-100 mg*h/L). Dose adjustment was based on the estimated AUC of the preceding dosing day(s). Additional TDM was performed in the event of large dose adjustments (≥25%). The choice of TDM regimen was solely based on the first day the busulfan dose was administered (regimen d1 + 2 occurred when conditioning started on a Saturday). In all patients, blood sampling was performed on day 4 for evaluation. The AUCcum was estimated using a validated population pharmacokinetic model. Busulfan target exposure was compared between both TDM regimen groups using a propensity score adjusted logistic regression model. The variance in the AUCcum between the TDM regimens was compared using the F-test. Patients were stratified for age (categorical). In regimen d1, 87.6% (n = 113/129) attained a therapeutic busulfan exposure, while in regimen d1 + 2 a proportion of 97.4% was found (n = 74/76, adjusted odds ratio for non-therapeutic AUC = 0.19, 95% confidence interval [95% CI]: 0.04-0.89). Variance of busulfan exposure in the regimen d1 group (SD = 6.8 mg*h/L) differed significantly from the variance in the regimen d1 + 2 group (SD = 3.6 mg*h/L, F-test, P < .001). Performing busulfan TDM on both day 1 and day 2, rather than only on day 1, improves busulfan target exposure attainment in adults undergoing HCT, provided that subsequent TDM is carried out if required.

Fludarabine exposure in the conditioning prior to allogeneic hematopoietic cell transplantation predicts outcomes.

Fludarabine is the most frequently used agent in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). Body surface area-based dosing leads to highly variable fludarabine exposure. We studied the relation between fludarabine exposure and clinical outcomes. A retrospective, pharmacokinetic-pharmacodynamic analysis was conducted with data from patients undergoing HCT with fludarabine (160 mg/m2) as part of a myeloablative conditioning (busulfan targeted to an area under the plasma-concentration-time curve [AUC] of 90 mg*h/L) and rabbit antithymocyte globulin (6-10 mg/kg; from day -9/-12) between 2010 and 2016. Fludarabine exposure as AUC was calculated for each patient using a previously published population pharmacokinetic model and related to 2-year event-free survival (EFS) by means of (parametric) time-to-event models. Relapse, nonrelapse mortality (NRM), and graft failure were considered events. One hundred ninety-two patients were included (68 benign and 124 malignant disorders). The optimal fludarabine exposure was determined as an AUC of 20 mg*h/L. In the overexposed group, EFS was lower (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.5; P = .02), due to higher NRM (HR, 3.4; 95% CI, 1.6-6.9; P <001) associated with impaired immune reconstitution (HR, 0.43; 95% CI, 0.26-0.70; P <001). The risks of NRM and graft failure were increased in the underexposed group (HR, 3.3; 95% CI, 1.2-9.4; P = .02; HR, 4.8; 95% CI, 1.2-19; P = .02, respectively). No relationship with relapse was found. Fludarabine exposure is a strong predictor of survival after HCT, stressing the importance of optimum fludarabine dosing. Individualized dosing, based on weight and "renal function" or "therapeutic drug monitoring," to achieve optimal fludarabine exposure might improve survival.

Efficacy of oral prophylactic antibiotics in neutropenic afebrile oncology patients: a systematic review of randomised controlled trials.

The use of oral prophylactic antibiotics in oncology patients is still a matter of debate. A systematic review was performed to assess the evidence for the effectiveness of oral prophylactic antibiotics to decrease bacteraemia and infection-related mortality in oncology patients during neutropenic episodes. Medline, Embase and the Cochrane register of controlled trials were searched from 1966 until 2002. The main outcome was the number of patients with documented bacteraemia (Gram-negative or Gram-positive bacteraemia) and infection related mortality. Data-extraction and quality assessment were performed independently by two reviewers. A total of 22 trials met the inclusion criteria. Seventeen trials compared prophylaxis (quinolones or Trimethoprim/sulfamethoxazole (TMP/SMZ)) to no prophylaxis. The incidence of Gram-negative bacteraemia decreased significantly (pooled OR 0.39, 95% CI 0.24-0.62) without an increase in Gram-positive bacteraemia. Quinolone-based regimens showed a stronger reduction in Gram-negative bacteraemia while TMP/SMZ based regimens were more effective in Gram-positive bacteraemia. Infection related mortality due to bacterial causes decreased with the use of prophylactic antibiotics (pooled OR 0.49, 95% CI 0.27-0.88). No increase in fungaemia or fungal related mortality was seen with the use of oral prophylaxis. In conclusion, this study has shown that oral prophylactic antibiotics decreased Gram-negative bacteraemia and infection related mortality due to bacterial causes during neutropenic episodes in oncology patients.

Normal IncA expression and fusogenicity of inclusions in Chlamydia trachomatis isolates with the incA I47T mutation.

To investigate the correlation between the incA I47T mutation in Chlamydia trachomatis and the nonfusogenic phenotype, the incA genes of 25 isolates were sequenced. Four major sequence types were identified. Seven isolates (28%) had the I47T mutation. Isolates representing the four sequence types expressed IncA in the membrane of one large single inclusion. In conclusion, the incA I47T mutation is not associated with the nonfusogenic phenotype.