Absolute Neutrophil Count Nadir Research Articles

Correlation of pharmacokinetics of CPT-11 in FOLFIRI with phenotyping of CYP3A4 and UGT1A1 activity.

e13002 Background: CPT-11 has complex PK and PD; genotyping of UGT1A1 is recommended for higher doses in *28 carriers (Caucasian) and *6 carriers (Asian) because of a higher risk of toxicity. Raltegravir is mainly metabolized to raltegravir glucuronide by UGT1A1. CPT-11 is mainly eliminated by cytochrome P450 isoform 3A (CYP3A)-mediated oxidation and by esterase cleavage to form SN-38, which is further conjugated by uridine-diphosphate glucuronosyltransferase (UGT) isozymes to the inactive SN-38 glucuronide. We prospectively explored the correlation of midazolam and raltegravir PK with CPT-11 clearance (CL) and SN-38 levels respectively and toxicity in patients undergoing chemotherapy with CPT-11. Methods: Twenty-five Asian patients with advanced cancer received CPT-11 as a 2-weekly 90-minute infusion (180 mg/m2) as part of the FOLFIRI regimen. Subjects were administered raltegravir 400 mg orally (as a UGT1A1 probe) and intravenous midazolam 1 mg (as a CYP3A4 probe) one day before the first dose of their chemotherapy. Blood sampling for drug concentrations was performed for 2 days after probe drug administration. Non-compartmental PK analyses were performed using WinNonLin. Genomic DNA was isolated and screened for the known genetic variants in UGT1A1*6. Results: One patient developed grade 3 diarrhea and 16 developed grade 3-4 neutropenia. The mean CPT-11 CL was 21.9 + 7.8L/h. SN-38G/SN-38 AUC ratio was highly correlated with Raltegravir glucuronide/ Raltegravir AUC ratio (r=0.784 p<0.01). Midazolam CL was highly correlated with CPT-11 CL (r=0.563 p<0.01). SN38 AUC correlated well with neutropenia (Log10Nadir Absolute Neutrophil Count (ANC) (r=-0.397 p<0.05). Neither CPT-11 nor midazolam CL correlated with Log10 Nadir ANC. Of the 24 patients with genotyping of UGT1A1*6 done, 17 were wild type (GG), 7 heterozygotes (AG) and 0 were mutant (AA). No differences in toxicity or SN38 pharmacokinetics were observed in the UGT1A1*6 variants. Conclusions: Raltegravir glucuronide ratio is a good predictor of SN-38 glucuronidation, and has potential to predict neutropenia from FOLFIRI treatment. Prospective studies with dose adjustments should be done to develop raltegravir as a probe to optimize CPT-11 therapy.

Healthcare-Associated Infections at a Children's Cancer Hospital, 1983–2008

Little is known about the incidence and etiology of healthcare-associated infections in immunosuppressed children. Data collected prospectively between 1983 and 2008 were used to analyze changes in the rate, types of infection, and infecting organisms over time in patients treated at a children's cancer hospital. Neutropenia was evaluated as a risk factor. Over the 26-year study period, 1986 healthcare-associated infections were identified during 1653 hospitalizations. The infection rate decreased significantly from 5.6 to 2.0 infections per 100 discharges (P<.01) and from 9.0 to 3.7 infections per 1000 patient-days (P<.01). Bloodstream infections were the most common type of infection (32.7% of all infections). Staphylococci (46.4% of Gram-positive bacteria), Escherichia coli (36.7% of Gram-negative bacteria), and Candida spp. (68.7% of fungi) were the most common pathogens isolated. An absolute neutrophil count (ANC) nadir <100 per mm(3) was significantly associated (P<.0001) with an increased rate of infections compared with higher ANC nadirs. Despite a steady expansion in hospital capacity and patient encounters over the last 3 decades, rates of healthcare-associated infections decreased significantly at our hospital. These data suggest that sustained decreases in the rate of healthcare-associated infections in immunosuppressed children are possible. An ANC <100 per mm(3) is a risk factor for healthcare-associated infections in this population.

Pharmacogenetic Study of 5-Fluorouracil-Related Severe Toxicity in Thai Cancer Patients: A Novel SNP Detection

Objective: The objective of this study is to determine the extent of (DPYD) Dihydropyrimidine Dehydrogenase Gene] polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: The study was conducted a pharmacogenetic analysis to determine the polymorphisms of DPYD gene in 116. Thai cancer patients. 76 patients developed severe (grade 3-4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared. Results: We detected 13 SNPs of which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in intron but only IVS14+1G>A is the intron splice site. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistically significant difference in actual ANC change and percentage of neutrophil change in homozygous GG [P = .011 and .009] were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP has cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A might be the cause of (DPD) Dihydro Pyrimidine Dehydrogenase deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study.

Abstract 5409: Protection of chemotherapy-induced myelosuppresion by cytotech labs API 31543

Abstract High pulses of Calcitriol have been demonstrated to treat myelodysplastic syndrome without hypercalcemia. We have previously demonstrated that calcitriol protects chemotherapy-induced alopecia without calcemic effects. We thus hypothesized that a regimen of non-hypercalcemic high pulses of API 31543, a formulation containing calcitriol, may protect the bone marrow and circulating progenitors without protecting the cancer cells. 5-day old Long Evans rats were injected with MIAC51, a chloroleukemic cell line. On day 21, rats were randomized into 3 groups for each chemotherapy regimen. Group I received vehicle, group II received 10 µg API 31543. A pulse dose of vehicle or API 31543 was given 4 days prior to chemotherapy administration. Groups I and II were separated on day 21 into 2 groups and received the following chemotherapies: cyclophosphamide (CTX; 150mg/kg), cyclophosphamide and doxorubicin (CTX/DOXO; 100 mg/kg, 25 mg/kg, respectively) and cyclophosphamide, doxorubicin and paclitaxel, (CTX/DOXO/PAC 100 mg/kg, 25 mg/kg, 10 mg/kg, respectively). Starting on day 20 through day 32, complete granulocyte counts were then assessed. Baseline absolute neutrophil counts (ANC) prior to chemotherapy administration ranged from 3621 ±154 mm3 to 3000 ±254 mm3. Once chemotherapy was administered, ANC values dropped significantly between days 24 and 27. For CTX and vehicle the nadir ANC was 10% of the normal values. In contrast, the nadir of CTX and API 31543 was close to the normal count. In the group receiving CTX/DOXO, ANC was also reduced by 90%. For CTX/DOXO and vehicle nadir ANC was less than 10% of normal counts, while groups receiving CTX/DOXO and API 31543 were normal. Similarly, in groups receiving CTX/DOXO/PAC and vehicle, nadir ANC was less than 10%, while in groups receiving CTX/DOXO and API 31543 ANC values were normal. On day 32, a complete leukocyte count was performed in all animals and those positive for MIAC51 were sacrificed. Bone marrow cultures were performed on days 22, 25 and 32. Bone marrow cultures supported the ANC data. We therefore performed the same experiments on adult rats to mimic the multiple courses of chemotherapy. For the second cycle of chemotherapy, survivors were re-randomized and treated with the same chemotherapy regimens. Neutrophil counts were measured as previously described. The second pulse of API 31543 was administered on day 48, and chemotherapy was started. On day 52, rats were re-randomized for each chemotherapy regimen. Group I received vehicle only, group II received 20 µg API 31543. Results with the both regimens and all chemotherapies were similar. These results indicate that API 31543 significantly decreases the nadir ANC and confers bone marrow protection against chemotherapy, while not protecting the cancer cell. The data herein supports further development of this work and suggest that API 31543 may be a potential clinical agent for prevention of chemo-induced myelosuppression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5409. doi:10.1158/1538-7445.AM2011-5409

Rituximab‐induced late onset neutropenia in newly‐diagnosed B‐cell lymphoma correlates with Fc receptor FcγRIIIa 158(V/F) polymorphism

Rituximab is a commonly utilized treatment agent for B-cell lymphoma. Late onset neutropenia (LON) has been identified as a complication associated with rituximab, primarily in conjunction with hematopoietic stem cell transplantation (HSCT). Scant data exists regarding rituximab-related LON outside the spectrum of HSCT, including newly-diagnosed lymphoma. We examined a large cohort of newly-diagnosed B-cell lymphoma patients treated with rituximab-based therapy. We identified patients with LON and analyzed the characteristics and outcomes. Furthermore, we utilized multiplex PCR for the detection of the FcgRIIIa 158 V/F polymorphism and correlated this with LON. Eighty consecutive B-cell lymphoma patients were examined. Nine of 80 (11.3%) patients developed LON. The clinical course of LON was generally self-limiting without adverse events. The onset of LON occurred at a mean of 66 days after the last course of treatment, while the mean duration of LON was 97 days. Moreover, the V/V and V/F polymorphisms were significantly associated with the occurrence of LON (P 5 0.046) yielding an odds ratio for the development of LON of1.47 (95% CI 1.21-1.78). We identified an incidence of LON following frontline rituximab-based treatment of 11.3%. The FcgRIIIa polymorphism was highly associated with development of LON.

Lack of effect of casopitant on the pharmacokinetics of docetaxel in patients with cancer

The neurokinin-1 receptor antagonist, casopitant, is a weak-to-moderate inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A) and has the potential to inhibit the metabolism of CYP3A substrates such as docetaxel. Fourteen cancer patients were enrolled in this phase 1, open-label, randomized, two-period crossover study. Intravenous (i.v.) docetaxel was coadministered with oral ondansetron and dexamethasone with (Regimen B) or without (Regimen A) 150 mg single-dose oral casopitant. The geometric least-squares mean Regimen B: Regimen A ratios (90% confidence interval) for docetaxel maximum plasma concentration and area under the concentration-time curve from time 0 extrapolated to infinity were 0.97 (0.83, 1.12) and 1.06 (0.94, 1.19), respectively. Coadministration of casopitant and docetaxel was well tolerated, with adverse event profiles and absolute neutrophil count nadirs similar for both treatments. C(max) and AUC of docetaxel were similar when given as monotherapy or when given in combination with casopitant. Likewise, absolute neutrophil count nadirs were similar for docetaxel alone or docetaxel with casopitant.

Safety and efficacy of pegfilgrastim in pediatric solid tumor patients (pts).

e20007 Background: Progressive intensification of chemo-radiotherapy regimens has led to improved outcome of children with solid tumors. Marrow toxicity and neutropenia have become the main dose-limiting toxicities, often resulting in life-threatening infectious complications. Hematopoietic growth factors were introduced into clinical practice to minimize these complications. Recently Pegfilgrastim, a PEG-conjugated form of r-metHuG-CSF (filgrastim) with much longer serum half-life and a comparable safety and efficacy profile in adults has become available. We describe our retrospective institutional experience with Pegfilgrastim after myelosuppressive chemotherapy in children with solid tumours. Methods: Pts received a single subcutaneous injection of Pegfilgrastim, administered 72-96 hours after the completion of chemotherapy, at the dose of 100 μ g/kg (in children < 40 kg of weight) or 6 mg flat dose (in pts > 40 kg). Diagnoses were: CNS tumours (3), neuroblastoma (6), rhabdomyosarcoma (3), Ewing sarcoma (6), renal cancer (1) and other solid tumors (3). We analyzed: incidence and duration of grade IV neutropenia, presence and length of fever, incidence of bacteremia, absolute neutrophil count (ANC) nadir, number of platelet (Plt) and packed red blood cell (PRBC) transfusions, PBSC harvests and incidence of adverse events. Results: Between February 2008 and April 2009, 22 patients, M/F 13/9, median age 70 months (range 26-191), median body weight 19.2 kg (range 14-60.5) received 80 doses. We observed: grade IV neutropenia in 86% of courses, median ANC nadir of 0.03×109/L (range 0- 3.360×109/L), median recovery time of 14 days (range 8-30) and median duration of grade IV neutropenia of 4 days (range 0-16). Febrile neutropenia occurred in 58% of courses, with 7 cases of documented sepsis; patients received 88 PRBC transfusions and 148 Plt transfusions. 83% of PBSC harvests were successful, with a median harvest of 6,7 × 106 CD34+ cells/kg (range 2.16-60); no significant adverse events were recorded. Conclusions: A single dose of pegfilgrastim per chemotherapy course is as safe and effective as daily filgrastim in children with solid malignancies both in enhancing neutrophil recovery and in CD34+ mobilization. No significant financial relationships to disclose.

Pharmacodynamic Genes do not Influence Risk of Neutropenia in Cancer Patients Treated with Moderately High-Dose Irinotecan

A recent study found that variation in camptothecin pharmacodynamic genes (TOP1, PARP1, TDP1 and XRCC1) correlated with efficacy and risk of neutropenia in irinotecan-treated cancer patients (median dose: 180 mg/m2), which suggests that these genes might predict outcomes to irinotecan-based therapies. The present study was conducted to evaluate previous gene associations using an independent sample of patients receiving irinotecan. DNA was isolated from 85 advanced cancer patients treated with 300 or 350 mg/m2 irinotecan and genotyped for haplotype-tag polymorphisms across TOP1, PARP1, TDP1 and XRCC1. Associations between genotypes and haplotypes and log(absolute neutrophil count nadirs) were assessed by linear regression. No associations were observed. Our findings suggest that the genes we tested do not influence toxicity of irinotecan when adminstered at 300-350 mg/m2.

Semi-Mechanistic Model for Neutropenia after High Dose of Chemotherapy in Breast Cancer Patients

To describe the absolute neutrophil counts (ANC) profile in breast cancer patients receiving high-dose of chemotherapy and peripheral blood stem-cells (PBSC) transplantation. Data from 41 subjects receiving cyclophosphamide, thiotepa and carboplatin were used to develop the ANC model consisting of a drug-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments. PBSC were incorporated into the first transit compartment following a zero-order process, k(in), and the rebound effect was explained by a feedback mechanism. A 'kinetics of drug action' model was used to quantify the HDC effect on the progenitor cells according to a linear function, with a slope (alpha). The typical of the ANC at baseline (Circ(0)), mean transit time (MTT), feedback parameter (gamma), k(in) and alpha were estimated to be 5,610 x 10(6)/L, 3.25 days, 0.145, 0.954 cell/kg/day and 2.50 h/U, respectively. rHuG-CSF shortens the MTT by 92% and increases the mitotic activity by 120%. Bootstrap analysis, visual predictive check and numerical predictive checks evidenced accurate prediction of the ANC nadir, time to ANC nadir and time to grade 4 neutropenia recovery. The time course of neutropenia following high-dose of chemotherapy and PBSC transplantation was accurately predicted. Higher amount of CD34+ cells in the PBSC transplantation and earlier administration rHuG-CSF were associated with faster haematological recovery.

Good outcome of AIDS-related Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL) with abbreviated cycles of EPOCH-rituximab

The addition of rituximab to CHOP chemotherapy may augment tumor response but in patients with low CD4 counts, one study suggested that this benefit may be offset by increased infectious deaths (Kaplan. Blood 2005; 106:1538). We hypothesized that the addition of rituximab to EPOCH chemotherapy could improve tumor kill, allowing fewer cycles of treatment and therefore reducing toxicity. Patients received EPOCH-R (in mg/m2/d – etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–5; cyclophosphamide 750 mg IV d 5; prednisone 60 po days 1–5 and rituximab 375 IV d 1,5 and G-CSF sc d 6–15) every 21 days. Prophlactic IT methotrexate was administered and HAART was suspended during therapy. Cyclophosphamide was adjusted based on absolute neutrophil count (ANC) nadir. Response was assessed by CT and FDG-PET scan and patients received one cycle beyond CR for a minimum of three cycles. Characteristics of 40 enrolled patients are: median (range) age 42 (9–60) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD4 count 222 (0–835) cells/mm3; HIV viral load 34,766 (0–6,080000) RNA copies/mL; male sex 35 (88%); LDH > N 27 (68%); stage IV 27 (68%) and histology DLBCL 32 (80%) and BL 8 (20%). Of 38 evaluable patients (2NE), median (range) number of cycles given is three (3–5) with CR/CRu in 35 (92%) and PR in one (3%) patients. All eight patients with Burkitt lymphoma are in continuous remission. At four years median potential follow-up, PFS and OS are 86 percent and 70 percent. For patients with CD4 > and 100/mm3 have an extremely favorable outcome with and survival following EPOCH-R. The addition of rituximab did not appear to contribute to infection related complications or deaths. EPOCH-R showed excellent efficacy in eight patients with BL with an OS and PFS of 100 percent. PET scanning has a high negative but low positive predictive value for subsequent relapse. Accrual continues.

Safety analysis of radioimmunotherapy (RIT) in patients with relapsed or refractory low grade, follicular or transformed non-Hodgkin's lymphoma and mantle cell lymphoma based on age at time of therapy

e19529 Background: Radioimmunotherapy is a therapeutic option for relapsed or refractory indolent, follicular and transformed non Hodgkin's lymphoma and mantle cell lymphoma. Although prolongued myelotoxicity has been described with use of iodine I 131 tositumomab (TOSI) and yttrium 90 ibritumomab tiuxetan (IBRI), analysis of toxicity according to patients’ age at therapy still lacks. Methods: Utilizing the Rush University Medical Center database 61 subjects who received RIT between November/2003 and June/2008, either with TOSI or IBRI were divided in 2 groups according to age at time of therapy. Group 1 included patients between 33 and 60 (51.8±6.5) years of age (N=29) and group 2 included patients 61 years old or older (70.1±7.8) (N=32). Parameters compared between groups were: Time to nadir of lowest absolute neutrophil count (ANC), time to recovery ANC above 1000/mcL, time to nadir of lowest hemoglobin levels, time to recovery to hemoglobin levels above 8g/dL, time to lowest platelet count and time to recovery to platelet count above 100,000/mcL. Incidence o myelodysplastic syndrome (MDS) was also compared between groups. Groups characteristics such as sex, type of RIT, presence of disease in bone marrow, FLIPI/IPI and use of G-CSF were noted. Results: There was no significant statistical difference between groups in time (number of days) to achieve nadir of ANC (group 1 85.3±208; group 2 50.3±19.9), nadir of hemoglobin levels (group 1 106±60.6; group 2 84±57.0) and time to nadir of platelet level (group 1 53.5±70.7; group 2 41.8±9.6). There was no statistical significant difference between groups in duration of cytopenias, except for time for platelet recovery which was significant longer in group 2 using the Pearson Correlation analysis. (p=0.008). (Days for platelets recovery to levels above 100,000/mcL group 1 29.4±27.7; group 2 108.8 ±207.3). One patient in group 1 and three patients on group 2 were diagnosed with MDS but were also treated with different chemotherapy regimens. Conclusions: RIT should be considered a safe therapeutic modality in patients with refractory or relapsed indolent, follicular, NHL, transformed and Mantle Cell lymphoma regardless of age. [Table: see text]

Comprehensive Pharmacogenetic Analysis of Irinotecan Neutropenia and Pharmacokinetics

We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.

Population Pharmacokinetic/Pharmacodynamic Analyses of Pemetrexed and Neutropenia: Effect of Vitamin Supplementation and Differences between Japanese and Western Patients

The objectives of the analysis were to characterize the time course of neutropenia after pemetrexed administration using an established semimechanistic-physiologic model, characterize the relationship between pemetrexed exposure and neutropenia, and describe differences in neutropenic response by vitamin supplementation status and between Japanese and Western patients. An eight-compartment population pharmacokinetic/pharmacodynamic model was used to describe the absolute neutrophil count (ANC)-time profile (neutropenic response) following pemetrexed doses of 300 to 1,400 mg/m(2) administered every 21 days. The analyses pooled data from 13 studies including 279 patients (161 supplemented with oral folic acid and intramuscular vitamin B(12), and 118 unsupplemented; 248 Western and 31 Japanese) who received 857 treatment cycles. Vitamin supplementation status, ethnic origin, and drug exposure were the dominant predictors of neutropenic response. Vitamin supplementation diminishes neutropenic response to pemetrexed. Model-predicted ANC nadirs for the "typical" Western patient receiving 500 mg/m(2) pemetrexed +/- vitamin supplementation were 2.74 x 10(9)/L and 1.70 x 10(9)/L, respectively. Japanese patients had a less pronounced neutropenic response to pemetrexed relative to Western patients. The model-predicted ANC nadir for Japanese patients receiving 500 mg/m(2) pemetrexed with vitamin supplementation was 2.66 x 10(9)/L. Values for the 1,000 mg/m(2) dose with vitamin supplementation were 1.91 x 10(9)/L and 1.34 x 10(9)/L for Japanese and Western patients, respectively. Increased albumin, decreased cystathionine, and decreased body surface area were also associated with increased neutropenic response. The neutropenic response to higher pemetrexed doses administered with vitamin supplementation is tolerable. All other factors equal, Japanese patients have a lesser neutropenic response to pemetrexed relative to Western patients.

The safety and efficacy of day 1 versus day 2 administration of pegfilgrastim in patients receiving myelosuppressive chemotherapy for gynecologic malignancies

Objective Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with gynecologic malignancies who are receiving myelosuppressive chemotherapy. We sought to compare the safety and efficacy of day 1 pegfilgrastim administration to day 2 administration in patients with gynecologic malignancies. Methods We retrospectively evaluated patients receiving both chemotherapy and pegfilgrastim from June 1, 2006 to August 31, 2007 for a gynecologic malignancy. Abstracted data included patient demographics, pathology, blood counts, toxicity, and chemotherapy. After administration of chemotherapy, all patients either received 6 mg of pegfilgrastim subcutaneously on day 1 or day 2. Results 1226 administrations of pegfilgrastim in 230 patients were identified. 490 administrations of pegfilgrastim were given on day 1 compared to 736 on day 2. 70% of patients had ovarian cancer with a median age of 64 years (range 15–88). 79% of patients had stage III, IV, or recurrent disease and 67% were undergoing primary chemotherapy. The most common chemotherapy was docetaxel/carboplatin (53%) followed by paclitaxel/carboplatin (19%). The mean absolute neutrophil count (ANC) nadir was 4810/mm 3 in the day 1 cohort compared to 4212/mm 3 in the day 2 cohort ( p = .004). The incidence of Grade 3/4 neutropenia was similar in both groups (4.9% in day 1 vs. 5.7% in day 2; p = .63). Grade 3/4 febrile neutropenia was uncommon in both cohorts (0 episodes vs. 3 episodes; p = .41). Treatment delays were similar in both cohorts (5.9% vs. 7.5%; p = .35). Dose modifications were also similar in both cohorts (2.8% vs. 5.3%; p = .06). Conclusion Day 1 administration of pegfilgrastim is as effective as day 2 administration in the prevention of neutropenia in patients with gynecologic malignancies. Treatment delays and dose modifications were not increased after day 1 administration of pegfilgrastim. Administering pegfilgrastim on day 1 appears to be safe, effective, and convenient in selected patients receiving myelopsuppressive chemotherapy for gynecologic malignancies.

Utility of Pretreatment Bilirubin Level and UGT1A1 Polymorphisms in Multivariate Predictive Models of Neutropenia Associated with Irinotecan Treatment in Previously Untreated Patients with Colorectal Cancer.

PurposeStatistical models for predicting hematologic toxicity were evaluated based on UGT1A1 polymorphisms and baseline serum bilirubin.MethodsBlood DNA samples were collected from 113 patients with untreated metastatic colorectal cancer receiving irinotecan (FOLFIRI, n = 36; mIFL, n = 41; CapeIRI, n = 36). The primary endpoint was absolute neutrophil count nadir during first treatment cycle. Linear regression models, with increased R2 implying important additional predictive power, sequentially added age, sex, baseline bilirubin level, and UGT1A1 genotype.ResultsAll models demonstrated low R2, suggesting unaccounted variables. UGT1A1 genotype added ∼8–9% during cycle 1 and from ∼7% [mIFL regimen] to 26% [CapeIRI regimen] after cycle 1. Correlation between genotype and overall ANC nadir without regard to treatment was low (R = −0.201, P = 0.035). Patients with genotype 7/7 may have increased risk for severe neutropenia, but data are insufficient to characterize this. Contribution of baseline bilirubin level was negligible.ConclusionsAbility of UGT1A1 or baseline bilirubin to predict neutropenia is low and depends on regimen.

Long-Term Outcome of AIDS-Related Lymphoma Treated with Abbreviated Cycles of EPOCH-RR: A Prospective Study of 40 Patients

We hypothesized that the addition of rituximab to EPOCH chemotherapy could improve tumor kill, allowing delivery of fewer cycles of treatment and therefore reducing toxicity. Patients received EPOCH-RR (in mg/m2/d – etoposide 50, vincristine 0.4 and doxorubicin 10 all CIV d 1–5; cyclophosphamide 750 mg IV d 5; prednisone 60 po days 1–5 and rituximab 375 IV d 1,5 and G-CSF sc d 6–15) every 21 days. Prophylactic IT methotrexate was administered and HAART was suspended during therapy. Cyclophosphamide was adjusted based on absolute neutrophil count (ANC) nadir. Response was assessed by CT and FDG-PET scan and patients received 1 cycle beyond CR for a minimum of 3 cycles. Characteristics of 40 enrolled patients are: median (range) age 42 (9–60) years; IPI 3 (0–4); ECOG PS 1 (1–4), CD4 count 222 (0–835) cells/mm3; HIV viral load 34,766 (0–6,080000) RNA copies/mL; male sex 35 (88%); LDH > N 27 (68%); stage IV 27 (68%) and histology diffuse large B-cell lymphoma (DLBCL) 32 (80%) and Burkitt lymphoma (BL) 8 (20%). Of 38 evaluable patients (2NE), median (range) number of cycles given is 3 (3–5) with CR/CRu in 35 (92%) and PR in 1 (3%) patients. At 4 years median follow-up, PFS and OS are 86% and 70%, respectively. Eight patients with BL are in continuous CR. For patients with CD4 > and < 100 cells/mm3, PFS is 96% and 69%, respectively. IPI did not impact OS and PFS. Early PET scanning (after cycle 2) had a high negative predictive value (100%) but low positive predictive value (20%). Fever/neutropenia occurred on 30%, ANC < 500/mm3 on 40%, and platelets < 50,000/mm3 on 23% of cycles. EPOCH-RR was associated with less CD4 loss - median 128 cells/mm3 (range +154 to −639) compared to historical data with EPOCH alone (median 189 cells/mm3 (range +19 to −973). Patients with CD4 < 100/mm3 had good tumor control, but OS was only 31% due to late deaths from advanced AIDS. Patients with CD4 counts > 100/mm3 had an extremely good PFS and OS. The addition of rituximab did not appear to cause serious infection related complications or deaths. However, one treatment-related death occurred from complications of mycobacterium avium intercellulare. Abbreviated EPOCH-RR is highly effective and tolerable in ARL and enables the administration of fewer treatment cycles (median 3 versus 6). PET scanning has a very high negative but low positive predictive value for subsequent relapse, possibly due to HIV associated PET changes. Accrual continues.

CYP3A phenotype-based individualized dosing of irinotecan to reduce interindividual variability in pharmacokinetics and toxicity: Results from a randomized trial

2506 Background: Irinotecan, a prodrug of SN-38, is mainly metabolized by CYP3A. Based on the known relationship between midazolam clearance, a measure of CYP3A activity, and irinotecan disposition (Mathijssen et al, JNCI 2004), a randomized trial was performed comparing the pharmacokinetics and toxicity of irinotecan following conventional BSA-based dosing and dosing based on a formula derived from midazolam clearance, γGT, and height. Methods: Forty patients were randomized 1:1 to receive irinotecan at a dose of 350 mg/m2 (arm A) or at a dose based on the formula (arm B). UGT1A1*28 status, blood samples for pharmacokinetics, and toxicities were obtained during the first course. Pharmacokinetic parameters were calculated using WinNonLin. Results: Patient characteristics (22 males/18 females; median age, 58 years) were balanced between both arms, including the UGT1A1*28 status (p = 0.87). Doses ranged from 480–780 mg (mean 645) in arm A and 380–1,060 mg (mean 698) in arm B. The mean area under the curve (AUC) of irinotecan (22.4 vs 21.1 μg×h/mL) and SN-38 (0.57 vs 0.51 μg×h/mL) did not differ significantly between both arms (p> 0.44). Although the variability in dose was higher in arm B (10 vs 26%), the interindividual variability in AUC was reduced by 19% for irinotecan (31 vs 25%) and 26% for SN-38 (46 vs 34%). In addition, a lower interindividual variability in the nadir of the absolute neutrophil count (ANC) was found (80 vs 55%). Compared to arm A, the incidence of grade 3–4 neutropenia decreased by 75% (42 vs 11%; p= 0.03), which was unrelated to UGT1A1*28 genotype status (p > 0.79). Similarly, the incidence of grade 4 neutropenia was reduced (26 vs 5%). The incidence of grade 3–4 diarrhea was equal in both arms (11%). Conclusions: Individualization of irinotecan dosage based on CYP3A phenotyping results in a substantially reduced interindividual pharmacokinetic variability for irinotecan and SN-38. The variability in nadir ANC and the incidence of severe neutropenia decline as well. In combination with UGT1A1*28 genotyping approaches to predict the extent of SN-38 inactivation, CYP3A phenotype-determination should be explored further as a strategy to identify patients that are at risk for experiencing severe side effects. No significant financial relationships to disclose.

Hematologic toxicity and dose intensity in older patients with colorectal cancer receiving systemic chemotherapy

4052 Background: While the risk of colorectal cancer (CRC) as well as comorbidities increase with age, systemic chemotherapy has become a mainstay of treatment across age groups. Trends in chemotherapy dosing, toxicity, and supportive care for patients with CRC from a nationwide study were examined. Methods: Patients with CRC (N=521), including 255 ≥ 65 years of age, were prospectively registered at 115 US community oncology practices. Primary outcomes included anemia (hemoglobin <10g/dL), thrombocytopenia (platelets <75x109/L), febrile neutropenia (FN; fever/infection and absolute neutrophil count (ANC) nadir <1x109/L) or severe neutropenia (SN; ANC <5x109/L), and both planned and actual relative dose intensity (RDI) compared to standard regimens. Differences among patients age 18–64 (50.5%) and age ≥ 65 (49.5%) were compared. Results: No significant differences in disease stage or type of chemotherapy regimen were reported between older and younger patients. Older patients in this study, however, were more likely to have comorbid conditions (p=0.048) and significantly poorer ECOG performance status (p=0.0004) than younger patients. CRC patients ≥ 65 years of age compared with patients <65 experienced significantly higher rates of neutropenic complications: 12.1% vs. 5.9% (p=0.015), anemia: 22.9% vs. 14.9% (p=0.023), and thrombocytopenia: 6.3% vs. 1.6% (p=0.007), respectively. Actual RDI <85% over four cycles was observed in 42.2% of patients with half of reductions in RDI planned from the start of chemotherapy. Although older patients with CRC were less likely to have body surface area >2 m2 than younger patients (p=0.002), no difference in average actual or planned RDI or colony-stimulating factor (CSF) use between older and younger patients was observed. Prophylactic CSF was administered in <10% in both older and younger patients. Conclusions: Older patients with CRC experienced higher rates of chemotherapy-related hematologic toxicity compared with younger patients. While CSFs have been shown to reduce the risk of SN in CRC, this study demonstrates that most patients with nonmetastatic disease do not receive CSF prophylaxis but rather undergo substantial reductions in chemotherapy dose intensity potentially compromising curative treatment. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen Amgen

Dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (SNP) in Thai patients treated with 5-FU based regimens

14537 Background: DPD deficiency is a genetic disease caused by molecular defects in the DPD gene (DPYD). Cancer patients with DPD deficiency developed severe toxicity after receiving 5-FU based chemotherapy. The objective of this study is to determine the extent of DPYD gene polymorphisms of Thai cancer patients who received 5-FU based chemotherapy regimens. Methods: We conducted a molecular analysis to determine the polymorphisms of DPYD gene in 116 Thai cancer patients. 76 patients developed severe (grade 3–4) toxicities after receiving the first or second cycle of 5-FU based chemotherapy. The other subject group consisted of 40 patients without severe toxicity. The clinical characteristics (sex, age, diagnosis, regimen and dosage) of both groups were recorded. We isolated genomic DNA from buffy coat of their peripheral blood samples then performed PCR. The DNA sequencing of every amplicon was done to identify 11 mutations as reported in Asian population. The actual change of absolute neutrophil count (ANC), hematocrit, platelet and percentage of neutrophil were compared in each SNP using Mann Whitney U test. Results: We detected 13 SNPs which 6 SNPs were found in exons; 967G>A, 1011A>T, 1236G>A, 1774C>T, 1896T>C and 1627A>G. The other 7 SNPs were found in introns but only IVS14+1G>A is the intron splice site. There have never been report in 10 SNPs; 967G>A, 1011A>T, 1236G>A, 1774C>T, IVS8–118A>G, IVS8–17A>C, IVS11–15T>C, IVS14–68T>G, IVS14+19C>A and IVS14+134G>T. We found homozygous GG of 1627A>G in 4 patients who had severe toxicities. Statistic significant in actual ANC change and percentage of neutrophil change in homozygous GG (p=.011 and .009) were found. The median nadir ANC of homozygous GG is 399.6 cells/mm3. This SNP cause the amino acid change from isoleucine to valine. Novel heterozygous SNPs (967G>A, 1774C>T) that cause the amino acid change were found in two patients with severe toxicities. Conclusions: 1627A>G, 967G>A, 1774C>T and IVS14+G>A may be the cause of DPD deficiency in Thai patients. The further study needs to establish the functional DPD protein in this population. Ten novel SNPs were discovered in our study. No significant financial relationships to disclose.

Association Between Bone Marrow Dosimetric Parameters and Acute Hematologic Toxicity in Anal Cancer Patients Treated With Concurrent Chemotherapy and Intensity-Modulated Radiotherapy

To test the hypothesis that the volume of pelvic bone marrow (PBM) receiving 10 and 20 Gy or more (PBM-V(10) and PBM-V(20)) is associated with acute hematologic toxicity (HT) in anal cancer patients treated with concurrent chemoradiotherapy. We analyzed 48 consecutive anal cancer patients treated with concurrent chemotherapy and intensity-modulated radiation therapy. The median radiation dose to gross tumor and regional lymph nodes was 50.4 and 45 Gy, respectively. Pelvic bone marrow was defined as the region extending from the iliac crests to the ischial tuberosities, including the os coxae, lumbosacral spine, and proximal femora. Endpoints included the white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin, and platelet count nadirs. Regression models with multiple independent predictors were used to test associations between dosimetric parameters and HT. Twenty patients (42%) had Stage T3-4 disease; 15 patients (31%) were node positive. Overall, 27 (56%), 24 (50%), 4 (8%), and 13 (27%) experienced acute Grade 3-4 leukopenia, neutropenia, anemia, and thrombocytopenia, respectively. On multiple regression analysis, increased PBM-V(5), V(10), V(15), and V(20) were significantly associated with decreased WBC and ANC nadirs, as were female gender, decreased body mass index, and increased lumbosacral bone marrow V(10), V(15), and V(20) (p < 0.05 for each association). Lymph node positivity was significantly associated with a decreased WBC nadir on multiple regression analysis (p < 0.05). This analysis supports the hypothesis that increased low-dose radiation to PBM is associated with acute HT during chemoradiotherapy for anal cancer. Techniques to limit bone marrow irradiation may reduce HT in anal cancer patients.