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OBJECTIVES: Linezolid is an oxazolidin commonly related to the development of haematological toxicity, being renal clearance the major factor involved in the drug clearance. The aim of this study is to evaluate the influence of increased filtration rates in the incidence of linezolid-induced haematological toxicity by comparing augmented renal clearance (ARC) patients versus normal renal function patients. MATERIAL AND METHODS: A retrospective, observational study was conducted on hospitalized patients treated with linezolid for 5 days or more during 2014-2019 period. Patients with a filtration rate of ≥130 mL/min versus reference patients (60-90 mL/min) were compared. Haematological toxicity was defined as a decrease of 25% in platelets, of 25% in haemoglobin, and/or 50% in neutrophils from baseline. Toxicity relevance was classified according to Common Terminology Criteria for Adverse Events v5. Incidence of haematological toxicity between groups was studied by chi-square and Fisher test. Furthermore, percentage diminution of all 3 parameters was calculated and compared by Mann-Whitney test and treatment interruption and transfusion requirements were registered. RESULTS: 30 ARC patients and 38 reference patients were included. Haematological toxicity was observed in 16.66% of ARC patients vs 44.74% of reference patients (P=.014); thrombocytopenia in 13.33% vs 36.84% (P=.051), anaemia in 3.3% vs 10.52% (P=.374) and neutropenia in 10% vs 23.68% (P=.204). Median percentage of platelets decrease in ARC patients was -10.36 (-193.33-62.03) vs 2.68 (-163.16-82.71) in reference patients (P=.333), while haemoglobin decrease was 2.50 (-12.12-25.93) vs 9.09 (-17.72-30.63) (P=.047) and neutrophils decrease was 9.14 (-73.91-76.47) vs 27.33 (-86.66-90.90) (P=.093). 10.5% of normal renal function patients reported at least 1 adverse event grade 3 or superior while 2.6% of them interrupted treatment and 5.2% had transfusion requirements. No major events or interruptions were reported in ARC patients. CONCLUSION: Our findings suggest a lower incidence and clinical relevance of haematological toxicity in augmented renal clearance patients. Thrombocytopenia was the major event in both populations. This might be related to a lower exposure to the drug due to the higher clearance and likely lower therapeutic efficiency. These results suggest a potential benefit of therapeutic drug monitoring on high risk patients.

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WHAT IS KNOWN AND OBJECTIVES: Haematological toxicity including thrombocytopenia, anaemia and leucopenia is the main adverse events of linezolid (LZD) therapy. This study aimed to investigate the risk factors for LZD-induced haematological toxicity and define the threshold of plasma trough concentration to minimize the haematological toxicity. METHODS: 145 patients who received LZD for more than 10 days were retrospectively reviewed to determine the incidence of LZD-induced haematological toxicity. Meanwhile, the risk factors of haematological toxicity were confirmed by univariate and multivariate logistic regression analysis. RESULTS AND DISCUSSION: 9 (6.2%) patients developed leucopenia, while 52 (35.9%) and 26 (17.9%) patients developed thrombocytopenia and anaemia, respectively. The estimated glomerular filtration rate (eGFR) <90 ml/min/1.73 m2 (OR, 2.744; 95% CI, 1.117-6.734; p = 0.028) and baseline platelet count <200 × 109 /L (OR, 6.817; 95% CI, 2.870-16.193; p < 0.0001) were found to be significant risk factors for LZD-related thrombocytopenia. Aspartate aminotransferase (AST) >80 U/L (OR, 4.844; 95% CI, 1.207-19.451; p = 0.026) and eGFR <90 ml/min/1.73 m2 (OR, 7.132; 95% CI, 2.088-24.357; p = 0.002) were the risk factors for LZD-related anaemia. However, no significant risk factors were identified for LZD-related leucopenia. Moreover, LZD plasma trough concentration >8 mg/L [OR, 3.047; 95% CI, 1.233-7.539; p = 0.016] could be a predictor for the development of thrombocytopenia and anaemia. WHAT IS NEW AND CONCLUSION: Hepatic and/or renal dysfunction are the risk factors for LZD-related haematological toxicity, while the target plasma trough concentration within 8 mg/L via dose reduction could minimize the haematological toxicity induced by LZD.

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BACKGROUND: Fumonisin B1 (FB1) is one of the most common mycotoxins contaminating feed and food. Although regulatory limits about fumonisins have been established in some countries, it is still very important to conduct research on lower doses of FB1 to determine the tolerance limits. The aim of this study was to investigate the effects of different concentrations of FB1, provide further evidence about the toxic doses- and exposure time-associated influence of FB1 on mice, especially low levels of FB1 for long-term exposure. METHODS: Female BALB/c mice were treated intragastrically (i.g.) with fumonisin B1 (FB1) solutions (0 mg/kg body weight (BW), 0.018 mg/kg BW, 0.054 mg/kg BW, 0.162 mg/kg BW, 0.486 mg/kg BW, 1.458 mg/kg BW and 4.374 mg/kg BW) once a day for 8 weeks to obtain dose- and time-dependent effects on body and organ weights, hematology, blood chemical parameters and liver and kidney histopathology. RESULTS: After the long-term administration of FB1, the body weights of the mice tended to decrease. Over time, FB1 first increased the relative spleen weight, then increased the relative kidney weight, and finally increased the relative liver weight. The mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hemoglobin (HGB), white blood cells (WBC), platelets (PLT), and mean platelet volume (MPV) were significantly elevated after treatment with FB1 for 8 weeks. Moreover, exposure time-dependent responses were found for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) level, which were coupled with hepatic histopathological findings, necroinflammation and vacuolar degeneration and detrital necrosis. Linear dose response was also found for liver histopathology, in which, even the minimum dose of FB1 exposure also caused changes. Renal alterations were moderate compared to hepatic alterations. CONCLUSION: In conclusion, we demonstrated the systemic toxic effects of different doses of FB1 in female BALB/c mice at different times. Our data indicated that the effects observed in this study at the lowest dose tested are discussed in relation to the currently established provisional maximum tolerable daily intake (PMTDI) for fumonisins. This study suggested that recommendations for the concentration of FB1 in animals and humans are not sufficiently protective and that regulatory doses should be modified to better protect animal and human health. The toxicity of FB1 needs more attention.

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PURPOSE: The aim was to explore the correlation between increasing doses of [6R]-5,10-methylenetetrahydrofolate (arfolitixorin) and plasma concentrations of deoxyuridine (dUr) in patients with metastatic colorectal cancer (mCRC), subjected to 5-fluorouracil (5-FU)-based chemotherapy. The aim was further to investigate the possibility to predict toxicity and clinical response during treatment using gender, age, and plasma dUr as explanatory variables. METHODS: Thirty-three patients from the ISO-CC-005 phase I/IIa study, which investigated safety and tolerability of arfolitixorin at four dose levels, were included. Toxicity and clinical response were evaluated after 4 cycles of chemotherapy. Plasma dUr was quantified before (0 h) and 24 h after 5-FU administration at the first (C1) and fourth (C4) cycle using LC-MS/MS. Fit modelling was used to predict toxicity and clinical response. RESULTS: The dUr levels increased with increasing arfolitixorin dose. Females had higher total and haematological toxicity scores (p = 0.0004 and 0.0089, respectively), and needed dose reduction more often than males (p = 0.012). Fit modeling showed that gender and the dUr levels at C1-0 h and C4-24 h predicted total toxicity (p = 0.0011), whereas dUr C4-0 h alone was associated with gastrointestinal toxicity (p = 0.026). Haematological toxicity was predicted by gender and age (p = 0.0071). The haematological toxicity score in combination with the dUr levels at C1-24 h and C4-24 h predicted early clinical response (p = 0.018). CONCLUSION: The dUr level before and during administration of 5-FU and arfolitixorin was predictive for toxicity and early clinical response and could be a potential surrogate marker for thymidylate synthase inhibition in patients with mCRC. TRIAL REGISTRATION: NCT02244632, first posted on ClinicalTrials.gov on September 19, 2014.

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Although methotrexate (MTX) for rheumatoid arthritis (RA) sometimes causes severe haematological toxicities in users with chronic kidney disease (CKD), data are limited regarding the risk of these events and the preventive effect of folic acid. This study evaluated the risk of haematological toxicities and the efficacy of folic acid in MTX users with CKD using the Japanese Adverse Drug Event Report. In total, 5,648 oral MTX users with RA were identified, including 630 with haematological toxicities. MTX users with CKD had significantly increased risk of haematological toxicities compared with those without CKD when folic acid was not used (OR 3.72; 95% CI 2.87-4.81; P < 0.01). Multivariate logistic analysis showed that the risk of haematological toxicities was significantly decreased by only folic acid (OR 0.16; 95% CI 0.04-0.62; P < 0.01). This result provides useful information for preventing severe haematological toxicities in MTX users with CKD and RA.

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Developing precision medicine is a major trend in clinical oncology. The main adverse effects of ifosfamide, actinomycin D and vincristine (IVA) treatment for rhabdomyosarcoma are haematological toxicities such as neutropenia or thrombocytopenia. The severity of these effects vary among patients but their dynamic profiles are similar. A non-empirical adjustment of the chemotherapy dose to avoid severe toxicities could help secure the treatment administration. Twenty-four patients with rhabdomyosarcoma treated with IVA chemotherapy courses were selected. Before and during each cycle, routine multiple blood cell counts were performed allowing for a dynamic study of the haematological toxicities. We developed a machine learning analysis using a gradient boosting regression technique to forecast the ifosfamide induced haematological toxicities as a function of neutrophils and platelets initial levels and the initial ifosfamide dose. To validate models' accuracy, predicted and observed neutrophils and platelets levels were compared. The model was able to reproduce the dynamic profiles of the haematological toxicities. Among all cycles, the mean absolute errors between predicted and observed neutrophils and platelets levels were 1.0 and 72.8 G/L, respectively. Adjusting a patient's ifosfamide dose based upon the predicted haematological toxicity levels at the end of a treatment cycle could enable tailored treatment.

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BACKGROUND AND PURPOSE: To determine if suppression of active bone marrow, as defined on FDG PETCT, is seen in on-treatment imaging of anal cancer patients receiving concurrent chemoradiation. METHODS AND MATERIALS: Scans from 26 patients participating in the ART trial (full title: Anal squamous cell carcinoma: Investigation of functional imaging during chemoRadioTherapy), a single center observational study with FDG PETCT prior to radiotherapy and at fraction 8-10 of concurrent chemoradiation were analysed. Active bone marrow was contoured in both the pelvis and un-irradiated thoracic spine. SUV and volume of active bone marrow after 8-10 fractions of treatment were compared to baseline. Dose metrics to pelvic active bone marrow were extracted and compared to reduction in SUV/active bone marrow volume and to blood count nadir using linear regression. RESULTS: Suppression of active bone marrow is seen in the pelvis by a reduction in mean SUV and volume of active bone marrow after 8-10 fractions of treatment. Suppression is not seen in un-irradiated thoracic spine. Dose metrics were associated with reduced SUV and reduced volume of active bone marrow. Volume of active bone marrow receiving <20 Gy was associated with WCC/ANC nadir. 20 Gy was identified as the most likely clinically meaningful dose threshold for toxicity. Volume of active bone marrow receiving <20 Gy correlated to WCC and ANC with an increase of 100 cc being associated with an increase of 0.4 and 0.3 respectively. CONCLUSION: The effect of concurrent chemoradiation in suppression of active bone marrow is seen in on-treatment FDG PETCT scans. Chemotherapy appears well tolerated after 2 weeks of treatment.

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BACKGROUND: (177)Lu-DOTATATE is a valuable treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. Though well tolerated in general, bone marrow toxicity can, besides renal exposure, become dose limiting and affect the ability to sustain future therapies. The aim of this study was to develop a novel planar image-based method for bone marrow dosimetry and evaluate its correlation with haematological toxicity during (177)Lu-DOTATATE treatment. In this study, 46 patients with advanced neuroendocrine tumours were treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Planar gamma camera images were acquired at 2, 24, 48 and 168 h post-injection. Whole-body regions of interest were created in the images, and a threshold-based segmentation algorithm was applied to separate the uptake of (177)Lu-DOTATATE into high and low uptake compartments. The conjugate view method was used to quantify the activity, the accumulated activity was calculated and the absorbed dose to the bone marrow was estimated according to the MIRD scheme. Patients were monitored for haematological toxicity based on haemoglobin (Hb), white blood cell (WBC) and platelet (PLT) counts every other week during the treatment period. RESULTS: The mean absorbed dose to the bone marrow was estimated to 0.20 Gy (0.11-0.37 Gy) per 7.4 GBq of (177)Lu-DOTATATE, and the mean dose per fraction correlated with a decrease in Hb (p = 0.01), WBC (p < 0.01) and PLT (p < 0.01) counts. The total mean absorbed dose to the bone marrow was 0.64 Gy (0.30-1.5 Gy) per 24 GBq (8.2-37 GBq) of (177)Lu-DOTATATE and also correlated with a decrease in Hb (p < 0.01), WBC (p = 0.01) and PLT (p < 0.01) counts. CONCLUSIONS: The planar image-based method developed in this study resulted in similar absorbed doses to the bone marrow as reported in earlier studies with blood-based bone marrow dosimetry. The results correlated with haematological toxicity, making it a promising method for estimating bone marrow doses in (177)Lu-DOTATATE treatment without the need for blood and urine sampling.

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INTRODUCTION: Hypofractionated External Beam Radiotherapy (HFRT) is a relatively new adjuvant Radiotherapy (RT) schedule for breast cancers following breast conservation surgery and less commonly, following mastectomy. Here we report our experience on normal tissue exposure and acute toxicity of HFRT after mastectomy. AIM: To assess the dosimetric outcomes and acute toxicity profile of adjuvant HFRT following mastectomy for breast cancer. MATERIALS AND MATERIALS: This prospective observational study considered consecutive patients planned for adjuvant HFRT (42.5 Gy in 16 sessions delivered over 3 weeks) to the chest wall with/without regional nodes between October 2014 and June 2015. The dosimetric parameters including dose homogeneity to the target volume and exposure to heart and lung were analyzed. Acute haematological and dermatological toxicity was recorded until upto three months after completion of RT. RESULTS: Among the 56 patients treated with HFRT, the mean age was 49 years (range: 28-69 years). Pathologically positive nodes and ≥pT3 primary was observed in 44 (78.6%) and 12 (21.4%) patients, respectively. Majority (87.5%) received prior adjunct chemotherapy. RT to the supraclavicular fossa was delivered for 39 (69.6%) patients. The mean V90 and V95 to the Planning Target Volume (PTV) were 95% (± 3.3%) and 93% (± 4%), respectively. The maximum dose received was on average 47.7 Gy (112%; range: 46.2-48.5 Gy). The mean lung dose was 10.2 Gy (± 3.5 Gy) and V20 was 20.9% (± 6%). The mean V25 to heart was 6.6% (± 4.8%) for left sided and 0% for right sided tumours (p=0.001). Acute skin toxicity peaked at completion of RT and was tolerable (grade 0, I, II and III reactions were 75%, 16% and 1.8%, respectively). No patient had ≥ grade III haematological toxicity, and treatment was not interrupted for any patient. CONCLUSION: Adjuvant HFRT could be planned while meeting the dose constraints to normal tissues in all patients and was well tolerated, with mild to moderate acute adverse effects that did not warrant any therapeutic intervention or treatment interruption.

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BACKGROUND: Somatostatin analogue-based radionuclide therapy with (177)Lu-DOTATATE is an important treatment option for patients with advanced neuroendocrine tumours overexpressing somatostatin receptors. In addition to the kidneys, the bone marrow is a major dose-limiting organ. The correlation between developed haematological toxicity and absorbed dose to the bone marrow is poor, which indicates that other factors affect haematological response. The spleen has an important role in the haematopoetic system, including being a reservoir for blood cells. It is also the organ that receives the highest mean absorbed dose during (177)Lu-DOTATATE treatment. The aim of this study was to analyse mean absorbed dose to the spleen and its correlation with haematological toxicity, and to explore changes in splenic volume. The study included 41 patients treated with 7.2 GBq (3.5-8.3 GBq) of (177)Lu-DOTATATE on two to five occasions. Following each fraction, planar whole-body scans were acquired at 2, 24, 48, and 168 h, and a SPECT/CT at 24 h post-injection. Mean absorbed spleen dose was calculated utilising planar images for time-activity data and SPECT to adjust activity amounts. Splenic volume information was collected from diagnostic CT scans at baseline and follow-up. RESULTS: Median and total absorbed spleen doses were estimated to 4.5 and 15 Gy, respectively. Total absorbed spleen dose correlated with decrease in Hb (p = 0.02), but not WBC (p = 0.31) or PLT (p = 0.65) counts. For patients without bone metastases, mean absorbed spleen dose correlated with decrease in PLT (p = 0.04) but not Hb (p = 0.16) or WBC (p = 0.42) counts. The spleen volume was reduced to 75 % (p < 0.001) of original values (200 vs. 260 ml) at a mean follow-up of 36 months. CONCLUSIONS: Haematological toxicity according to Hb counts was moderately but significantly correlated with total absorbed spleen dose. This supports the possibility that radiation exposure of the spleen affects overall haematological response during (177)Lu-DOTATATE treatment.

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AIM: Rhenium-188-HEDP ((188)Re-HEDP) is an effective radiopharmaceutical for the palliative treatment of osteoblastic bone metastases. However, only limited data on its routine use are available and its effect on quality of life (QoL) has not been studied. Therefore, we evaluated the clinical benefit of (188)Re-HEDP in routine clinical care. PATIENTS AND METHODS: Prostate or breast cancer patients with painful bone metastases receiving (188)Re-HEDP as a routine clinical procedure were eligible for evaluation. Clinical benefit was assessed in terms of efficacy and toxicity. Pain palliation and QoL were monitored using the visual analogue scale (VAS), corrected for opioid intake, and the EORTC QLQ-C30 Global health status/QoL-scale. Thrombocyte and leukocyte nadirs were used to assess haematological toxicity. RESULTS: 45 and 47 patients were evaluable for pain palliation and QoL, respectively. After a single injection of (188)Re-HEDP, the overall pain response rate was 69% and mean VAS-scores decreased relevantly and significantly (p < 0.05). Repeated treatment resulted in similar pain response. The overall QoL response rate was 68% and mean Global health status/QoL-scores increased relevantly and significantly. Haematological side effects were mild and transient. CONCLUSION: The clinically relevant response on pain and quality of life and the limited adverse events prove clinical benefit of treatment with (188)Re-HEDP and support its use in routine clinical care. Its effectiveness appears comparable to that of external beam radiotherapy.

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BACKGROUND AND PURPOSE: To determine if there are differences between dose to pelvic bone marrow (PBM) using intensity modulated radiotherapy (IMRT) under UK guidance versus conformal radiotherapy (CRT) per ACT II protocol and if differences translate to rates of early haematological adverse events grade 3 or greater (HT3+). METHODS AND MATERIALS: Two groups of 20+ patients, treated under IMRT and CRT regimes respectively, were identified. All patients underwent weekly blood cell count: haemoglobin (HgB), white cell count (WCC), absolute neutrophil count (ANC) and platelets (plats). Percent volume of PBM and sub structures receiving 5-25 Gy were tested for statistical significance. Regression models were used to test for correlation to blood counts. NTCP modeling was also performed. RESULTS: PMB dose metrics showed a significant increase in the IMRT group. Regression analysis showed iliac and lumbosacral PBM dose metrics to associate with reduced nadir ANC and WCC. NTCP at HT3+ was 0.13 using IMRT relative to 0.07 using CRT (p<0.05). CONCLUSION: Whilst this is a relatively small retrospective study and lacks information on the distribution of active PBM, IMRT treatment has been shown to significantly increase PMB irradiation. PBM dose metrics have been shown to be predictive of WCC and ANC suppression. NTCP modeling predicts much high risk of HT3+. Paradoxically, actual rates of HT3+ were comparable suggesting that differences in the distributions of dose metrics maybe a significant factor and/or that there are insufficiency in the NTCP modeling.

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BACKGROUND: Late-onset neutropenia (LON) is a known adverse effect to rituximab therapy. Information about its real incidence and clinical implications comes from case reports and few retrospective studies specifically designed to study LON. However, large prospective studies of LON are lacking in the literature. We aimed to determine the incidence of LON in a group of non-Hodgkin lymphoma patients treated with rituximab and to analyze the clinical course, complications, and risk factors associated with LON. PATIENTS AND METHODS: We retrospectively reviewed 183 patients with a diagnosis of non-Hodgkin lymphoma consecutively treated with rituximab alone or in combination with chemotherapy. RESULTS: We identified 11 patients with grade 3/4 LON (13 episodes) out of 183 patients (6%). The median time to onset of LON was 75 days, and the median time to recovery from neutropenia was 100 days. The median neutrophil count nadir was 0.55 × 10(9)/L (range, 0.06-0.9 × 10(9)/L). Two patients presented infectious complications, one with fatal outcome. CONCLUSION: In our experience, the incidence of recognized LON is low (6%), although its real incidence may be greater because of the asymptomatic course and quick recovery in most cases. Infectious complications are unusual, but life-threatening complications can emerge. A careful evaluation of all cases of LON is warranted.

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BACKGROUND: Recent research suggests a significant relationship between lean body mass (LBM) and toxicity from chemotherapeutic agents. We investigated if higher drug doses per kg LBM were associated with increased toxicity in stage IIIB/IV non-small cell lung cancer (NSCLC) patients receiving a first-line chemotherapy regimen dosed according to body surface area (BSA). METHODS: Data from patients randomised to receive intravenous gemcitabine 1000 mg/m(2) plus orally vinorelbine 60 mg/m(2) days 1 and 8 in a phase III trial comparing two chemotherapy regimens were analysed. LBM was estimated from assessment of the cross-sectional muscle area at the third lumbar level (L3) on computed tomography images obtained before chemotherapy commenced. Common terminology criteria for adverse events (CTCAE) grade 3-4 haematological toxicity and dose reduction and/or stop of treatment after the first course of chemotherapy were defined as primary and secondary toxicity outcomes. RESULTS: The study sample included 153 patients, mean age was 66 years, 55% were men, 87% had disease stage IV and 75% had performance status (PS) 0-1. Gemcitabine doses per kg LBM varied from 23.2 to 53.1 mg/kg LBM, and vinorelbine doses from 1.5 to 3.3 mg/kg LBM. Higher doses of gemcitabine per kg LBM were significantly associated with grade 3-4 haematological toxicity in bivariate (OR=1.12, 95% CI 1.03-1.23, p=0.008) and multivariate analyses (OR=1.15, 95% CI 1.01-1.29, p=0.018), as were also higher doses of vinorelbine per kg LBM. No significant association was found between drug doses per kg LBM and dose reduction and/or stop of treatment. CONCLUSION: The study showed that dose estimates according to BSA lead to a substantial variation in drug dose per kg LBM, and higher doses per kg LBM are a significant predictor for chemotherapy-induced haematological toxicity. The results indicate that taking LBM into account may lead to a better dose individualisation of chemotherapy.

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INTRODUCTION: Isoniazid (INH) is a widely used drug in the prophylaxis and treatment of tuberculosis. In the present study, isoniazid (INH)-induced toxicity was investigated according to the dosing-time in the 24-h scale in mice. METHODS: Two studies were carried out on a total of 180 male Swiss mice synchronized for 3 weeks to 12-hour light (rest) and 12-hour dark (activity) cycle (L/D: 12/12). In the first study a potentially lethal dose of INH (180 mg/kg) was administered by intraperitoneal (i.p.) route at six different circadian-times: 1, 5, 9, 13, 17 and 21 hours after light onset (HALO). In the second one, a sublethal dose (120 mg/kg) was administered at three circadian-times (1, 9 and 17 HALO) in order to evaluate the variation of haematological toxicity. Rectal temperature, body weight loss, survival (study 1) and complete cell count (study 2) were determined as toxicity endpoints. The Cosinor and ANOVA methods were used for the data statistical analysis. RESULTS: The Cosinor analysis of rectal temperature time series prior to treatment validated a circadian rhythm, which demonstrates that mice were well synchronized. Following INH injection, rectal temperature increased in all the six circadian stages at days 2 and 3. Body weight loss varied from -12% at 1 HALO to -7% at 13 HALO (P<0.001). The 24-h mean of mortality induced by INH was 38%. Such lethal toxicity varied according to the circadian dosing-time. Maximum (60%) and minimum (20%) survival rates were observed when INH was administered at 9 and 1 HALO respectively. The highest survival time (25 days) occurred when INH was injected at 9 HALO while the lowest survival time (7 days) occurred when INH was given at 1 HALO. The decrease of haematological variables (cytopenia) was dependent on the circadian dosing-time (P<0.001). The least haematological toxicity illustrated by leukopenia index, anaemia and thrombocytopenia was observed in the middle of the second half of the light-rest phase (9 HALO).

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BACKGROUND AND PURPOSE: The purpose of this study was to investigate the correlation between the haematological toxicity observed in patients treated with craniospinal irradiation, and the dose distribution in normal tissue, specifically the occurrence of large volumes exposed to low dose. MATERIALS AND METHODS: Twenty adult male patients were included in this study; eight treated with helical tomotherapy (HT), and twelve with three-dimensional conformal radiation therapy. The relative volume of red bone marrow and body that was exposed to low dose (i.e. the so-called dose bath) was evaluated and correlated with nadir blood values during treatment, i.e. the severity of anaemia, leukopaenia, and thrombocytopaenia. The correlation was tested for different dose levels representing the dose bath using the Pearson product-moment correlation method. RESULTS: We found a significant correlation between the volume of red bone marrow exposed to low dose and the severity of thrombocytopaenia during treatment. Furthermore, for the HT patients, a significant correlation was found between the relative volume of the body exposed to low dose and the severity of anaemia and leukopenia. CONCLUSIONS: The severity of haematological toxicity correlated with the fraction of red bone marrow or body that was exposed to low dose.

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OBJECTIVES: Thrombocytopenia is sometimes observed during linezolid therapy. Here, we aimed to investigate the factors affecting linezolid-induced thrombocytopenia. METHODS: A prospective observational study was performed between October 2009 and February 2011; 30 patients were included. Plasma linezolid trough concentrations were measured on days 3, 7 and 14 after initial drug administration. Platelet counts and haemoglobin levels were also monitored. RESULTS: Thrombocytopenia occurred in 17 patients (56.7%). Median linezolid trough concentrations on day 3 were significantly higher in patients with renal impairment (creatinine clearance <60 mL/min) than in patients without renal impairment (14.7 versus 4.8 mg/L; P < 0.0001). Median linezolid trough concentrations on day 3 in patients who developed thrombocytopenia were also significantly higher than those in patients who did not (13.4 versus 4.3 mg/L, P < 0.0001). Development of thrombocytopenia occurred significantly more frequently in patients with linezolid trough concentration >7.5 mg/L (OR, 90.0; P < 0.0001) and renal impairment (OR, 39.0; P = 0.0002). The Kaplan-Meier plot showed that the median time from the initiation of therapy to development of thrombocytopenia was 11 days. CONCLUSIONS: Patients with renal impairment are more likely to have a high plasma linezolid concentration. In addition, a high plasma linezolid concentration and renal impairment significantly affected the development of linezolid-induced thrombocytopenia. Further studies are required to evaluate whether therapeutic drug monitoring-guided dosage adjustment of linezolid decreases the adverse effects while maintaining treatment efficacy in patients with renal dysfunction.

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AIMS: Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic-pharmacodynamic model for eribulin-associated neutropenia. METHODS: A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework. RESULTS: Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 10(9) neutrophils l(-1) [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 µg l(-1) (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time. CONCLUSIONS: The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

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