Degree Of Myelosuppression Research Articles

Hepatectomy After Conversion Therapy for Initially Unresectable HCC: What is the Difference?

Conversion therapy gives some patients with initially unresectable hepatocellular carcinoma (HCC) access to surgery. The purpose of this study was to evaluate the safety and efficacy of hepatectomy after conversion therapy and how it differed from those who undergoing direct hepatectomy. From January 2018 to April 2022, 745 patients underwent hepatectomy for HCC were enrolled. Among them, 41 patients of unresectable HCC underwent hepatectomy after conversion therapy. A demographically and clinically comparable cohort was created from the remaining patients in a 1:1 ratio using propensity score matching. The median duration of conversion therapy was 108 (42-298) days, 8 patients achieved complete response (CR) and 33 achieved partial response (PR). Conversion therapy resulted in some degree of myelosuppression, but liver function index remained good. Compared with the direct hepatectomy group, the conversion group had more blood loss (600 mL vs 400 mL, p=0.015), longer operative time (270 min vs 240 min, p=0.02), higher blood transfusion rates, and longer hospital stay (8 days vs 11 days, p<0.001). Patients in the conversion group had significantly more complications of any grade (82.9% vs 51.2%, p=0.002) and grade 3/4 (26.8% vs 4.9%, p=0.013), and 6 patients developed post-hepatectomy liver failure (PHLF). There were no deaths in either group. All patients achieved R0 resection, 6 (6/41, 14.6%) achieved pathological complete response (pCR), 14 achieved major pathologic responses (MPR). During a median follow-up of 12.8 months, 14 patients in the conversion group experienced recurrence or metastasis, no deaths. Hepatectomy after conversion therapy was more difficult than direct hepatectomy, but accurate preoperative assessment could ensure the safety of the surgery. The damage of liver function after conversion therapy was more severe than expected, PHLF should be prevented and treated. Hepatectomy was effective and necessary, postoperative pathological examination could provide guidance for adjuvant therapy.

Predictive marker for exposure-driven haematological toxicity of tegafur-uracil and proposed modified-dosage regimen by pharmacometric approach in rats

Myelosuppression is a dose-limiting toxicity of uracil-tegafur (UFT), which contains uracil and the 5‑fluorouracil prodrug tegafur, and inhibits the continuation of chemotherapy, causing treatment failure. A proper dosing strategy to avoid severe myelosuppression-induced discontinuation of chemotherapy is required. Plasma drug concentrations were determined in rats after single oral UFT administration of 15, 30, or 60 mg/kg. Blood cell counts were also measured after oral UFT administration for 5 days. Pharmacokinetic-toxicodynamic (PK-TD) modelling and simulation were performed to describe the time-course alterations in the blood cell counts. Severe neutropenia was observed in rats treated with 60 mg/kg UFT on day 7. A significant decrease in neutrophil counts from baseline levels prior to UFT administration was observed on day 3, whereas leukocyte and lymphocyte counts decreased on day 7. The semi-physiological PK-TD model successfully captured alterations in neutrophil counts after UFT administration, whereas the model could not well describe the platelet, leukocyte, and lymphocyte counts, possibly due to the absence of severe thrombocytopenia, leukocytopenia, and lymphocytopenia, respectively. Neutrophils are sensitive markers for estimating the grade of haematological toxicity of UFT, and a PK-TD model might be an attractive tool for quantitatively evaluating the onset and degree of myelosuppression.

Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P = 8.26 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 10–6; OR = 8.05; 95% CI 2.96–21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P > 0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P = 0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P > 0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P = 0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.

Clinical Observation of Hypofractionated Simultaneous Integrated Boost Radiotherapy in Breast-Conserving Surgery

Comparing the skin toxicity, cosmetic effect, myelosuppression and other adverse reactions between hypofractionated simultaneous integrated boost (HF-SIB) and conventional fractionated (CF) radiotherapy for breast cancer patients after breast-conserving surgery, to evaluate the short-term efficacy and safety of HF-SIB. A total of 236 early breast cancer patients received radiotherapy after breast-conserving surgery were prospectively enrolled in this study. All patients divided into two groups according to the dose of radiotherapy. HF-SIB included 126 patients and the dose of whole-breast radiation reach to 42.56Gy in 16 fractions and simultaneously tumor bed boost to 48Gy in 16 fractions, which course of radiotherapy was 22 days. The 110 patients of CF group received whole breast radiation to 50Gy in 25 fractions and followed by tumor bed boost to 10Gy in 5 fractions, which course of radiotherapy was 40 days. The indexes such as acute skin reaction, late skin toxicity, myelosuppression, cosmetic effect and radiation pneumonia were recorded and analyzed by Rank sum test and chi-square test. After a median follow-up of 14.6 months (7-18 months), HF-SIB group have no cases of recurrence (0/126) and the survival rate was 100% (126/126). After a median follow-up of 33.4 month (25-45 months) in CF group, the recurrence rate was 3.6% (4/110) and the 2-year survival rate was 100% (110/ 110). The incidence of acute skin reaction of grade 1, grade 2 and grade 3 in HF-SIB group was 52.7%, 15.8% and 2.6%, respectively and that in CF group is 50%, 25% and 5%. The incidence of late skin reaction in grade 1 and grade 2 was 25% and 5.2% in HF-SIB group and 20% and 3.3% in CF group respectively. The excellent and good rate of cosmetic effect of HF-SIB group and CF group at an interval of six months after radiotherapy was 97.4% vs 90%, and that of one year after radiotherapy was 93.1% vs 86.7%. The incidence of grade 1 and 2 radiation pneumonia in the HF-SIB group was 6.6% and 3.9%, while that in the CF group was 5.0% and 1.7%, respectively. There was no statistical difference in skin toxicity, cosmetic effect and radiation pneumonia between the two groups. In terms of myelosuppression, the HF-SIB group was better than the CF group. There was no significant difference in age, chemotherapy, fractionated dose and posture on skin reaction and cosmetic effect, but there was a correlation between the volume of breast and the incidence of skin reaction. The evaluation of clinic effect in HF-SIB group was not inferior to that in CF group, and there was no significant difference between HF-SIB group and CF group in terms of skin reaction and cosmetic effect. The degree of myelosuppression in HF-SIB group was lower than that in CF group. HF-SIB group can shorten the treatment time and reduce medical expenses. Moreover, the short-term effect was similar to that of CF group, so it can be used as one of the radiotherapy modes for early breast cancer patients after breast-conserving surgery.

Pharmacokinetics of tablet and liquid formulations of oral 6-mercaptopurine in children with acute lymphoblastic leukemia.

Mercaptopurine (6MP) is essential to cure childhood acute lymphoblastic leukemia (ALL). A liquid 6MP formulation was recently introduced to facilitate oral 6MP administration, especially to children. Its approval and bioequivalence with 6MP tablet were based on comparative pharmacokinetics in 60 healthy adults. Due to potential pharmacokinetic differences between healthy adults and children with ALL, we compared pharmacokinetics of tablet and liquid 6MP formulations in children with ALL. Pharmacokinetics of 50mg 6MP tablet (Puri-Nethol®) and 20mg/ml 6MP liquid suspension (Xaluprine®) were compared in a non-blinded, random order, single-dose, cross-over study in 16 children with ALL (eight males). 6MP was administered after a 12h fast, and 6MP plasma concentrations measured consecutively over seven hours post-dose. Pharmacokinetic outcomes were as follows: Area under the curve (AUC), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), and terminal half-life (T½). Liquid 6MP formulation resulted in a 26% lower AUC (p = 0.02) compared with tablet (median 1215 vs. 1805 h × nmol/l). No significant differences were observed for Cmax,Tmax and T½ (p = 0.28, p = 0.09, p = 0.41, respectively). Based on criteria declared by the World Health Organization the results did not establish non-inferiority of liquid 6MP formulation compared with 6MP tablet. Non-inferiority of liquid 6MP formulation compared with 6MP tablet was not demonstrated. Yet, maintenance therapy doses are adjusted by degree of myelosuppression and not by 6MP dose. Thus, in spite of a lower bioavailability, a liquid 6MP formulation is still desirable in a clinical setting, especially for children. However, if shifting between 6MP formulation is indicated, dose adjustments should be anticipated to maintain equivalent treatment intensity in children with ALL. The study is registered on clinicaltrials.gov (NCT01906671). Date of registration: 24.07.13.

ACT-18 SHOULD THE DOSE OF TEMOZOLOMIDE BE DECREASED FOR PATIENTS WITH HIGH-GRADE GLIOMAS WHO ARE ON HEMODIALYSIS?

BACKGROUNDThe pharmacokinetics of temozolomide in patients with severe renal impairments (creatinine clearance less than 36 mL/min/m2) or in hemodialysis patients has not been investigated. Temozolomide and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in hemodialysis patients harboring a high-grade glioma.METHODSEight hemodialysis patients with high-grade gliomas from seven institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated.RESULTSThe histopathological diagnoses were Isocitrate dehydrogenase (IDH) wild-type glioblastoma in four cases, Not other specified (NOS) glioblastoma in two cases and IDH-mutant anaplastic astrocytoma in one case. Five of the seven patients completed radiotherapy (48–60 Gy) with concomitant temozolomide (75 mg/m2) followed by adjuvant 5-day temozolomide (150 mg/m2) every 28 days. During the entire course of treatment with temozolomide, severe (Common Terminology Criteria for Adverse Events (CTCAE) more than grade 3) lymphocytopenia occurred in 57%(41.7–61%: non hemodialysis patients data, the same as below), neutropenia in 0%(1–15.4%) and thrombocytopenia in 14%(0–16.7%) of the patients. Generally, the frequency and degree of myelosuppression do not increase in hemodialysis patients with high-grade gliomas. Two of the seven (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression that is similar rate of 21.9% of the death results from infection in hemodialysis patients in Japan.CONCLUSIONSThe high-grade glioma patients under study on hemodialysis did not require decreasing doses of Temozolomide during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

Temozolomide radiochemotherapy for high-grade glioma patients with hemodialysis: a case series of 7 patients

The pharmacokinetics of temozolomide (TMZ) in patients with severe renal impairments (creatinine clearance, <36 mL/min/m2) or in hemodialysis (HD) patients has not been investigated. TMZ and its metabolic products are mainly excreted in urine, as retention of these in the body may result in increased adverse events in HD patients. Seven HD patients with high-grade gliomas from 6 institutions were included in the study. Patient characteristics, treatment schedule, clinical course, pathological/molecular findings, and adverse events were evaluated. The histopathological diagnoses were isocitrate dehydrogenase (IDH) wild-type glioblastoma in 4 cases, not other specified (NOS) glioblastoma in 2 cases, and IDH-mutant anaplastic astrocytoma in 1 case. Five of the 7 patients completed radiotherapy (48-60 Gy) with concomitant TMZ (75 mg/m2) followed by adjuvant 5-day TMZ (150 mg/m2) every 28 days. During the entire course of treatment with TMZ, severe (Common Terminology Criteria for Adverse Events [CTCAE] ≥ Grade 3) lymphocytopenia occurred in 57%, neutropenia in 0%, and thrombocytopenia in 14% of the patients. Generally, the frequency and degree of myelosuppression do not increase in HD patients with high-grade gliomas. Two of the 7 (28.5%) patients died of infectious disease despite having no direct correlation to myelosuppression; that is similar to the death rate of 21.9% resulting from infection in HD patients in Japan. Decreasing the dose of TMZ might not be required in HD patients with high-grade gliomas during concomitant radiochemotherapy and maintenance therapy. However, careful clinical and hematological observation is required to avoid critical hematotoxicity and infection.

PS02.101: PREOPERATIVE TREATMENT BASED ON THE DCF CHEMOTHERAPY AND SUPPORTIVE THERAPY FOR ESOPHAGEAL CANCER

Abstract Background The neoadjuvant chemotherapy using CDDP and 5-FU(CF) is the standard treatment for advanced esophageal cancer, defined as clinical stage II/III in Japan. However, more powerful chemotherapy has been required for the treatment of cases of cStageIII cases. In 2011, the combination treatment of CF and Docetaxel (DCF) was introduced for the treatment of those cases in our institute. DCF therapy increased chemotherapy remarkable cases. But, adverse events occur at high rates, including high myelosuppression. Therefore, it is necessary to ensure support by early intervention of supportive therapy so as not to exacerbate adverse events. We report about treatment outcome in preoperative DCF therapy cases. Methods We treated 128 esophageal cancer patients who underwent surgery following preoperative DCF therapy between 2011 and July 2017, and preoperative DCF was administered to 128 patients 2 course completely. The neoadjuvant chemotherapy regimen using DCF is Docetaxel:70mg/m2 (day1) + CDDP:70mg/m2 (day1) + 5-FU:700mg/m2 (day1–5). Results In the preoperative DCF group, overall response rate (over PR) was 51.5%. There were 37 cases in 128 cases of pathological tissue effect judgment for Grade 2 and 3. 14 cases of them (14cases/37cases:37.8%) had lymph node metastasis. Therefore it is necessary to control lymph node metastasis by surgery even in a remarkable group. Almost all patients experienced grade 4 adverse events, particularly neutropenia is a high frequency. From the start of chemotherapy, pretreatment of intraoral infection lesion and prevention and treatment of oral mucositis are performed. Considering the degree of myelosuppression during initial chemotherapy, in the second course, we actively administer G-CSF preparation. Conclusion A good prognosis can be expected if preoperative DCF therapy is effective. It is necessary to perform intensive and safe preoperative chemotherapy with appropriate supportive therapy intervention. Disclosure All authors have declared no conflicts of interest.

Clinical Analysis of 7 Children with Mature B-cell Acute Lymphoblastic Leukemia

To evaluate the efficacy of CCCG-BNHL-2015 protocol in treatment of children with mature B-cell acute lymphoblastic leukemia (mature B-ALL). Seven pediatric patients with newly diagnosed mature B-ALL were treated by CCCG-BNHL-2015 protocol (risk group R4) in Children's Hospital of Nanjing Medical University from November 2014 to January 2017. The median age of patients at initial diagnosis was 7.2 years (range 4.1 to 11.75 years) with a male predominance (5:2), the clinical characters were as follows: 4 cases combined with thoracic and/or abdominal lumps, only lymphonode was involved in 1 case, bone destruction was complicated in 2 cases and 1 case was complicated with central nervous system leukemia. In 2 children, tumor lysis syndrome appeared at early phase. The lactate dehydrogenase level at diagnosis of all patients extremely increased. All patients achieved complete remission after 2 to 4 courses of therapy. Two among them underwent autologous hematopoietic stem cell transplantation. One with primary central nervous system leukemia relapsed before the last course, then the treatment was abandoned. The rest of 6 patients survived with a median follow-up period of 14 months (ranged from 7 to 28 months), and suffered from different degrees of myelosuppression and infection. No one died from serious complications. The CCCG-BNHL-2015 protocol (risk group R4) shows better curative effect, higher safety and remission rate in childhood mature B-cell lymphoblastic leukemia.

Relationship between traditional Chinese medicine constitutional types with chemotherapy-induced nausea and vomiting in patients with breast cancer: an observational study.

BackgroundThe theory of traditional Chinese medicine (TCM) constitution involves genetic characteristics, psychological factors, organ functions, and many other aspects. Studies have shown that TCM constitution is associated with HLA polymorphisms and has a genetic basis. A large number of Chinese studies have suggested that the clinical evolution of breast cancer may differ among patients with different TCM constitutions. In addition, patients with breast cancer and different TCM constitutions may have different degrees of myelosuppression after chemotherapy. Some studies have revealed that some constitutions may become predictive factors for death and morbidity of some diseases. The study was to investigate the risk factors among TCM constitutions for chemotherapy-induced nausea and vomiting (CINV) in patients with primary breast cancer undergoing chemotherapy.MethodsFrom September 2008 to January 2014, 612 patients who underwent surgery and chemotherapy for breast cancer in three hospitals in Xi’an, Shanxi province, underwent TCM constitution assessment using the Nine Basic Constitutions in Chinese Medicine Questionnaire before chemotherapy. CINV was monitored during treatments. Patients were asked to complete the Functional Living Index-Emesis (FLIE) questionnaire. The most severe CINV grade during chemotherapy was recorded according to the WHO standard. The relationships between TCM constitutions, CINV, and clinical and pathological characteristics of the cancers were assessed.ResultsThere were no differences in the incidence of CINV among breast cancer patients receiving different chemotherapy regimens, and among patients with different TCM constitutions. The wetness-heat score was an independent risk factor for severe CINV (grade III-IV) (OR = 1.012, 95 % CI: 1.007–1.021, P < 0.001). In-depth analyses of the wetness-heat constitution showed that bitter taste/smelly mouth was an independent risk factor for severe CINV (OR = 1.209, 95 % CI: 1.035–1.412, P = 0.017), as well as progesterone receptor-positive cancer (OR = 1.429, 95 % CI: 1.030–1.981, P = 0.032). Vomiting history was a protective factor against CINV (OR = 0.548, 95 % CI: 0.353–0.849, P = 0.007).ConclusionRisk of grade III-IV nausea and vomiting was higher in breast cancer patients with TCM constitution of wetness-heat, especially bitter taste or smelly mouth.

Comparison of MACT and 5Fu+ACT-D chemotherapy regimens in the treatment of low-risk gestational trophoblastic neoplasia

The study aimed to compare the efficacy of methotrexate (MTX) cervical injections + actinomycin-D (ACT-D)(MACT) and 5-fluorouracil (5-Fu) + actinomycin-D (5-Fu plus ACT-D) chemotherapy regimens for low-risk gestational trophoblastic neoplasia (LR-GTN). Clinical data from 66 LR-GTN patients, admitted to the Beijing Obstetrics and Gynecology Hospital from January 2010 to April 2012, were analysed retrospectively. In total, 32 patients were treated with a MACT therapeutic regimen and the remaining 34 with a 5Fu + ACT-D therapeutic regimen. Complete remission rates (CR), duration of treatment, hospital stay and toxicity effects were compared. There was no statistical difference in CR for the MACT (90.63%) or the 5-Fu plus ACT-D (100%) therapeutic regimens (p = 0.0676) or in the duration of treatment [MACT (3.50) or 5-Fu plus ACT-D (3.71; p = 0.2021)]. Moreover, the hospital stay in the 5-Fu plus ACT-D group (32.88 days) was significantly longer than for the MACT group (22.09 days; p ＜ 0.001). Furthermore, the degree of myelosuppression, nausea and vomiting, diarrhoea, stomatitis and alopecia was more severe in the 5Fu + ACT-D group (p ＜ 0.01). However, there was no statistical difference in the severity of liver function damage between the two groups. A shorter hospital stay, lower hospitalization cost and slightly more toxic effects were observed in LR-GTN patients treated with the MACT therapeutic regimen. We suggest that the MACT regimen should be used as first-line chemotherapy for LR-GTN.

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.

Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Imputation of TPMT defective alleles for the identification of patients with high-risk phenotypes.

Background: The activity of thiopurine methyltransferase (TPMT) is subject to genetic variation. Loss-of-function alleles are associated with various degrees of myelosuppression after treatment with thiopurine drugs, thus genotype-based dosing recommendations currently exist. The aim of this study was to evaluate the potential utility of leveraging genomic data from large biorepositories in the identification of individuals with TPMT defective alleles.Material and methods: TPMT variants were imputed using the 1000 Genomes Project reference panel in 87,979 samples from the biobank at The Children's Hospital of Philadelphia. Population ancestry was determined by principal component analysis using HapMap3 samples as reference. Frequencies of the TPMT imputed alleles, genotypes and the associated phenotype were determined across the different populations. A sample of 630 subjects with genotype data from Sanger sequencing (N = 59) and direct genotyping (N = 583) (12 samples overlapping in the two groups) was used to check the concordance between the imputed and observed genotypes, as well as the sensitivity, specificity and positive and negative predictive values of the imputation.Results: Two SNPs (rs1800460 and rs1142345) that represent three TPMT alleles (*3A, *3B, and *3C) were imputed with adequate quality. Frequency for the associated enzyme activity varied across populations and 89.36–94.58% were predicted to have normal TPMT activity, 5.3–10.31% intermediate and 0.12–0.34% poor activities. Overall, 98.88% of individuals (623/630) were correctly imputed into carrying no risk alleles (553/553), heterozygous (45/46) and homozygous (25/31). Sensitivity, specificity and predictive values of imputation were over 90% in all cases except for the sensitivity of imputing homozygous subjects that was 80.64%.Conclusion: Imputation of TPMT alleles from existing genomic data can be used as a first step in the screening of individuals at risk of developing serious adverse events secondary to thiopurine drugs.

Prompt administration of antibiotics is associated with improved outcomes in febrile neutropenia in children with cancer

Time-to-antibiotic (TTA) administration is a widely used quality-of-care measure for children with cancer and febrile neutropenia (FN). We sought to determine whether TTA is associated with outcomes of FN. A single-center, retrospective cohort study was conducted of 1,628 FN admissions from 653 patients from 2001 to 2009. Outcome variables included (1) an adverse event (AE) composite of in-hospital mortality, pediatric intensive care unit (PICU) admission within 24 hours of presentation, and/or fluid resuscitation ≥ 40 ml/kg within 24 hours of presentation and (2) length of stay (LOS). TTA was measured as a continuous variable and in 60-minute intervals. Mixed regression models were constructed to evaluate associations of TTA with the outcome variables after adjusting for relevant covariates including cancer diagnosis, degree of myelosuppression, and presence of bacteremia. The composite AE outcome occurred in 11.1% of admissions including 0.7% in-hospital mortality, 4.7% PICU admission, and 10.1% fluid resuscitation. In univariate analysis, TTA was associated with the composite AE outcome (Odds Ratio [OR] 1.29, 95% CI 1.02-1.64) but not LOS. In multivariate analysis, after adjustment for relevant covariates, 60-minute TTA intervals were associated with the composite AE outcome (61-120 minutes vs. ≤ 60 minutes, OR 1.81, 95% CI 1.01-3.26). Unexpectedly, admission from the emergency department (ED) was also independently associated with the composite AE outcome (ED vs. clinic, OR 3.15, 95% CI 1.95-5.09). TTA and presentation to the ED are independently associated with poor outcomes of FN.

Development of a limited‐sampling model for prediction of doxorubicin exposure in dogs

Understanding the relationship between drug dose and exposure (pharmacokinetics, PK) and the relationship between exposure and effect (pharmacodynamics) is an important component of pharmacology when attempting to predict clinical effects of anticancer drugs. PK studies can provide a better understanding of these relationships; however, they often involve intensive sampling over an extended period of time, resulting in increased cost and decreased compliance. Doxorubicin (DOX), one of the most widely used antineoplastic agents in veterinary cancer therapy, is characterized by large interpatient variability in overall drug exposure and the development and degree of myelosuppression following equivalent dosages. We have developed and validated a limited-sampling strategy for DOX, in which three blood samples are obtained over 1 h post-treatment, that accurately predicts patient exposure. This strategy could allow for refining of dosing variables and utilization of therapeutic drug monitoring to ensure optimized dosing.

Lenalidomide-Induced Cytopenias In Patients with MDS Are Negatively Impacted by Reduced Glomerular Filtration Rate

AbstractAbstract 4958 Background:The myelodsyplastic syndromes (MDS) are a heterogeneous group of hematopoietic stem cell disorders caused by dysplastic cellular proliferation accompanied by chronic peripheral cytopenias. Up to 90% of patients are found to be anemic upon presentation. Treatment with lenalidomide, a renally excreted drug, has been shown to abolish the need for red blood cell (RBC) transfusions in approximately two-thirds of MDS patients who harbor the deletion 5q abnormality. To date, there is no data regarding the degree of myelosuppression in patients with chronic kidney disease (CKD) who are receiving lenalidomide for the treatment of their MDS. Notably, increased myelosuppression related to abnormal glomerular filtration rate (GFR in mL/min) has been reported in myeloma patients on lenalidomide but has yet to be studied in patients with MDS (Niesvizky et al., 2007). We sought to evaluate the extent of cytopenias relative to GFR in patients who received lenalidomide for treatment of their MDS in the setting of the MDS 002/003 trials. Method and Patients:This is a retrospective chart review of patients with RBC transfusion dependent MDS treated with lenalidomide for symptomatic anemia in the setting of the 002/003 MDS trials at our center. All patients had an IPSS of low or intermediate risk-1 and were started on lenalidomide at 10mg daily. Patients were excluded from participation in the studies if their serum creatinine was > 2.5mg/dL. Blood counts prior to therapy and with each dosage change (defined as reduction, held dose or discontinuation) were recorded. Patients were stratified according to GFR <60 and GFR ≥60, with cytopenias related to lenalidomide identified in each group. Results:31 patients were identified. The median age was 70.5 years. 10 patients were male. 13 patients had normal karyotypes. 16 patients had del5q. 3 patients had other cytogenetic abnormalities. 17 patients were receiving ESAs prior to the study. 9 patients had a GFR of < 60 (including 2 with del5q), and 22 patients had a GFR ≥ 60 (including 13 with del5q). Of the 9 patients with a GFR < 60, 7 patients (78%) had their dose reduced/held for one or more grade 3/4 cytopenias: 5 with neutropenia, 2 with thrombocytopenia, and 1 with anemia. Of the 22 patients with a GFR ≥ 60, 17 (77%) required a dose change with 3 discontinuing lenalidomide. However, only 10 of these 22 patients (45%) required a dose change for one or more grade 3/4 cytopenias: 8 with neutropenia, 7 with thrombocytopenia, and 1 with anemia. Patients with a GFR <60 were maintained on lenalidomide for an average of 15 cycles (range 1 – 30). Patients with GFR ≥ 60 were maintained on lenalidomide for an average of 20 cycles (range 2 – 60 months). Conclusion:The results of this study suggest that patients with CKD have a higher incidence of grade 3/4 myelosuppression when treated with lenalidomide. This effect appears to be greater than expected in those with non-del5q karyotypes and concurrent CKD. These observations require further investigation in a prospective manner. In the interim, consideration for initiating lenalidomide at a lower dose in patients with MDS and decreased renal function may reduce the incidence of myelosuppression, thereby potentially allowing for fewer dose modifications and longer treatment times. Our conclusion is in line with the recently published lenalidomide dose modification recommendations in patients with renal impairment and should prompt clinicians planning to treat MDS patients with lenalidomide to calculate GFR to determine an appropriate starting dose. Disclosures:Gregory: Celgene: Research Funding. Venugopal: Celgene: Speakers Bureau. Shammo: Celgene: Honoraria, Research Funding, Speakers Bureau.

The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse

Drug doses, blood levels of drug metabolites and myelotoxicity during 6-mercaptopurine/methotrexate (MTX) maintenance therapy were registered for 59 adolescents (>or=10 years) and 176 non-adolescents (<10 years) with B-cell precursor acute lymphoblastic leukemia (ALL) and a white blood cell count (WBC) <50 x 10(9)/l at diagnosis. Event-free survival was lower for adolescents than non-adolescents (pEFS(12y):0.71 vs 0.83, P=0.04). For adolescents staying in remission, the mean WBC during maintenance therapy (mWBC) was related to age (r(S)=0.36, P=0.02), which became nonsignificant for those who relapsed (r(S)=0.05, P=0.9). The best-fit multivariate Cox regression model to predict risk of relapse included mWBC and thiopurine methyltransferase activity, which methylates mercaptopurine and reduces the intracellular availability of cytotoxic 6-thioguanine nucleotides (coefficient: 0.11, P=0.02). The correlation of mWBC to the risk of relapse was more pronounced for adolescents (coefficient=0.65, P=0.003) than for non-adolescents (coefficient=0.42, P=0.04). Adolescents had higher mean neutrophil counts (P=0.002) than non-adolescents, but received nonsignificantly lower mercaptopurine and MTX doses during maintenance therapy. Red blood cell MTX levels were significantly related to the dose of MTX among adolescents who stayed in remission (r(S)=0.38, P=0.02), which was not the case for those who developed a relapse (r(S)=0.15, P=0.60). Thus, compliance to maintenance therapy may influence the risk of relapse for adolescents with ALL.

Interethnic differences in Cyp3A4 inhibition by ketoconazole on docetaxel pharmacokinetics (PK) and pharmacodynamics (PD)

2526 Background: Use of concomitant medications that inhibit drug metabolizing enzymes such as Cyp3A4 is common and may affect chemotherapy PK/PD. We studied the effects of Cyp3A4 inhibition with ketoconazole on docetaxel PK/PD in 3 Asian ethnic groups. Methods: Two cohorts of chemonaive breast cancer patients were compared. The first cohort comprised of 95 patients (62 Chinese, 26 Malay, 7 Indian) treated with 75mg/m2 docetaxel unmodulated by ketoconazole, while the second cohort comprised of 31 patients (14 Chinese, 14 Malay, 3 Indian) treated with docetaxel 70mg flat dose modulated by oral ketoconazole, a regimen we previously reported to result in comparable docetaxel AUC as 75mg/m2 docetaxel. Plasma docetaxel concentrations were obtained at 0, 0.5, 1, 2, 5, 7 and 24 hours, and blood counts monitored on days 8 and 15 of cycle 1. Results: No significant differences in docetaxel PK or neutropenia between the races were observed in response to 75mg/m2 docetaxel unmodulated by ketoconazole (docetaxel clearance 36.4±16.9, 34.3±12.5, 44.2±27.7L/h, p=0.702; docetaxel AUC 3.6±2.7, 3.5±1.2, 2.9±1.3mg/L h, p=0.418; day 8 neutrophil count 0.5±0.6, 0.8±0.8, 0.4±0.3x109/L, p=0.138; grade 4 neutropenia 66%, 50%, 86%, p=0.157). In contrast, when docetaxel was administered with ketoconazole to inhibit Cyp3A4, inter-ethnic differences in docetaxel PK/PD were observed, with Chinese having the lowest docetaxel clearance and highest docetaxel AUC, followed by Malays and Indians (docetaxel clearance 18.6±5.7, 23.7±9.3, 30.6±6.7L/h, p=0.048; p=0.017 trend test; docetaxel AUC 4.2±1.4, 4.1±3.9, 2.4±0.5 mg/L h, p=0.048, p=0.017 trend test), although there were no statistically significant differences in body weight or surface area between the races. In concordance, Chinese patients experienced greatest degree of myelosuppression, followed by Malays and Indians (day 8 neutrophil count 0.8±0.8, 1.5±1.1, 1.7±1.1x109/L, p=0.046, p=0.013 trend test), and were more likely to develop grade 4 neutropenia (57%, 14%, 0%, p=0.024) from docetaxel + ketoconazole. Conclusions: Inter-ethnic differences in CYP3A inhibition by ketoconazole exist, and are important when evaluating the impact of concomitant medications with chemotherapy that may inhibit Cyp3A4. No significant financial relationships to disclose.

Ifosfamide May Be Safely Used in Patients with End Stage Renal Disease on Hemodialysis

Background. Pharmacokinetic data on clearance of ifosfamide in hemodialysis patients are limited. Consequently, these patients are excluded from therapy with this agent. We review the outcomes for patients at our institution with end stage renal disease on dialysis who received ifosfamide for metastatic sarcoma. Patients and Methods. We treated three patients with end stage renal disease on hemodialysis with escalating doses of ifosfamide. Data on radiographic response to therapy, WBC and platelet counts, signs or symptoms of infection, neuropathy and bladder toxicity are reported. Starting doses of ifosfamide were based on review of the literature available with subsequent modifications based on each patient's prior exposure to myelosuppressive agents and on symptoms of neurotoxicity and the degree of myelosuppression following each cycle of chemotherapy. Results. Myelosuppression was the most common side effect from therapy, but no patient developed a life threatening infection, neurotoxicity, or hematuria. One patient developed epistaxis in the setting of thrombocytopenia while on warfarin therapy. All patients had clinical evidence for therapeutic response and two had documented radiographic improvement following ifosfamide administration. Conclusion. Ifosfamide can be used safely in combination with hemodialysis in patients with end stage renal disease.

Changes in Cellular Immunity during Chemotherapy for Primary Breast Cancer with Anthracycline Regimens

Anthracyclines are the most widely used anticancer agents for breast cancer, of which doxorubicin and epirubicin have been reported to have equal efficacy. Unfortunately, the integrity of the immune system of breast cancer patients is severely affected by chemotherapy. This study compared the effect of combination chemotherapy with epirubicin (5-fluorouracil, epirubicin, cyclophosphamide (FEC)) and doxorubicin (5-fluorouracil, doxorubicin, cyclophosphamide (FDC)) regimens on subsets of the immune cells of patients with primary malignant breast tumors. Our aim was to determine the best regimen that produces the least degree of myelosuppression. Blood from 80 breast cancer patients undergoing chemotherapy (40 FEC and 40 FDC) was taken before chemotherapy and after every cycle (3 weeks) for 6 cycles. Blood was also taken from 40 normal healthy donors who served as normal control. Subsets of lymphocytes T-helper cells (CD3+CD4+), T-cytotoxic cells (CD3+CD8+), B-cells (CD19+CD20+) and NK cells (CD16+/CD56+CD3-) were analyzed by flow cytometry (FacsCalibur, BD) using monoclonal antibodies (Multitest, BD). All patients in the FEC and FDC groups suffered from myelosuppressive side effects. Both regimens led to an increase in the counts of monocytes but decreased polymorphonuclear cells (PMNs) and lymphocytes. Percentages of T-cytotoxic cells and NK cells were increased, but the percentage of B-cells was dramatically decreased. The phagocytic and intracellular killing ability of PMNs were also suppressed (p<0.01). No significant difference was found between the epirubicin-based regimen and doxorubicin-based regimen with regard to numbers of immune cells, percentages of lymphocytes subsets, Th/CTL ratio, engulfment and killing abilities of PMNs. In conclusion, we found that the epirubicin-based regimen is not superior to the doxorubicin-based regimen with respect to their toxicity of the immune cells, Th/CTL ratio and PMN count and functions. Moreover, both FEC and FDC regimens appear to conserve the cell-mediated immunity response needed for fighting against cancer cells.